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Pancreatic Neoplasms: HELP
Articles by Brian Matthew Wolpin
Based on 81 articles published since 2009
(Why 81 articles?)
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Between 2009 and 2019, B. Wolpin wrote the following 81 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Guideline Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. 2012

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen W / Ben-Josef, Edgar / Benson, Al B / Casper, Ephraim S / Cohen, Steven J / Czito, Brian / Ellenhorn, Joshua D I / Hawkins, William G / Herman, Joseph / Hoffman, John P / Ko, Andrew / Komanduri, Srinadh / Koong, Albert / Ma, Wen Wee / Malafa, Mokenge P / Merchant, Nipun B / Mulvihill, Sean J / Muscarella, Peter / Nakakura, Eric K / Obando, Jorge / Pitman, Martha B / Sasson, Aaron R / Tally, Anitra / Thayer, Sarah P / Whiting, Samuel / Wolff, Robert A / Wolpin, Brian M / Freedman-Cass, Deborah A / Shead, Dorothy A / Anonymous2631481. ·UCSF Helen Diller Family Comprehensive Cancer Center. ·J Natl Compr Canc Netw · Pubmed #22679115.

ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

3 Editorial Metabolic Alterations as a Signpost to Early Pancreatic Cancer. 2019

Khalaf, Natalia / Wolpin, Brian M. ·Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas. Electronic address: Natalia.khalaf@bcm.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Electronic address: bwolpin@partners.org. ·Gastroenterology · Pubmed #30926350.

ABSTRACT: -- No abstract --

4 Editorial Pancreatic Cancer. 2015

Wolpin, Brian M. ·Center for Gastrointestinal Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: bwolpin@partners.org. ·Hematol Oncol Clin North Am · Pubmed #26226911.

ABSTRACT: -- No abstract --

5 Editorial Defining determinants of pancreatic cancer risk: are we making progress? 2009

Wolpin, Brian M / Stampfer, Meir J. · ·J Natl Cancer Inst · Pubmed #19561317.

ABSTRACT: -- No abstract --

6 Review Borderline resectable pancreatic cancer: conceptual evolution and current approach to image-based classification. 2017

Gilbert, J W / Wolpin, B / Clancy, T / Wang, J / Mamon, H / Shinagare, A B / Jagannathan, J / Rosenthal, M. ·Department of Imaging, Dana-Farber Cancer Institute. · Department of Radiology, Brigham and Women's Hospital. · Harvard Medical School. · Department of Medical Oncology, Dana-Farber Cancer Institute. · Division of Surgical Oncology, Department of Surgery, Brigham and Women's Hospital. · Gastrointestinal Surgical Center, Dana-Farber/Brigham and Women's Cancer Center. · Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, USA. ·Ann Oncol · Pubmed #28407088.

ABSTRACT: Background: Diagnostic imaging plays a critical role in the initial diagnosis and therapeutic monitoring of pancreatic adenocarcinoma. Over the past decade, the concept of 'borderline resectable' pancreatic cancer has emerged to describe a distinct subset of patients existing along the spectrum from resectable to locally advanced disease for whom a microscopically margin-positive (R1) resection is considered relatively more likely, primarily due to the relationship of the primary tumor with surrounding vasculature. Materials and methods: This review traces the conceptual evolution of borderline resectability from a radiological perspective, including the debates over the key imaging criteria that define the thresholds between resectable, borderline resectable, and locally advanced or metastatic disease. This review also addresses the data supporting neoadjuvant therapy in this population and discusses current imaging practices before and during treatment. Results: A growing body of evidence suggests that the borderline resectable group of patients may particularly benefit from neoadjuvant therapy to increase the likelihood of an ultimately margin-negative (R0) resection. Unfortunately, anatomic and imaging criteria to define borderline resectability are not yet universally agreed upon, with several classification systems proposed in the literature and considerable variance in institution-by-institution practice. As a result of this lack of consensus, as well as overall small patient numbers and lack of established clinical trials dedicated to borderline resectable patients, accurate evidence-based diagnostic categorization and treatment selection for this subset of patients remains a significant challenge. Conclusions: Clinicians and radiologists alike should be cognizant of evolving imaging criteria for borderline resectability given their profound implications for treatment strategy, follow-up recommendations, and prognosis.

