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Pancreatic Neoplasms: HELP
Articles by Lauren K. Brais
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, L. Brais wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. 2019

Yurgelun, Matthew B / Chittenden, Anu B / Morales-Oyarvide, Vicente / Rubinson, Douglas A / Dunne, Richard F / Kozak, Margaret M / Qian, Zhi Rong / Welch, Marisa W / Brais, Lauren K / Da Silva, Annacarolina / Bui, Justin L / Yuan, Chen / Li, Tingting / Li, Wanwan / Masuda, Atsuhiro / Gu, Mancang / Bullock, Andrea J / Chang, Daniel T / Clancy, Thomas E / Linehan, David C / Findeis-Hosey, Jennifer J / Doyle, Leona A / Thorner, Aaron R / Ducar, Matthew D / Wollison, Bruce M / Khalaf, Natalia / Perez, Kimberly / Syngal, Sapna / Aguirre, Andrew J / Hahn, William C / Meyerson, Matthew L / Fuchs, Charles S / Ogino, Shuji / Hornick, Jason L / Hezel, Aram F / Koong, Albert C / Nowak, Jonathan A / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu. · Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. · Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. · Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA. · Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. · Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA. · Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA. · Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA. · Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. · Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·Genet Med · Pubmed #29961768.

ABSTRACT: PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

2 Article Characterization of the Neuroendocrine Tumor Immune Microenvironment. 2018

da Silva, Annacarolina / Bowden, Michaela / Zhang, Sui / Masugi, Yohei / Thorner, Aaron R / Herbert, Zachary T / Zhou, Chensheng Willa / Brais, Lauren / Chan, Jennifer A / Hodi, F Stephen / Rodig, Scott / Ogino, Shuji / Kulke, Matthew H. ·Center for Cancer Genome Discovery. · Molecular Biology Core Facilities, and. · Department of Pathology, Brigham and Women's Hospital. ·Pancreas · Pubmed #30153220.

ABSTRACT: OBJECTIVES: The immune environment and the potential for neuroendocrine tumors (NETs) to respond to immune checkpoint inhibitors remain largely unexplored. We assessed immune checkpoint marker expression, lymphocytic infiltrate, and associated mutational profiles in a cohort of small intestine and pancreatic NETs. METHODS: We assessed expression of PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2) in archival tissue from 64 small intestine (SINETs) and 31 pancreatic NETs (pNET). We additionally assessed T-cell infiltrates, categorizing T-cell subsets based on expression of the T-cell markers CD3, CD8, CD45RO (PTPRC), or FOXP3. Finally, we explored associations between immune checkpoint marker expression, lymphocytic infiltrate, and tumor mutational profiles. RESULTS: Expression of PD-1 or PD-L1 in small intestine or pancreatic NET was rare, whereas expression of PD-L2 was common in both NET subtypes. T-cell infiltrates were more abundant in pNET than in SINET. We found no clear associations between immune checkpoint marker expression, immune infiltrates, and specific mutational profile within each tumor type. CONCLUSIONS: Our findings provide an initial assessment of the immune environment of well-differentiated NETs. Further studies to define the immunologic differences between pNET and SINET, as well as the role of PD-L2 in these tumors, are warranted.

3 Article Altered exocrine function can drive adipose wasting in early pancreatic cancer. 2018

Danai, Laura V / Babic, Ana / Rosenthal, Michael H / Dennstedt, Emily A / Muir, Alexander / Lien, Evan C / Mayers, Jared R / Tai, Karen / Lau, Allison N / Jones-Sali, Paul / Prado, Carla M / Petersen, Gloria M / Takahashi, Naoki / Sugimoto, Motokazu / Yeh, Jen Jen / Lopez, Nicole / Bardeesy, Nabeel / Fernandez-Del Castillo, Carlos / Liss, Andrew S / Koong, Albert C / Bui, Justin / Yuan, Chen / Welch, Marisa W / Brais, Lauren K / Kulke, Matthew H / Dennis, Courtney / Clish, Clary B / Wolpin, Brian M / Vander Heiden, Matthew G. ·Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada. · Mayo Clinic, Rochester, MN, USA. · Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · University of California San Diego School of Medicine, La Jolla, CA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. · MD Anderson, Department of Radiation Oncology, Houston, TX, USA. · Stanford Cancer Institute, Stanford, CA, USA. · David Geffen School of Medicine at University of California, Los Angeles, CA, USA. · Section of Hematology/Oncology, Boston University and Boston Medical Center, Boston, MA, USA. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. bwolpin@partners.org. · Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mvh@mit.edu. · Dana-Farber Cancer Institute, Boston, MA, USA. mvh@mit.edu. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. mvh@mit.edu. ·Nature · Pubmed #29925948.

