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Pancreatic Neoplasms: HELP
Articles by Charles Stewart Fuchs
Based on 62 articles published since 2009
(Why 62 articles?)
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Between 2009 and 2019, C. Fuchs wrote the following 62 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. 2015

Genkinger, J M / Kitahara, C M / Bernstein, L / Berrington de Gonzalez, A / Brotzman, M / Elena, J W / Giles, G G / Hartge, P / Singh, P N / Stolzenberg-Solomon, R Z / Weiderpass, E / Adami, H-O / Anderson, K E / Beane-Freeman, L E / Buring, J E / Fraser, G E / Fuchs, C S / Gapstur, S M / Gaziano, J M / Helzlsouer, K J / Lacey, J V / Linet, M S / Liu, J J / Park, Y / Peters, U / Purdue, M P / Robien, K / Schairer, C / Sesso, H D / Visvanathan, K / White, E / Wolk, A / Wolpin, B M / Zeleniuch-Jacquotte, A / Jacobs, E J. ·Department of Epidemiology, Mailman School of Public Health, Columbia University, New York Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York jg3081@columbia.edu. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda. · Division of Cancer Etiology, City of Hope National Medical Center, Duarte. · Westat, Rockville. · Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, DHHS, Bethesda, USA. · Cancer Epidemiology Centre, Cancer Council of Victoria, and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. · Department of Epidemiology, Biostatistics and Population Medicine and The Center for Health Research, Loma Linda University School of Medicine, Loma Linda, USA. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø Department of Research, Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Department of Epidemiology, Harvard School of Public Health, Boston. · Division of Epidemiology and Community Health, School of Public Health, and Masonic Cancer Center, University of Minnesota, Minneapolis. · Department of Epidemiology, Harvard School of Public Health, Boston Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston. · Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston Department of Medical Oncology, Dana-Farber Cancer Institute, Boston. · Epidemiology Research Program, American Cancer Society, Atlanta. · Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston Massachusetts Veterans Epidemiology Research and Information Center, Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Boston. · The Prevention & Research Center, Mercy Medical Center, Baltimore Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda Division of Public Health Sciences, Washington University School of Medicine, St Louis. · Fred Hutchinson Cancer Research Center, Seattle Department of Epidemiology, University of Washington, Seattle. · Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington. · Department of Epidemiology, Harvard School of Public Health, Boston Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore Department of Medical Oncology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, Baltimore, USA. · Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. · Department of Population Health and Perlmutter Cancer Center, New York University, New York, USA. ·Ann Oncol · Pubmed #26347100.

ABSTRACT: BACKGROUND: Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. DESIGN: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. RESULTS: Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)). CONCLUSIONS: Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.

2 Review Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies. 2014

Genkinger, J M / Wang, M / Li, R / Albanes, D / Anderson, K E / Bernstein, L / van den Brandt, P A / English, D R / Freudenheim, J L / Fuchs, C S / Gapstur, S M / Giles, G G / Goldbohm, R A / Håkansson, N / Horn-Ross, P L / Koushik, A / Marshall, J R / McCullough, M L / Miller, A B / Robien, K / Rohan, T E / Schairer, C / Silverman, D T / Stolzenberg-Solomon, R Z / Virtamo, J / Willett, W C / Wolk, A / Ziegler, R G / Smith-Warner, S A. ·Department of Epidemiology, Mailman School of Public Health, Columbia University, New York jg3081@columbia.edu. · Department of Epidemiology, Harvard School of Public Health, Boston Department of Biostatistics, Harvard School of Public Health, Boston. · Department of Epidemiology, Harvard School of Public Health, Boston. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda. · Division of Epidemiology and Community Health, School of Public Health, Masonic Cancer Center, University of Minnesota, Minneapolis. · Division of Cancer Etiology, Department of Population Science, Beckman Research Institute and City of Hope National Medical Center, Duarte, USA. · Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands. · Cancer Epidemiology Centre, Cancer Council of Victoria, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. · Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo. · Division of Medical Oncology, Dana-Farber Cancer Institute, Boston Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston. · Epidemiology Research Program, American Cancer Society, Atlanta, USA. · Department of Prevention and Health, TNO Quality of Life, Leiden, The Netherlands. · Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. · Cancer Prevention Institute of California, Fremont, USA. · Department of Social and Preventive Medicine, University of Montreal, Montreal. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. · Department of Epidemiology and Biostatistics, School of Public Health and Health Services, George Washington University, Washington, DC. · Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, USA. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · Department of Epidemiology, Harvard School of Public Health, Boston Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston Department of Nutrition, Harvard School of Public Health, Boston, USA. · Department of Epidemiology, Harvard School of Public Health, Boston Department of Nutrition, Harvard School of Public Health, Boston, USA. ·Ann Oncol · Pubmed #24631943.