7 Review Nurses' Health Study Contributions on the Epidemiology of Less Common Cancers: Endometrial, Ovarian, Pancreatic, and Hematologic. 2016

Birmann, Brenda M / Barnard, Mollie E / Bertrand, Kimberly A / Bao, Ying / Crous-Bou, Marta / Wolpin, Brian M / De Vivo, Immaculata / Tworoger, Shelley S. ·Brenda M. Birmann, Ying Bao, Marta Crous-Bou, Immaculata De Vivo, and Shelley S. Tworoger are with the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Mollie E. Barnard is with the Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston. Kimberly A. Bertrand is with the Slone Epidemiology Center, Boston University, Boston. Brian M. Wolpin is with the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School. ·Am J Public Health · Pubmed #27459458.

ABSTRACT: OBJECTIVES: To review the contributions of the Nurses' Health Study (NHS) to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. METHODS: We reviewed selected NHS publications from 1976 to 2016, including publications from consortia and other pooled studies. RESULTS: NHS studies on less common cancers have identified novel risk factors, such as a reduced risk of endometrial cancer in women of advanced age at last birth, and have clarified or prospectively confirmed previously reported associations, including an inverse association between tubal ligation and ovarian cancer. Through biomarker research, the NHS has furthered understanding of the pathogenesis of rare cancers, such as the role of altered metabolism in pancreatic cancer risk and survival. NHS investigations have also demonstrated the importance of the timing of exposure, such as the finding of a positive association of early life body fatness, but not of usual adult body mass index, with non-Hodgkin lymphoma risk. CONCLUSIONS: Evidence from the NHS has informed prevention strategies and contributed to improved survival from less common but often lethal malignancies, including endometrial, ovarian, pancreatic, and hematologic cancers.

8 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.

9 Review Therapeutic Approaches for Metastatic Pancreatic Adenocarcinoma. 2015

Rubinson, Douglas A / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA. · Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA; Pancreas and Biliary Tumor Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: bwolpin@partners.org. ·Hematol Oncol Clin North Am · Pubmed #26226909.

ABSTRACT: Since the US Food and Drug Administration's approval of gemcitabine in 1996, numerous randomized trials have investigated treatment programs to further improve the quality of life and survival of patients with advanced pancreatic cancer. After little progress over the ensuing 15 years, 2 combination treatment programs recently conferred improved survival compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer: FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel. Importantly, our understanding of the biology of pancreatic cancer continues to grow. This improved biologic understanding holds great promise for integrating new targeted and immune-modifying therapies into current treatment programs.

10 Clinical Trial Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer. 2016

Liu, J F / Moore, K N / Birrer, M J / Berlin, S / Matulonis, U A / Infante, J R / Wolpin, B / Poon, K A / Firestein, R / Xu, J / Kahn, R / Wang, Y / Wood, K / Darbonne, W C / Lackner, M R / Kelley, S K / Lu, X / Choi, Y J / Maslyar, D / Humke, E W / Burris, H A. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston joyce_liu@dfci.harvard.edu. · Division of Gynecologic Oncology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston. · Department of Oncology, New England Cancer Care Specialists, Kennebunk. · Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville. · Early Development, Genentech, South San Francisco, USA. ·Ann Oncol · Pubmed #27793850.

ABSTRACT: BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

11 Clinical Trial A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers. 2016

Coveler, Andrew L / Ko, Andrew H / Catenacci, Daniel V T / Von Hoff, Daniel / Becerra, Carlos / Whiting, Nancy C / Yang, Jing / Wolpin, Brian. ·Seattle Cancer Care Alliance, University of Washington, 825 Eastlake Ave E, Seattle, WA, 98109, USA. acoveler@u.washington.edu. · Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA. · University of Chicago, Chicago, IL, USA. · TGen Clinical Research Service at Scottsdale Healthcare, Scottsdale, AZ, USA. · Texas Oncology, Baylor Sammons Cancer Center, Dallas, TX, USA. · Seattle Genetics, Inc., Bothell, WA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. ·Invest New Drugs · Pubmed #26994014.