ABSTRACT: Malignancy is accompanied by changes in the metabolism of both cells and the organism

4 Article Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. 2018

Aguirre, Andrew J / Nowak, Jonathan A / Camarda, Nicholas D / Moffitt, Richard A / Ghazani, Arezou A / Hazar-Rethinam, Mehlika / Raghavan, Srivatsan / Kim, Jaegil / Brais, Lauren K / Ragon, Dorisanne / Welch, Marisa W / Reilly, Emma / McCabe, Devin / Marini, Lori / Anderka, Kristin / Helvie, Karla / Oliver, Nelly / Babic, Ana / Da Silva, Annacarolina / Nadres, Brandon / Van Seventer, Emily E / Shahzade, Heather A / St Pierre, Joseph P / Burke, Kelly P / Clancy, Thomas / Cleary, James M / Doyle, Leona A / Jajoo, Kunal / McCleary, Nadine J / Meyerhardt, Jeffrey A / Murphy, Janet E / Ng, Kimmie / Patel, Anuj K / Perez, Kimberly / Rosenthal, Michael H / Rubinson, Douglas A / Ryou, Marvin / Shapiro, Geoffrey I / Sicinska, Ewa / Silverman, Stuart G / Nagy, Rebecca J / Lanman, Richard B / Knoerzer, Deborah / Welsch, Dean J / Yurgelun, Matthew B / Fuchs, Charles S / Garraway, Levi A / Getz, Gad / Hornick, Jason L / Johnson, Bruce E / Kulke, Matthew H / Mayer, Robert J / Miller, Jeffrey W / Shyn, Paul B / Tuveson, David A / Wagle, Nikhil / Yeh, Jen Jen / Hahn, William C / Corcoran, Ryan B / Carter, Scott L / Wolpin, Brian M. ·Dana-Farber Cancer Institute, Boston, Massachusetts. andrew_aguirre@dfci.harvard.edu carter.scott@jimmy.harvard.edu brian_wolpin@dfci.harvard.edu. · Broad Institute of Harvard and MIT, Cambridge, Massachusetts. · Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Biomedical Informatics, Department of Pathology, Stony Brook University, Stony Brook, New York. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medical Affairs, Guardant Health, Inc., Redwood City, California. · BioMed Valley Discoveries, Kansas City, Missouri. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. ·Cancer Discov · Pubmed #29903880.

ABSTRACT: Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame

5 Article Plasma inflammatory cytokines and survival of pancreatic cancer patients. 2018

Babic, A / Schnure, N / Neupane, N P / Zaman, M M / Rifai, N / Welch, M W / Brais, L K / Rubinson, D A / Morales-Oyarvide, V / Yuan, C / Zhang, S / Poole, E M / Wolpin, B M / Kulke, M H / Barbie, D A / Wong, K / Fuchs, C S / Ng, K. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. · Perelman School of Medicine, University of Pennsylvania Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA. · Thomas Jefferson University, 1020 Walnut Street, Philadelphia, PA, 19107, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA. · Yale Cancer Center, Yale School of Medicine, Smilow Cancer Hospital, 333 Cedar Street, New Haven, CT, 06510, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. Kimmie_Ng@dfci.harvard.edu. ·Clin Transl Gastroenterol · Pubmed #29691365.

ABSTRACT: OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend <0.0001 for all four comparisons). Furthermore, patients with higher circulating concentrations of all four cytokines had a median survival of 3.7 months; whereas, those with lower levels had a median survival of 19.2 months (HR = 4.55, 95% CI: 2.87-7.20, P-trend <0.0001). CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted.

6 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

7 Article Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Qian, Zhi Rong / Rubinson, Douglas A / Nowak, Jonathan A / Morales-Oyarvide, Vicente / Dunne, Richard F / Kozak, Margaret M / Welch, Marisa W / Brais, Lauren K / Da Silva, Annacarolina / Li, Tingting / Li, Wanwan / Masuda, Atsuhiro / Yang, Juhong / Shi, Yan / Gu, Mancang / Masugi, Yohei / Bui, Justin / Zellers, Caitlin L / Yuan, Chen / Babic, Ana / Khalaf, Natalia / Aguirre, Andrew / Ng, Kimmie / Miksad, Rebecca A / Bullock, Andrea J / Chang, Daniel T / Tseng, Jennifer F / Clancy, Thomas E / Linehan, David C / Findeis-Hosey, Jennifer J / Doyle, Leona A / Thorner, Aaron R / Ducar, Matthew / Wollison, Bruce / Laing, Angelica / Hahn, William C / Meyerson, Matthew / Fuchs, Charles S / Ogino, Shuji / Hornick, Jason L / Hezel, Aram F / Koong, Albert C / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. · Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California. · Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, University of Rochester Medical Center, Rochester, New York. · Department of Pathology, University of Rochester Medical Center, Rochester, New York. · Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. · Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts. · Division of Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston. ·JAMA Oncol · Pubmed #29098284.