ABSTRACT: Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing ≥500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice-cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77-1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk.

3 Review Folate intake and risk of pancreatic cancer: pooled analysis of prospective cohort studies. 2011

Bao, Ying / Michaud, Dominique S / Spiegelman, Donna / Albanes, Demetrius / Anderson, Kristin E / Bernstein, Leslie / van den Brandt, Piet A / English, Dallas R / Freudenheim, Jo L / Fuchs, Charles S / Giles, Graham G / Giovannucci, Edward / Goldbohm, R Alexandra / Håkansson, Niclas / Horn-Ross, Pamela L / Jacobs, Eric J / Kitahara, Cari M / Marshall, James R / Miller, Anthony B / Robien, Kim / Rohan, Thomas E / Schatzkin, Arthur / Stevens, Victoria L / Stolzenberg-Solomon, Rachael Z / Virtamo, Jarmo / Wolk, Alicja / Ziegler, Regina G / Smith-Warner, Stephanie A. ·Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. ·J Natl Cancer Inst · Pubmed #22034634.

ABSTRACT: BACKGROUND: Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies. METHODS: We analyzed primary data from 14 prospective cohort studies that included 319,716 men and 542,948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided. RESULTS: During 7-20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, P(trend) = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, P(trend) = .90). No between-study heterogeneity was observed (for dietary folate, P(heterogeneity) = .15; for total folate, P(heterogeneity) = .22). CONCLUSION: Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis.

4 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

5 Clinical Trial Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. 2014

Wolpin, Brian M / Rubinson, Douglas A / Wang, Xiaoxu / Chan, Jennifer A / Cleary, James M / Enzinger, Peter C / Fuchs, Charles S / McCleary, Nadine J / Meyerhardt, Jeffrey A / Ng, Kimmie / Schrag, Deborah / Sikora, Allison L / Spicer, Beverly A / Killion, Leah / Mamon, Harvey / Kimmelman, Alec C. ·Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA akimmelman@partners.org bwolpin@partners.org. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA. ·Oncologist · Pubmed #24821822.

ABSTRACT: BACKGROUND: Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. METHODS: Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. The primary endpoint was 2-month progression-free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients. RESULTS: Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment-related grade 3/4 adverse events were lymphopenia (n = 1) and elevated alanine aminotransferase (n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3-II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3-II in patient lymphocytes demonstrated inconsistent autophagy inhibition. CONCLUSION: Mouse studies identified LC3-II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy.

6 Clinical Trial Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. 2013

McCaffery, Ian / Tudor, Yanyan / Deng, Hongjie / Tang, Rui / Suzuki, Samuel / Badola, Sunita / Kindler, Hedy L / Fuchs, Charles S / Loh, Elwyn / Patterson, Scott D / Chen, Li / Gansert, Jennifer L. ·Genentech, One DNA Way, South San Francisco, CA 94080, USA. mccaffery.ian@gene.com ·Clin Cancer Res · Pubmed #23741071.

ABSTRACT: PURPOSE: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. RESULTS: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. CONCLUSIONS: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.

7 Clinical Trial A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. 2013

Strosberg, J R / Chan, J A / Ryan, D P / Meyerhardt, J A / Fuchs, C S / Abrams, T / Regan, E / Brady, R / Weber, J / Campos, T / Kvols, L K / Kulke, M H. ·Department of GI Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA. jonathan.strosberg@moffitt.org ·Endocr Relat Cancer · Pubmed #23572164.

ABSTRACT: The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.

8 Clinical Trial A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. 2012

Kindler, H L / Richards, D A / Garbo, L E / Garon, E B / Stephenson, J J / Rocha-Lima, C M / Safran, H / Chan, D / Kocs, D M / Galimi, F / McGreivy, J / Bray, S L / Hei, Y / Feigal, E G / Loh, E / Fuchs, C S. ·Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Ann Oncol · Pubmed #22700995.

ABSTRACT: BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.