ABSTRACT: Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

12 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.

13 Clinical Trial Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. 2013

Wolpin, B M / O'Reilly, E M / Ko, Y J / Blaszkowsky, L S / Rarick, M / Rocha-Lima, C M / Ritch, P / Chan, E / Spratlin, J / Macarulla, T / McWhirter, E / Pezet, D / Lichinitser, M / Roman, L / Hartford, A / Morrison, K / Jackson, L / Vincent, M / Reyno, L / Hidalgo, M. ·Dana-Farber Cancer Institute, Boston, MA 02215, USA. bwolpin@partners.org ·Ann Oncol · Pubmed #23448807.

ABSTRACT: BACKGROUND: We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. RESULTS: Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. CONCLUSIONS: This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291.

14 Clinical Trial A phase 2 study of oral MKC-1, an inhibitor of importin-β, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer. 2012

Faris, Jason E / Arnott, Jamie / Zheng, Hui / Ryan, David P / Abrams, Thomas A / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Enzinger, Peter C / Hezel, Aram F / Ng, Kimmie / Wolpin, Brian M / Kwak, Eunice L. ·Department of Medical Oncology, Massachusetts General Hospital Cancer Center, POB 221, Boston, MA 02114, USA. ·Invest New Drugs · Pubmed #21800081.

ABSTRACT: BACKGROUND: MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer. METHODS: Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100 mg/m(2) dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150 mg per day. RESULTS: 20 of an original target of 33 patients were accrued, with a median age of 61 (range 44-81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia. CONCLUSIONS: MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.

15 Article Testing for Verification Bias in Reported Malignancy Risks for Side-Branch Intraductal Papillary Mucinous Neoplasms: A Simulation Modeling Approach. 2019

Weaver, Davis T / Lietz, Anna P / Mercaldo, Sarah F / Peters, Mary Linton B / Hur, Chin / Kong, Chung Yin / Wolpin, Brian M / Megibow, Alec J / Berland, Lincoln L / Knudsen, Amy B / Pandharipande, Pari V. ·1 Institute for Technology Assessment, Massachusetts General Hospital, 101 Merrimac St, Ste 1010, Boston, MA 02114. · 2 Department of Radiology, Massachusetts General Hospital, Boston, MA. · 3 Harvard Medical School, Boston, MA. · 4 Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA. · 5 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA. · 6 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA. · 7 Department of Radiology, New York University Medical Center, New York, NY. · 8 Department of Radiology, University of Alabama Birmingham School of Medicine, Birmingham, AL. ·AJR Am J Roentgenol · Pubmed #30620679.

ABSTRACT: OBJECTIVE: The objective of our study was to test for the possibility that published malignancy risks for side-branch intraductal papillary mucinous neoplasms (IPMNs) are overestimates, likely due to verification bias. MATERIALS AND METHODS: We tested for possible verification bias using simulation modeling techniques. First, in age-defined hypothetical cohorts of 10 million persons, we projected the frequency of pancreatic ductal adenocarcinoma (PDAC) arising from side-branch IPMNs over 5 years using published estimates of their prevalence (4.4%) and rate of malignant transformation (1.9%). Second, we projected the total number of PDAC cases in corresponding cohorts over the same time horizon using national cancer registry data. For each cohort, we determined whether the percentage of all PDAC cases that arose from side-branch IPMNs (i.e., side-branch IPMN-associated PDAC cases) was clinically plausible using an upper limit of 10% to define plausibility, as estimated from the literature. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. RESULTS: Across all cohorts, percentages of side-branch IPMN-associated PDACs greatly exceeded 10%. In the base case (mean age = 55.7 years), 80% of PDAC cases arose from side-branch IPMNs (7877/9786). In the oldest cohort evaluated (mean age = 75 years), this estimate was 76% (14,227/18,714). In a secondary analysis, we found that if an upper limit threshold of 10% for side-branch IPMN-associated PDAC was imposed, the model-predicted rate of malignancy for side-branch IPMNs would be less than 0.24% over a 5-year time horizon, substantially lower than most literature-based estimates. CONCLUSION: Our results suggest that reported malignancy risks associated with side-branch IPMNs are likely to be overestimates and imply the presence of verification bias.