ABSTRACT: Importance: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. Objective: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. Main Outcomes and Measures: The DFS and OS among patients with resected pancreatic adenocarcinoma. Results: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. Conclusions and Relevance: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

8 Article Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival. 2017

Morales-Oyarvide, Vicente / Rubinson, Douglas A / Dunne, Richard F / Kozak, Margaret M / Bui, Justin L / Yuan, Chen / Qian, Zhi Rong / Babic, Ana / Da Silva, Annacarolina / Nowak, Jonathan A / Khalaf, Natalia / Brais, Lauren K / Welch, Marisa W / Zellers, Caitlin L / Ng, Kimmie / Chang, Daniel T / Miksad, Rebecca A / Bullock, Andrea J / Tseng, Jennifer F / Swanson, Richard S / Clancy, Thomas E / Linehan, David C / Findeis-Hosey, Jennifer J / Doyle, Leona A / Hornick, Jason L / Ogino, Shuji / Fuchs, Charles S / Hezel, Aram F / Koong, Albert C / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. · Department of Medicine, Division of Hematology and Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Department of Radiation Oncology, Stanford Cancer Institute, 269 Campus Drive West, Stanford, CA 94305-5152, USA. · Department of Epidemiology, Harvard TH Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. · Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Department of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. · Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. · Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. · Department of Surgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Department of Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1840 Old Spanish Trail, Houston, TX 77054, USA. ·Br J Cancer · Pubmed #28982112.

ABSTRACT: BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all P CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

9 Article Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. 2016

Zhang, Mingfeng / Wang, Zhaoming / Obazee, Ofure / Jia, Jinping / Childs, Erica J / Hoskins, Jason / Figlioli, Gisella / Mocci, Evelina / Collins, Irene / Chung, Charles C / Hautman, Christopher / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Buring, Julie / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goodman, Gary E / Goodman, Phyllis J / Kamineni, Aruna / Kolonel, Laurence N / Kulke, Matthew H / Malats, Núria / Olson, Sara H / Sesso, Howard D / Visvanathan, Kala / White, Emily / Zheng, Wei / Abnet, Christian C / Albanes, Demetrius / Andreotti, Gabriella / Brais, Lauren / Bueno-de-Mesquita, H Bas / Basso, Daniela / Berndt, Sonja I / Boutron-Ruault, Marie-Christine / Bijlsma, Maarten F / Brenner, Hermann / Burdette, Laurie / Campa, Daniele / Caporaso, Neil E / Capurso, Gabriele / Cavestro, Giulia Martina / Cotterchio, Michelle / Costello, Eithne / Elena, Joanne / Boggi, Ugo / Gaziano, J Michael / Gazouli, Maria / Giovannucci, Edward L / Goggins, Michael / Gross, Myron / Haiman, Christopher A / Hassan, Manal / Helzlsouer, Kathy J / Hu, Nan / Hunter, David J / Iskierka-Jazdzewska, Elzbieta / Jenab, Mazda / Kaaks, Rudolf / Key, Timothy J / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Krogh, Vittorio / Kupcinskas, Juozas / Kurtz, Robert C / Landi, Maria T / Landi, Stefano / Le Marchand, Loic / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Neale, Rachel E / Oberg, Ann L / Panico, Salvatore / Patel, Alpa V / Peeters, Petra H M / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Purdue, Mark / Quiros, J Ramón / Riboli, Elio / Rothman, Nathaniel / Scarpa, Aldo / Scelo, Ghislaine / Shu, Xiao-Ou / Silverman, Debra T / Soucek, Pavel / Strobel, Oliver / Sund, Malin / Małecka-Panas, Ewa / Taylor, Philip R / Tavano, Francesca / Travis, Ruth C / Thornquist, Mark / Tjønneland, Anne / Tobias, Geoffrey S / Trichopoulos, Dimitrios / Vashist, Yogesh / Vodicka, Pavel / Wactawski-Wende, Jean / Wentzensen, Nicolas / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Kooperberg, Charles / Risch, Harvey A / Jacobs, Eric J / Li, Donghui / Fuchs, Charles / Hoover, Robert / Hartge, Patricia / Chanock, Stephen J / Petersen, Gloria M / Stolzenberg-Solomon, Rachael S / Wolpin, Brian M / Kraft, Peter / Klein, Alison P / Canzian, Federico / Amundadottir, Laufey T. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. · New York University Cancer Institute, New York, New York, USA,. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Cancer Epidemiology Centre, 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. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Group Health Research Institute, Seattle, Washington, USA,. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · 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, United Kingdom. · Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,. · Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France. · University Paris Sud, UMRS 1018, F-94805, Villejuif, France. · IGR, F-94805, Villejuif, France. · 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), Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Biology, University of Pisa, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA. · Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. · Preventive Medicine, University of Southern California, Los Angeles, California, USA. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. · Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Harvard School of Public Health, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · Department of Hematology, Medical University of Łodz, Łodz, Poland. · International Agency for Research on Cancer (IARC), Lyon, France. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. · School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain. · Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. · National School of Public Health, Athens, Greece. · Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland. · Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy. · Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. · Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. · CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. · Public Health and Participation Directorate, Asturias, Spain. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. · Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. · Hellenic Health Foundation, Athens, Greece. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. · Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA. · New York University Cancer Institute, New York, New York, USA. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #27579533.