9 Clinical Trial A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma : cancer and Leukemia Group B (CALGB) 80003. 2011

Mamon, Harvey J / Niedzwiecki, Donna / Hollis, Donna / Tan, Benjamin R / Mayer, Robert J / Tepper, Joel E / Goldberg, Richard M / Blackstock, A William / Fuchs, Charles S / Anonymous7500697. ·Dana Farber Cancer Institute, Boston, Massachusetts; Brigham and Women's Hospital, Boston, MA 02115, USA. hmamon@lroc.harvard.edu ·Cancer · Pubmed #21656739.

ABSTRACT: BACKGROUND: The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. METHODS: Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m(2) 5 days/week) and weekly gemcitabine (200 mg/m(2) ). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m(2) for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. RESULTS: Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. CONCLUSIONS: The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation.

10 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.

11 Article iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer. 2018

Lo, Justin H / Hao, Liangliang / Muzumdar, Mandar D / Raghavan, Srivatsan / Kwon, Ester J / Pulver, Emilia M / Hsu, Felicia / Aguirre, Andrew J / Wolpin, Brian M / Fuchs, Charles S / Hahn, William C / Jacks, Tyler / Bhatia, Sangeeta N. ·Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts. · Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Yale Cancer Center, New Haven, Connecticut. · Howard Hughes Medical Institute, Cambridge, Massachusetts. · Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts. sbhatia@mit.edu. · Marble Center for Cancer Nanomedicine, Massachusetts Institute of Technology, Cambridge, Massachusetts. ·Mol Cancer Ther · Pubmed #30097486.

ABSTRACT: Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with α

12 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.

13 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

14 Article Statin use and pancreatic cancer risk in two prospective cohort studies. 2018

Hamada, Tsuyoshi / Khalaf, Natalia / Yuan, Chen / Babic, Ana / Morales-Oyarvide, Vicente / Qian, Zhi Rong / Nowak, Jonathan Andrew / Ng, Kimmie / Kraft, Peter / Rubinson, Douglas Adam / Stampfer, Meir Jonathan / Giovannucci, Edward Luciano / Fuchs, Charles Stewart / Ogino, Shuji / Wolpin, Brian Matthew. ·Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. · Program in MPE Molecular Pathological Epidemiology, Department of Patholog, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. · Yale Cancer Center, New Haven, CT, USA. · Department of Medicine, Yale School of Medicine, New Haven, CT, USA. · Smilow Cancer Hospital, New Haven, CT, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA. bwolpin@partners.org. ·J Gastroenterol · Pubmed #29362938.

ABSTRACT: BACKGROUND: Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are common lipid-lowering agents and may reduce the risk of several cancer types including pancreatic cancer. However, the association between statin use and pancreatic cancer risk has not been fully evaluated in prospective studies. METHODS: We studied the association between statin use and incident pancreatic cancer in 113,059 participants from the prospective Nurses' Health Study and Health Professionals Follow-up Study. Statin use was self-reported via study questionnaires and updated biennially. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of pancreatic cancer were estimated using multivariable Cox proportional hazards models with adjustment for potential confounders. RESULTS: In total, 583 participants developed incident pancreatic cancer during 1.4 million person-years of follow-up. No difference was identified in pancreatic cancer risk for regular versus non-regular statin users (multivariable-adjusted HR 0.98; 95% CI 0.82-1.16). There was no significant heterogeneity in the association of statin use with pancreatic cancer risk between the cohorts. Similarly, longer duration of regular statin use was not associated with decreased risk of pancreatic cancer (P CONCLUSIONS: Regular statin use was not associated with pancreatic cancer risk in two large prospective cohort studies in the U.S.

15 Article Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies. 2018

Khalaf, Natalia / Yuan, Chen / Hamada, Tsuyoshi / Cao, Yin / Babic, Ana / Morales-Oyarvide, Vicente / Kraft, Peter / Ng, Kimmie / Giovannucci, Edward / Ogino, Shuji / Stampfer, Meir / Cochrane, Barbara B / Manson, JoAnn E / Clish, Clary B / Chan, Andrew T / Fuchs, Charles S / Wolpin, Brian M. ·Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Program of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · School of Nursing, University of Washington, Seattle, Washington. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. · Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Yale Cancer Center at Yale School of Medicine and Smilow Cancer Hospital, New Haven, Connecticut. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Electronic address: bwolpin@partners.org. ·Gastroenterology · Pubmed #29229401.

ABSTRACT: BACKGROUND & AIMS: Use of aspirin and/or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer. METHODS: We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from the Health Professionals Follow-up Study and Nurses' Health Study using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin, in 396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls). RESULTS: In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were not associated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; P CONCLUSIONS: Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies.

