Circulating inflammatory factors associated with worse long-term prognosis in colorectal cancer

Table 1 Clinical baseline characteristics in frequencies n (%)

	CRC patients	Others (survivors or deceased by other causes)	CRC specific mortality	P value
	n = 174	n = 134 (77)	n = 40 (23)
Age	70 (range 29-90)	70 (29-90)	72 (36-90)	0.2641
Gender	105 men (60)	83 men (62)	22 men (55)	0.431
Localization	105 colon (60)	78 colon (58)	27 colon (68)	0.292
Cancer recurrence	34 (20)	16 (12)	18 (45)	< 0.001
Radical surgery	165 (95)	130 (97)	35 (88)	< 0.051
TNM stage I/II/III/IV	24/54/67/29 (14/31/38/17)	22/51/54/7 (17/38/40/5)	2/3/13/22 (5/8/32/55)	< 0.0011
Preoperative treatment	41 (24)	36 (27)	5 (13)	0.0601
Adjuvant treatment	71 (41)	47 (35)	24 (60)	0.0051
Total mortality	66 (38)	26 (19)	40 (100)	< 0.001

¹Covariates with P < 0.20 together with age were selected for adjustment in Tables 3 and 4. CRC: Colorectal cancer.

Table 2 Levels of inflammatory factors significantly associated to TNM stage

Factor	TNM stage I (n = 24), Median1 (range)	TNM stage II (n = 54), Median1 (range)	TNM stage III (n = 67), Median1 (range)	TNM stage IV (n = 29), Median1 (range)	P value
CCL20	100 (77-242)	119.5 (80-272)	124 (89-183)	149 (111-378)	0.034
CCL27	11956 (9975-15131)	11293 (8799-14133)	10308 (8173-13923)	9461 (7619-12283)	0.035
IL-8	99 (81-439)	113 (97-146)	104 (85-153)	166 (113-243)	0.009
MIF	19565 (13546-33372)	23720 (14452-43786)	21900 (14146-33330)	47235 (20723-89267)	0.031

¹Median in pg/mL with 1^st-3^rd quartile range. Association was determined using Jonckheere Terpstra test.

Table 3 Total mortality and association with highest tertile level of inflammatory factors

Factor	Total mortality		Total mortality adjusted1
	HR (95%CI)	P value	HR (95%CI)	P value
Age	1.0 (1.0-1.1)	0.006	1.1 (1.0-1.1)	< 0.001
TNM stage II	1.5 (0.5-4.0)	0.464	1.2 (0.4-3.2)	0.777
TNM stage III	1.8 (0.7-4.8)	0.228	2.2 (0.8-6.1)	0.141
TNM stage IV	6.8 (2.6-17.9)	< 0.001	14.6 (6.0-42.6)	< 0.001
Radical surgery	0.2 (0.1-0.4)	< 0.001	0.3 (0.1-0.6)	0.002
Preoperative treatment	0.8 (0.4-1.5)	0.454	0.7 (0.4-1.4)	0.338
Adjuvant treatment	1.1 (0.6-1.7)	0.842	0.7 (0.4-1.3)	0.226
CCL1	3.2 (1.7-5.9)	< 0.001	2.7 (1.4-5.4)	0.004
CCL3	2.0 (1.1-3.6)	0.030	1.2 (0.6-2.2)	0.605
CCL15	2.3 (1.2-4.3)	0.010	1.9 (1.0-3.7)	0.046
CCL20	3.1 (1.6-6.0)	0.001	2.2 (1.1-4.3)	0.021
CCL26	1.7 (1.0-3.0)	0.055	1.7 (0.9-3.0)	0.078
CX3CL1	3.3 (1.8-6.1)	< 0.001	2.3 (1.2-4.5)	0.014
CXCL1	1.9 (1.0-3.4)	0.038	1.4 (0.8-2.6)	0.295
CXCL10	2.1 (1.1-4.0)	0.017	1.3 (0.7-2.6)	0.387
CXCL13	1.8 (1.1-3.2)	0.033	2.0 (1.0-3.7)	0.039
CXCL16	1.6 (0.9-2.8)	0.139	1.7 (0.9-3.1)	0.113
IFN-γ	3.1 (1.6-6.1)	0.001	3.5 (1.6-7.5)	0.001
IL-1β	2.1 (1.2-3.8)	0.012	1.7 (0.9-3.1)	0.081
IL-2	2.2 (1.2-4.2)	0.011	2.7 (1.4-5.4)	0.005
IL-4	2.4 (1.2-4.6)	0.014	2.3 (1.1-4.5)	0.018
IL-8/CXCL8	2.6 (1.4-4.6)	0.002	1.6 (0.9-3.0)	0.115
IL-10	2.2 (1.2-4.1)	0.014	2.3 (1.2-4.6)	0.014
TNF-α	1.6 (0.9-2.8)	0.104	1.5 (0.8-2.6)	0.202