16 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.

17 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

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

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

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

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

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

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

20 Article Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. 2018

Tiriac, Hervé / Belleau, Pascal / Engle, Dannielle D / Plenker, Dennis / Deschênes, Astrid / Somerville, Tim D D / Froeling, Fieke E M / Burkhart, Richard A / Denroche, Robert E / Jang, Gun-Ho / Miyabayashi, Koji / Young, C Megan / Patel, Hardik / Ma, Michelle / LaComb, Joseph F / Palmaira, Randze Lerie D / Javed, Ammar A / Huynh, Jasmine C / Johnson, Molly / Arora, Kanika / Robine, Nicolas / Shah, Minita / Sanghvi, Rashesh / Goetz, Austin B / Lowder, Cinthya Y / Martello, Laura / Driehuis, Else / LeComte, Nicolas / Askan, Gokce / Iacobuzio-Donahue, Christine A / Clevers, Hans / Wood, Laura D / Hruban, Ralph H / Thompson, Elizabeth / Aguirre, Andrew J / Wolpin, Brian M / Sasson, Aaron / Kim, Joseph / Wu, Maoxin / Bucobo, Juan Carlos / Allen, Peter / Sejpal, Divyesh V / Nealon, William / Sullivan, James D / Winter, Jordan M / Gimotty, Phyllis A / Grem, Jean L / DiMaio, Dominick J / Buscaglia, Jonathan M / Grandgenett, Paul M / Brody, Jonathan R / Hollingsworth, Michael A / O'Kane, Grainne M / Notta, Faiyaz / Kim, Edward / Crawford, James M / Devoe, Craig / Ocean, Allyson / Wolfgang, Christopher L / Yu, Kenneth H / Li, Ellen / Vakoc, Christopher R / Hubert, Benjamin / Fischer, Sandra E / Wilson, Julie M / Moffitt, Richard / Knox, Jennifer / Krasnitz, Alexander / Gallinger, Steven / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. · Department of Medicine, Stony Brook University, Stony Brook, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California. · New York Genome Center, New York, New York. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · SUNY Downstate Medical Center, Department of Medicine, New York, New York. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. · University Medical Center (UMC), Utrecht, the Netherlands. · Princess Maxime Center (PMC), Utrecht, the Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland. · Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts. · Department of Surgery, Stony Brook University, Stony Brook, New York. · Department of Pathology, Stony Brook University, Stony Brook, New York. · Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York. · Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. · University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Weill Cornell Medical College, New York, New York. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca. ·Cancer Discov · Pubmed #29853643.

ABSTRACT: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

21 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.

22 Article Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer. 2018

Hamada, Tsuyoshi / Khalaf, Natalia / Yuan, Chen / Morales-Oyarvide, Vicente / Babic, Ana / Nowak, Jonathan A / Qian, Zhi Rong / Ng, Kimmie / Rubinson, Douglas A / Kraft, Peter / Giovannucci, Edward L / Stampfer, Meir J / Fuchs, Charles S / Ogino, Shuji / Wolpin, Brian M. ·Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, 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. · Program in MPE Molecular Pathological Epidemiology, Department of Pathology, 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 Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. · Yale Cancer Center, New Haven, Connecticut; Department of Medicine, Yale School of Medicine, New Haven, Connecticut; Smilow Cancer Hospital, New Haven, Connecticut. · Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Electronic address: bwolpin@partners.org. ·Clin Gastroenterol Hepatol · Pubmed #29474971.

ABSTRACT: BACKGROUND & AIMS: Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear. METHODS: We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival. RESULTS: Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all P CONCLUSIONS: Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies.

23 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

24 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.

25 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.

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