Cancer and AAA: Causal role for chronic inflammation? Sakalihasan Natzi MD,PhD Department of Cardiovascular and Thoracic Surgery University hospital of Liège, Experimental Research Center of the Cardiovascular Surgery Department, GIGA-Cardiovascular Science Unit, University of Liège, Liège, BELGIUM
Disclosure Speaker name:...sakalihasan Natzi... Collaborative Project large-scale focused research project EU.Health-2007-2.3.2-2. Grant Agreement Number 2006 Aneurysmal Pathology Foundation, Belgium 2
Prevalence of cancer in AAA patients The frequency of neoplasia in AAA patients is reported to vary between 0.5% and 26%. Chan E., et al. Incidence of cancer and Abdominal Aortic Aneurysms, a logistic regression analysis. Annals New York Academy Of Sciences;1996; 800:68-73. Tilson, M.D., E.L. Fieg, M. Harvey. Malignant neoplasia in patients with abdominal aortic aneurysms. 1984; Arch. Surg. ;119:792-794 Robinson G, Hughes W, Lippey E. Abdominal aortic aneurysm and associated colorectal carcinoma: a management problem. Aust N Z J Surg 1994; 64: 475-8. Morris DM, Colquitt J. Concomitant abdominal aortic aneurysm and malignant disease: a difficult management problem. J Surg Oncol 1988; 39: 122-5. Veraldi GF, et al. Treatment of AAA associated with colorectal cancer: presentation of 14 cases and literature review. Int. J. Colorectal 2008; 23:425-430. Sakalihasan N, et al. Emission Tomography (PET) Evaluation of Abdominal Aortic Aneurysm (AAA) ; Eur. J. Vasc. Endovasc. Surg. 2002;23:431-436(26% ofpatients with concomitant AAAandcancer) EVAR Trial investigators. N Engl J Med 2010;362:1863 71. (25% of patients suffered from cancer followed after EVAR) DREAM study Group N Engl J Med 2010;362:1881 9 (Cancer related mortality during FU 10.8%)
Abdominal aortic aneurism and neoplasia: a prospective cohort study Material and Methods (ongoing study) 187 consecutive patients referred to our department with confirmed AAA with (-) PET/CT for cancer (2006-2009) 563 control patients with Coronary Artery Disease (CAD) during same period Patients were followed up for 96 months (8 years) At baseline, all patients were free of cancer
Primary endpoints 1. Occurrence of neoplasia within 96 months FU 2. Neoplasia free survival (NFS, days) defined as the time difference between occurrence of neoplasia and baseline (study entry)
Characteristics of AAA and CAD patients at Baseline
96-month incidence of neoplasia Total Neoplasia % CAD 563 100 17.8 AAA 187 51 27.3 RR = 1.54 (95%CI: 1.14-2.06) RR adjusted = 1.48 (95% CI : 1.08 2.03)
Type of cancer Lung Digestive Urologic Breast Other Total AAA (187) 13 13 12 1 12 51 (27.3%) CAD (563) 18 11 24 6 41 100 (17.8%)
Incidence of neoplasia with respect to AAA treatment Non-operated (N=45) Number (%) Operated (N=142) Number (%) P value Incidence of neoplasia 16 (35.6%) 35 (24.7%) P=0.15 EVAR (N=46) Number (%) Open Surgery (N=96) Number (%) P value 12 (26.1%) 23 (24.0%) P=0.78 01/2005 31/2006 Open surgery 150 patients (5-year FU) Occurrence of neoplasia 30/150 (20.5%)
Overall survival in CAD and AAA patients (P=0.0012) HR = 1.62 (95%CI: 1.21 2.17). The Kaplan-Meier overall survival (OS) curves. Cox regression analysis evidenced a significant difference between the two groups (P=0.0012) and yielded the following hazard ratio HR = 1.62 (95%CI: 1.21 2.17).
Neoplasia free survival in CAD and AAA patients HR = 1.56 (95% CI:1.10 2.20) HR adjusted = 1.42 (95% CI:0.96 2.12)
Relative Risk (RR) of neoplasia in AAA vs CAD according to baseline CRP levels CRP low* : RR=1.26 (95%CI: 0.82-1.91) CRP high**: RR=2.12 (95%CI: 1.25-3.60) * < 6mg/L **>6mg/L
AAA is Chronic Inflammatory Disease Thrombus aortic wall media & adventitia Natzi Sakalihasan et al, Journal of Vascular Surgery Volume 24, Issue 1, Pages 127-133 (July 1996) DOI: 10.1016/S0741 Nchimi A,.Sakalihasan N, Radiology 2010 Mar ;254(3):973-81
Representative example of MMP-2 and MMP-9 activity under latent or activated forms measured by gelatin zymography in extracts of normal (CAA) and diseased aortic wall (AAA and AOD). Olivier D Defawe, Natzi Sakalihasan. Cardiovasc Res 2003;60:205-213 Copyright 2003, European Society of Cardiology
ADVENTITIA PET 0 PET + - site + site MMP1 1 3 8* MMP2 1 MMP3 1 3 MMP9 1 MMP12 nd nd nd MMP13 nd 1 8 * # MMP14 1 2 ** # MMP15 1 TIMP1 1 TIMP2 1 RECK 1 PAI1 1 2 2 * TIMP3 1 upa 1 2 2.6 * # EMMPRI N 1 0.8 # COL1A1 1 5 ** # ELN 1 MCP1 1 IL1α 1 0.8 # IL6 1 4 2 IL8 1 4 COX2 1 TNFα 1 0.6* 0.5 * TGFα 1 0.8 * 0.7 * HIF1α 1 2 2 * CD31 1 0.7 * VEGF 1 0.6* # TSP1 1 αsma 1
Preoperative circulating CRP: median concentration (mg/l) in PET0 patients (and in PET+ patients (*P < 0.01, Mann Whitney U test. Audrey Courtois et al. J Nucl Med 2013;54:1740-1747 (c) Copyright 2014 SNMMI; all rights reserved
Mol Med. 2014; 20(1): 697 706
Fig 1. Circulating micrornas (mirnas) modulated in patients with aneurysms displaying positive[18f]fluorodeoxyglucose (FDG) uptake (A.) on positron emission tomography (PET) compared with patients displaying no uptake (A0) were measured by polymerase chain reaction (PCR) array. Seventeen mirnas are modulated in the three pools of plasmatic RNA from 17 A. patients compared with the four pools of RNA from 24 A0 patients. Nine are downregulated and eight are upregulated. Results are expressed as the fold-change relative to the median of mirnas expression in the A0 pools. P <.05 by Mann-Whitney U test.
Conclusion The present study purposed to draw attention on the possible association between AAA and cancer and to hypothesize some potential mechanisms. Based on these preliminary study results, EVAR and DREAM trials we believe that the incidence of cancer in AAA patients is higher than that published for the general population. In the present study, this finding is not only occasional or related to the age of both patient groups but may be due to the presence of chronic inflammatory cells and cytokines in AAA patients as well as their angiogenesis status. Further investigations are needed to test these hypotheses.