¹When adjusted for age, TNM stage, radical surgery, preoperative- and adjuvant treatment.

Table 4 Colorectal cancer specific mortality and the association with highest tertile level of inflammatory factors

Factor	CRC specific mortality		CRC specific mortality adjusted1
	HR (95%CI)	P value	HR (95%CI)	P value
Age	1.0 (1.0-1.0)	0.532	1.1 (1.0-1.1)	0.006
TNM stage II	0.7 (0.1-4.1)	0.674	0.5 (0.1-3.0)	0.444
TNM stage III	2.6 (0.6-11.7)	0.201	2.7 (0.6-12.9)	0.209
TNM stage IV	15.5 (3.6-66.3)	< 0.001	27.6 (5.8-131.1)	< 0.001
Radical surgery	0.2 (0.1-0.5)	0.001	0.19 (0.1-0.5)	0.001
Preoperative treatment	0.5 (0.2-1.2)	0.106	0.4 (0.1-0.9)	0.359
Adjuvant treatment	2.2 (1.2-4.2)	0.013	0.9 (0.5-2.0)	0.947
CCL1	3.2 (1.4-7.0)	0.004	2.8 (1.1-7.1)	0.025
CCL3	2.4 (1.1-5.3)	0.036	1.2 (0.5-2.8)	0.653
CCL15	2.8 (1.3-6.1)	0.011	2.0 (0.9-4.9)	0.107
CCL20	4.0 (1.6-10.1)	0.003	2.7 (1.0-7.0)	0.046
CCL24	2.2 (1.0-4.8)	0.061	2.5 (1.1-5.7)	0.037
CX3CL1	3.7 (1.6-8.3)	0.002	2.6 (1.1-6.4)	0.036
CXCL16	2.5 (1.1-5.4)	0.022	2.0 (0.8-4.8)	0.138
IFN-γ	1.8 (0.8-3.9)	0.138	1.7 (0.7-4.1)	0.253
IL-1β	1.9 (0.9-3.8)	0.090	1.7 (0.8-3.6)	0.193
IL-4	2.5 (1.1-5.7)	0.033	2.4 (1.0-5.5)	0.048
IL-8/CXCL8	3.3 (1.5-7.3)	0.003	1.5 (0.6-3.5)	0.344
TNF-α	2.0 (0.9-4.2)	0.078	2.3 (1.0-5.4)	0.047

¹When adjusted for age, TNM stage, radical surgery, preoperative- and adjuvant treatment. CRC: Colorectal cancer.

Table 5 Inflammatory factors not associated with colorectal cancer specific or total mortality

Factor	Factor
CCL2	CCL27
CCL7	CXCL2
CCL8	CXCL5
CCL11	CXCL6
CCL13	CXCL9
CCL17	CXCL11
CCL19	CXCL12
CCL21	GM-CSF
CCL22	IL-6
CCL23	IL-16
CCL25	MIF
CCL26