A Babic1, N Schnure2, N P Neupane3, M M Zaman4, N Rifai5, M W Welch1, L K Brais1, D A Rubinson1, V Morales-Oyarvide1, C Yuan1, S Zhang1, E M Poole6, B M Wolpin1, M H Kulke1, D A Barbie1, K Wong1, C S Fuchs7, K Ng8. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. 2. Perelman School of Medicine, University of Pennsylvania Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA. 3. Thomas Jefferson University, 1020 Walnut Street, Philadelphia, PA, 19107, USA. 4. Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. 5. Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA. 6. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA. 7. Yale Cancer Center, Yale School of Medicine, Smilow Cancer Hospital, 333 Cedar Street, New Haven, CT, 06510, USA. 8. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. Kimmie_Ng@dfci.harvard.edu.
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.
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 cancerpatients, 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 tumornecrosis 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 cancerpatient 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 cancerpatients are warranted.
Authors: Chen Yuan; Douglas A Rubinson; Zhi Rong Qian; Chen Wu; Peter Kraft; Ying Bao; Shuji Ogino; Kimmie Ng; Thomas E Clancy; Richard S Swanson; Megan J Gorman; Lauren K Brais; Tingting Li; Meir J Stampfer; Frank B Hu; Edward L Giovannucci; Matthew H Kulke; Charles S Fuchs; Brian M Wolpin Journal: J Clin Oncol Date: 2014-11-17 Impact factor: 44.544
Authors: Graziella Bellone; Carlo Smirne; Francesco Angelo Mauri; Elena Tonel; Anna Carbone; Alessandra Buffolino; Luca Dughera; Antonio Robecchi; Mario Pirisi; Giorgio Emanuelli Journal: Cancer Immunol Immunother Date: 2005-08-11 Impact factor: 6.968
Authors: Jeannine Bachmann; Mathias Heiligensetzer; Holger Krakowski-Roosen; Markus W Büchler; Helmut Friess; Marc E Martignoni Journal: J Gastrointest Surg Date: 2008-03-18 Impact factor: 3.452
Authors: Chen Yuan; Ying Bao; Chen Wu; Peter Kraft; Shuji Ogino; Kimmie Ng; Zhi Rong Qian; Douglas A Rubinson; Meir J Stampfer; Edward L Giovannucci; Brian M Wolpin Journal: J Clin Oncol Date: 2013-10-21 Impact factor: 44.544
Authors: Lucy Ireland; Almudena Santos; Muhammad S Ahmed; Carolyn Rainer; Sebastian R Nielsen; Valeria Quaranta; Ulrike Weyer-Czernilofsky; Danielle D Engle; Pedro A Perez-Mancera; Sarah E Coupland; Azzam Taktak; Thomas Bogenrieder; David A Tuveson; Fiona Campbell; Michael C Schmid; Ainhoa Mielgo Journal: Cancer Res Date: 2016-10-14 Impact factor: 12.701
Authors: Ana Babic; Michael H Rosenthal; Gloria M Petersen; Brian M Wolpin; William R Bamlet; Naoki Takahashi; Motokazu Sugimoto; Laura V Danai; Vicente Morales-Oyarvide; Natalia Khalaf; Richard F Dunne; Lauren K Brais; Marisa W Welch; Caitlin L Zellers; Courtney Dennis; Nader Rifai; Carla M Prado; Bette Caan; Tilak K Sundaresan; Jeffrey A Meyerhardt; Matthew H Kulke; Clary B Clish; Kimmie Ng; Matthew G Vander Heiden Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-09-18 Impact factor: 4.254
Authors: Mark B Ulanja; Alastair E Moody; Bryce D Beutler; Daniel Antwi-Amoabeng; Ganiyu A Rahman; Olatunji B Alese Journal: Oncotarget Date: 2022-06-15
Authors: Sharon Wei Ling Lee; R J Seager; Felix Litvak; Fabian Spill; Je Lin Sieow; Penny Hweixian Leong; Dillip Kumar; Alrina Shin Min Tan; Siew Cheng Wong; Giulia Adriani; Muhammad Hamid Zaman; And Roger D Kamm Journal: Integr Biol (Camb) Date: 2020-04-20 Impact factor: 2.192
Authors: Courtney W Houchen; Parthasarathy Chandrakesan; Janani Panneerselvam; Randal May; Nathaniel Weygant; Dongfeng Qu; William R Berry; Kamille Pitts; Ben Z Stanger; Chinthalapally V Rao; Michael S Bronze Journal: Mol Cancer Ther Date: 2020-05-05 Impact factor: 6.261
Authors: Chen Yuan; Vicente Morales-Oyarvide; Natalia Khalaf; Kimberly Perez; Fred K Tabung; Gloria Y F Ho; Charles Kooperberg; Aladdin H Shadyab; Lihong Qi; Peter Kraft; Howard D Sesso; Edward L Giovannucci; JoAnn E Manson; Meir J Stampfer; Kimmie Ng; Charles S Fuchs; Brian M Wolpin; Ana Babic Journal: J Natl Cancer Inst Date: 2021-09-04 Impact factor: 13.506
Authors: Calvin L Cole; John F Bachman; Jian Ye; Joseph Murphy; Scott A Gerber; Christopher A Beck; Brendan F Boyce; Gowrishankar Muthukrishnan; Joe V Chakkalakal; Edward M Schwarz; David Linehan Journal: J Cachexia Sarcopenia Muscle Date: 2021-05-07 Impact factor: 12.910
Authors: Suhu Liu; Helen I Gandler; Isidora Tošić; Darwin Q Ye; Zachary T Giaccone; David A Frank Journal: Mol Cancer Res Date: 2021-04-30 Impact factor: 5.852