ABSTRACT: Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

10 Article Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study. 2016

Du, Yeting / Ter-Minassian, Monica / Brais, Lauren / Brooks, Nichole / Waldron, Amanda / Chan, Jennifer A / Lin, Xihong / Kraft, Peter / Christiani, David C / Kulke, Matthew H. ·Harvard School of Public HealthBoston, Massachusetts, USA. · Harvard School of Public HealthBoston, Massachusetts, USA Dana-Farber Cancer InstituteBoston, Massachusetts, USA. · Dana-Farber Cancer InstituteBoston, Massachusetts, USA. · Harvard School of Public HealthBoston, Massachusetts, USA Massachusetts General HospitalBoston, Massachusetts, USA. · Dana-Farber Cancer InstituteBoston, Massachusetts, USA matthew_kulke@dfci.harvard.edu. ·Endocr Relat Cancer · Pubmed #27492634.

ABSTRACT: The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted.

11 Article Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach. 2016

Nishino, Mizuki / Brais, Lauren K / Brooks, Nichole V / Hatabu, Hiroto / Kulke, Matthew H / Ramaiya, Nikhil H. ·Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA. Electronic address: Mizuki_Nishino@DFCI.HARVARD.EDU. · Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02215, USA. · Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA. ·Eur J Cancer · Pubmed #26760924.

ABSTRACT: PURPOSE: The purpose of this study was to investigate the incidence of drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in patients with neuroendocrine tumours (NET) and characterise radiographic patterns of pneumonitis. METHODS: Sixty-six patients (39 males, 27 females, age: 22-79 years) with advanced NET treated with mTOR inhibitor, everolimus, were retrospectively studied. Chest computed tomography scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by an independent review of two radiologists. Extent, distributions, and specific findings were evaluated in cases positive for pneumonitis. Radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia. RESULTS: Drug-related pneumonitis was radiographically detected in 14 patients (21%). Time from the initiation of therapy to pneumonitis was within 6 months of therapy in 10 patients (71%), while it ranged from 1.0 to 27.7 months. Pneumonitis was more common in patients who had never smoked (p=0.03). Lower lungs were more extensively involved than upper and middle lungs. Peripheral and lower distributions were most common (n=8), followed by peripheral and multifocal distributions (n=3). Ground glass and reticular opacities were present in all cases, with consolidation in eight cases. The radiographic pattern of pneumonitis was classified as cryptogenic organising pneumonia (COP) pattern in eight patients, non-specific interstitial pneumonia (NSIP) pattern in five, and hypersensitivity pneumonitis pattern in one patient. CONCLUSION: Drug-related pneumonitis was noted in 21% of the advanced NET patients treated with everolimus. Radiographic pattern of pneumonitis was most commonly COP pattern, followed by NSIP pattern.

12 Article Survival among patients with pancreatic cancer and long-standing or recent-onset diabetes mellitus. 2015

Yuan, Chen / Rubinson, Douglas A / Qian, Zhi Rong / Wu, Chen / Kraft, Peter / Bao, Ying / Ogino, Shuji / Ng, Kimmie / Clancy, Thomas E / Swanson, Richard S / Gorman, Megan J / Brais, Lauren K / Li, Tingting / Stampfer, Meir J / Hu, Frank B / Giovannucci, Edward L / Kulke, Matthew H / Fuchs, Charles S / Wolpin, Brian M. ·Chen Yuan, Douglas A. Rubinson, Zhi Rong Qian, Shuji Ogino, Kimmie Ng, Megan J. Gorman, Lauren K. Brais, Tingting Li, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Dana-Farber Cancer Institute · Chen Wu, Peter Kraft, Shuji Ogino, Meir J. Stampfer, Frank B. Hu, and Edward L. Giovannucci, Harvard School of Public Health · and Ying Bao, Shuji Ogino, Kimmie Ng, Thomas E. Clancy, Richard S. Swanson, Meir J. Stampfer, Frank B. Hu, Edward L. Giovannucci, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ·J Clin Oncol · Pubmed #25403204.

ABSTRACT: PURPOSE: Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown. PATIENTS AND METHODS: We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage. RESULTS: In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival. CONCLUSION: Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.