16 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.

17 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.

18 Article Patterns of Chemotherapy Use in a U.S.-Based Cohort of Patients with Metastatic Pancreatic Cancer. 2017

Abrams, Thomas A / Meyer, Gary / Meyerhardt, Jeffrey A / Wolpin, Brian M / Schrag, Deborah / Fuchs, Charles S. ·Dana-Farber Cancer Institute, Boston, Massachusetts, USA thomas_abrams@dfci.harvard.edu. · IntrinsiQ Specialty Solutions, a part of AmerisouceBergen, Frisco, Texas, USA. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Yale Cancer Center, New Haven, Connecticut, USA. ·Oncologist · Pubmed #28476943.

ABSTRACT: PURPOSE: Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices. PATIENTS AND METHODS: We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices. RESULTS: Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all CONCLUSION: This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics. IMPLICATIONS FOR PRACTICE: This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.

19 Article Cigarette Smoking and Pancreatic Cancer Survival. 2017

Yuan, Chen / Morales-Oyarvide, Vicente / Babic, Ana / Clish, Clary B / Kraft, Peter / Bao, Ying / Qian, Zhi Rong / Rubinson, Douglas A / Ng, Kimmie / Giovannucci, Edward L / Ogino, Shuji / Stampfer, Meir J / Gaziano, John Michael / Sesso, Howard D / Cochrane, Barbara B / Manson, JoAnn E / Fuchs, Charles S / Wolpin, Brian M. ·Chen Yuan, Vicente Morales-Oyarvide, Ana Babic, Zhi Rong Qian, Douglas A. Rubinson, Kimmie Ng, Shuji Ogino, Charles S. Fuchs, and Brian M. Wolpin, Dana-Farber Cancer Institute and Harvard Medical School · Chen Yuan, Peter Kraft, Edward L. Giovannucci, Shuji Ogino, Meir J. Stampfer, Howard D. Sesso, and JoAnn E. Manson, Harvard School of Public Health · Ying Bao, Edward L. Giovannucci, Shuji Ogino, Meir J. Stampfer, John Michael Gaziano, Howard D. Sesso, JoAnn E. Manson, and Charles S. Fuchs, Brigham and Women's Hospital and Harvard Medical School · John Michael Gaziano, Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston · Clary B. Clish, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA · and Barbara B. Cochrane, University of Washington School of Nursing, Seattle, WA. ·J Clin Oncol · Pubmed #28358654.

ABSTRACT: Purpose Cigarette smoking is associated with increased incidence of pancreatic cancer. However, few studies have prospectively evaluated the association of smoking with patient survival. Patients and Methods We analyzed survival by smoking status among 1,037 patients from two large US prospective cohort studies diagnosed from 1986 to 2013. Among 485 patients from four prospective US cohorts, we also evaluated survival by prediagnostic circulating levels of cotinine, a metabolite of nicotine that is proportional to tobacco smoke exposure. On the basis of prediagnosis cotinine levels, we classified patients as nonsmokers (< 3.1 ng/mL), light smokers (3.1-20.9 ng/mL), or heavy smokers (≥ 21.0 ng/mL). We estimated hazard ratios (HRs) for death by using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, body mass index, diabetes status, diagnosis year, and cancer stage. Results The multivariable-adjusted HR for death was 1.37 (95% CI, 1.11 to 1.69) comparing current smokers with never smokers ( P = .003). A statistically significant negative trend in survival was observed for increasing pack-years of smoking ( P

20 Article Leucocyte telomere length, genetic variants at the 2017

Bao, Ying / Prescott, Jennifer / Yuan, Chen / Zhang, Mingfeng / Kraft, Peter / Babic, Ana / Morales-Oyarvide, Vicente / Qian, Zhi Rong / Buring, Julie E / Cochrane, Barbara B / Gaziano, J Michael / Giovannucci, Edward L / Manson, JoAnn E / Ng, Kimmie / Ogino, Shuji / Rohan, Thomas E / Sesso, Howard D / Stampfer, Meir J / Fuchs, Charles S / De Vivo, Immaculata / Amundadottir, Laufey T / Wolpin, Brian M. ·Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts, USA. · University of Washington School of Nursing, Seattle, Washington, USA. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System. · Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. · Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA. ·Gut · Pubmed #27797938.

