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Assessing Resolution of Inflammation as a Potential Novel Risk Determinant for Stage 3 Colon Cancer Recurrence: A Translational Study
Megan L. Sulciner*1, Kimmie Ng2, William Tan2, Lauren Brais2, Chandrajit Raut3, Charles Serhan4
1Department of Surgery, Brigham and Women's Hospital, Boston, MA; 2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 3Division of Surgical Oncology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 4Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA


Objective: Resolution of inflammation is the active process of returning to homeostasis after inflammatory insult, mediated by endogenous specialized pro-resolving mediators (SPMs). SPMs are biosynthesized endogenously from polyunsaturated fatty acids, and include several families, namely the resolvins and lipoxins. Failed resolution of inflammation secondary to surgery contributes to tumor recurrence in animal models. We sought to characterize a comprehensive profile to assesses whether it is possible to predict to tumor recurrence in stage 3 colon cancer patients after primary resection based on SPM values.

Design: Plasma collected postoperatively from stage 3 colon cancer patients was obtained from the Dana-Farber/Brigham Cancer Center biobank. Mediators were quantified via specific ELISAs and reported as mean. Patient characteristics, oncologic outcomes (type of recurrence), and surgical outcomes (postoperative complications within 30 days) were analyzed. Student t-test was used for comparison analysis.

Setting: A single tertiary academic medical center.

Patients: Inclusion criteria was adult patients with pathologic stage 3 colon cancer who underwent upfront resection.

Main Outcome Measure: Level of pro-inflammatory and pro-resolution mediator associated with tumor recurrence.

Results: A total of 34 patients were included in this study, 17 developed recurrence after primary resection (cohort 1) and 17 patients did not (cohort 2). Median follow-up was 49 months. Recurrence was either local, distant, or local and distant. Plasma levels of all acute inflammatory mediators checked IL-6, C-reactive protein, and leukotriene B4 were similar between the cohorts indicating no difference in the state of acute inflammation. Importantly, levels for resolvin D2 were significantly higher in cohort at 162.0 pg/ml, compared to 76.9 pg/ml in cohort 1 (p=0.02). Levels for other SPMS, including resolvin D1 and lipoxin A4, trended higher in patients with no recurrence, but were not statistically significant compared to cohort 1. (Table 1) The summation of resolvin D1, resolvin D2, and lipoxin A4 was used to provide a comprehensive quantification of each patient"ôs resolution state. Patients in cohort 2 had a significantly higher summation than cohort 1 (p=0.04).

Conclusions: Patients with stage 3 colon cancer that recurred after primary resection had lower plasma levels of resolvin D2 and total summation of SPMs. Trends noted with other SPMs need further investigation. Together, these findings hold the potential to shift the paradigm in which failure of the resolution of inflammation contributes to the pathophysiology, prognosis, and treatment of tumor recurrence.

Table 1. Postoperative levels of pro-inflammatory and pro-resolving mediators (n=34)
MediatorRecurrence (cohort 1, n=17)No Recurrence (cohort 2, n=17)p-value
 Mean (SEM)Mean (SEM) 
Pro-inflammatory   
IL-6 (pg/ml)4.5 (2.5)4.9 (1.4)0.29
C-reactive protein (ug/ml)3.1 (0.7)4.4 (6.9)0.20
Leukotriene B4 (pg/ml)50.2 (7.2)52.6 (7.0)0.41
Pro-resolving   
LipoxinA4 (pg/ml)232.8 (17.9)252.7 (3.4)0.29
Resolvin D1 (pg/ml)61.3 (8.6)68.8 (12.1)0.30
Resolvin D276.9 (7.5)162.0 (35.1)0.02
SPM summation371.0 (24.1)497.9 (64.9)0.04


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