ABSTRACT: OBJECTIVE: Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase ( DESIGN: We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the RESULTS: Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; p CONCLUSIONS: Prediagnostic leucocyte telomere length and genetic variants at the

21 Article Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms. 2016

Babic, Ana / Bao, Ying / Qian, Zhi Rong / Yuan, Chen / Giovannucci, Edward L / Aschard, Hugues / Kraft, Peter / Amundadottir, Laufey T / Stolzenberg-Solomon, Rachael / Morales-Oyarvide, Vicente / Ng, Kimmie / Stampfer, Meir J / Ogino, Shuji / Buring, Julie E / Sesso, Howard D / Gaziano, John Michael / Rifai, Nader / Pollak, Michael N / Anderson, Matthew L / Cochrane, Barbara B / Luo, Juhua / Manson, JoAnn E / Fuchs, Charles S / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland. · Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts. · Department of Laboratory Medicine, Children's Hospital Boston, Boston, Massachusetts. · Cancer Prevention Research Unit, Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. · Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. · University of Washington School of Nursing, Seattle, Washington. · Department of Community Medicine, West Virginia University, Morgantown, West Virginia. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. bwolpin@partners.org. ·Cancer Res · Pubmed #27780823.

ABSTRACT: Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27-7.16; P

22 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.

23 Article Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival. 2016

Yuan, Chen / Qian, Zhi Rong / Babic, Ana / Morales-Oyarvide, Vicente / Rubinson, Douglas A / Kraft, Peter / Ng, Kimmie / Bao, Ying / Giovannucci, Edward L / Ogino, Shuji / Stampfer, Meir J / Gaziano, John Michael / Sesso, Howard D / Buring, Julie E / Cochrane, Barbara B / Chlebowski, Rowan T / Snetselaar, Linda G / Manson, JoAnn E / Fuchs, Charles S / Wolpin, Brian M. ·Chen Yuan, Zhi Rong Qian, Ana Babic, Vicente Morales-Oyarvide, Douglas A. Rubinson, Kimmie Ng, Shuji Ogino, Charles S. Fuchs, and Brian M. Wolpin, Dana-Farber Cancer Institute and Harvard Medical School · Peter Kraft, Edward L. Giovannucci, Shuji Ogino, Meir J. Stampfer, Howard D. Sesso, Julie E. Buring, and JoAnn E. Manson, Harvard School of Public Health · Ying Bao, Edward L. Giovannucci, Shuji Ogino, Meir J. Stampfer, John Michael Gaziano, Howard D. Sesso, JoAnn E. Manson, and Charles S. Fuchs, Brigham and Women's Hospital and Harvard Medical School · John Michael Gaziano, Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA · Barbara B. Cochrane, University of Washington School of Nursing, Seattle, WA · Rowan T. Chlebowski, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA · and Linda G. Snetselaar, University of Iowa College of Public Health, Iowa City, IA. ·J Clin Oncol · Pubmed #27325858.

ABSTRACT: PURPOSE: Although vitamin D inhibits pancreatic cancer proliferation in laboratory models, the association of plasma 25-hydroxyvitamin D [25(OH)D] with patient survival is largely unexplored. PATIENTS AND METHODS: We analyzed survival among 493 patients from five prospective US cohorts who were diagnosed with pancreatic cancer from 1984 to 2008. We estimated hazard ratios (HRs) for death by plasma level of 25(OH)D (insufficient, < 20 ng/mL; relative insufficiency, 20 to < 30 ng/mL; sufficient ≥ 30 ng/mL) by using Cox proportional hazards regression models adjusted for age, cohort, race and ethnicity, smoking, diagnosis year, stage, and blood collection month. We also evaluated 30 tagging single-nucleotide polymorphisms in the vitamin D receptor gene, requiring P < .002 (0.05 divided by 30 genotyped variants) for statistical significance. RESULTS: Mean prediagnostic plasma level of 25(OH)D was 24.6 ng/mL, and 165 patients (33%) were vitamin D insufficient. Compared with patients with insufficient levels, multivariable-adjusted HRs for death were 0.79 (95% CI, 0.48 to 1.29) for patients with relative insufficiency and 0.66 (95% CI, 0.49 to 0.90) for patients with sufficient levels (P trend = .01). These results were unchanged after further adjustment for body mass index and history of diabetes (P trend = .02). The association was strongest among patients with blood collected within 5 years of diagnosis, with an HR of 0.58 (95% CI, 0.35 to 0.98) comparing patients with sufficient to patients with insufficient 25(OH)D levels. No single-nucleotide polymorphism at the vitamin D receptor gene met our corrected significance threshold of P < .002; rs7299460 was most strongly associated with survival (HR per minor allele, 0.80; 95% CI, 0.68 to 0.95; P = .01). CONCLUSION: We observed longer overall survival in patients with pancreatic cancer who had sufficient prediagnostic plasma levels of 25(OH)D.

24 Article Association of Common Susceptibility Variants of Pancreatic Cancer in Higher-Risk Patients: A PACGENE Study. 2016

Childs, Erica J / Chaffee, Kari G / Gallinger, Steven / Syngal, Sapna / Schwartz, Ann G / Cote, Michele L / Bondy, Melissa L / Hruban, Ralph H / Chanock, Stephen J / Hoover, Robert N / Fuchs, Charles S / Rider, David N / Amundadottir, Laufey T / Stolzenberg-Solomon, Rachael / Wolpin, Brian M / Risch, Harvey A / Goggins, Michael G / Petersen, Gloria M / Klein, Alison P. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. · Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan. · Baylor College of Medicine, Dan L. Duncan Cancer Center, Houston, Texas. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, U.S. Department of Health and Human Services, Bethesda, Maryland. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland. aklein1@jhmi.edu. ·Cancer Epidemiol Biomarkers Prev · Pubmed #27197284.

ABSTRACT: Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13-1.63; P = 9.29 × 10(-4); 7p13, rs17688601: OR = 0.76; 95% CI, 0.63-0.93; P = 6.59 × 10(-3)). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P < 5 × 10(-5)) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185-91. ©2016 AACR.

25 Article Association of Physical Activity by Type and Intensity With Digestive System Cancer Risk. 2016

Keum, NaNa / Bao, Ying / Smith-Warner, Stephanie A / Orav, John / Wu, Kana / Fuchs, Charles S / Giovannucci, Edward L. ·Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts5Department of Medicine, Harvard Medical School, Boston, Massachusetts. · Department of Medicine, Harvard Medical School, Boston, Massachusetts6Department of Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts2Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts5Department of Medicine, Harvard Medical School, Boston, Massachusetts. ·JAMA Oncol · Pubmed #27196375.

ABSTRACT: IMPORTANCE: Accumulating evidence indicates that common carcinogenic pathways may underlie digestive system cancers. Physical activity may influence these pathways. Yet, to our knowledge, no previous study has evaluated the role of physical activity in overall digestive system cancer risk. OBJECTIVE: To examine the association between physical activity and digestive system cancer risk, accounting for amount, type (aerobic vs resistance), and intensity of physical activity. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study followed 43 479 men from the Health Professionals Follow-up Study from 1986 to 2012. At enrollment, the eligible participants were 40 years or older, were free of cancer, and reported physical activity. Follow-up rates exceeded 90% in each 2-year cycle. EXPOSURES: The amount of total physical activity expressed in metabolic equivalent of task (MET)-hours/week. MAIN OUTCOMES AND MEASURES: Incident cancer of the digestive system encompassing the digestive tract (mouth, throat, esophagus, stomach, small intestine, and colorectum) and digestive accessory organs (pancreas, gallbladder, and liver). RESULTS: Over 686 924 person-years, we documented 1370 incident digestive system cancers. Higher levels of physical activity were associated with lower digestive system cancer risk (hazard ratio [HR], 0.74 for ≥63.0 vs ≤8.9 MET-hours/week; 95% CI, 0.59-0.93; P value for trend = .003). The inverse association was more evident with digestive tract cancers (HR, 0.66 for ≥63.0 vs ≤8.9 MET-hours/week; 95% CI, 0.51-0.87) than with digestive accessary organ cancers. Aerobic exercise was particularly beneficial against digestive system cancers, with the optimal benefit observed at approximately 30 MET-hours/week (HR, 0.68; 95% CI, 0.56-0.83; P value for nonlinearity = .02). Moreover, as long as the same level of MET-hour score was achieved from aerobic exercise, the magnitude of risk reduction was similar regardless of intensity of aerobic exercise. CONCLUSIONS AND RELEVANCE: Physical activity, as indicated by MET-hours/week, was inversely associated with the risk of digestive system cancers, particularly digestive tract cancers, in men. The optimal benefit was observed through aerobic exercise of any intensity at the equivalent of energy expenditure of approximately 10 hours/week of walking at average pace. Future studies are warranted to confirm our findings and to translate them into clinical and public health recommendation.

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