Introduction
Methods
Patients
Inclusion and exclusion criteria
Liver resection and definitions
Inflammatory markers
Follow-up
Cut-off value and inflammation score (IFS)
Statistical analysis
Results
The correlation of fifteen inflammatory markers
Construction of IFS system
No. | Variables | Cut-off | HR | Coefficient | Median coefficient† | Inflammatory-coefficient* | Cut-off score†† | IFS |
---|---|---|---|---|---|---|---|---|
1 | NLR | 2.22 | 1.821 | 0.6 | 0.662 | 1 | 0 or 1 | 1 or 0 |
2 | PLR | 75 | 2.346 | 0.853 | 0.662 | 1 | 0 or 1 | 1 or 0 |
3 | LMR | 2.48 | 0.465 | -0.766 | 0.662 | -1 | 0 or 1 | -1 or 0 |
4 | GPR | 1.1 | 1.603 | 0.472 | 0.662 | 1 | 0 or 1 | 1 or 0 |
5 | SII | 299.14 | 1.975 | 0.68 | 0.662 | 1 | 0 or 1 | 1 or 0 |
6 | PNI | 55.1 | 0.529 | -0.636 | 0.662 | -1 | 0 or 1 | -1 or 0 |
7 | APRI | 0.54 | 0.791 | -0.235 | - | - | - | - |
8 | ANRI | 7.18 | 0.789 | -0.238 | - | - | - | - |
9 | ALRI | 21.08 | 1.272 | 0.241 | - | - | - | - |
10 | NrLR | 188.4 | 2.207 | 0.792 | 0.662 | 1 | 0 or 1 | 1 or 0 |
11 | dNLR | 1.72 | 1.688 | 0.524 | 0.662 | 1 | 0 or 1 | 1 or 0 |
12 | PMLR | 64.93 | 1.904 | 0.644 | 0.662 | 1 | 0 or 1 | 1 or 0 |
13 | NMLR | 2.23 | 2.184 | 0.781 | 0.662 | 1 | 0 or 1 | 1 or 0 |
14 | SIS | 0 | 1.596 | 0.468 | 0.662 | 1 | 0 or 1 | 1 or 0 |
15 | GAR | 4.81 | 2.188 | 0.783 | 0.662 | 1 | 0 or 1 | 1 or 0 |
Patients were divided into three groups according to IFS
Baseline characteristics of the three groups in the training cohort
Variables | level | Low IFS score | Median IFS score | High IFS score | P value |
---|---|---|---|---|---|
N = 149 | N = 187 | N = 110 | |||
Age, year (mean ± SD) | 54.36 ± 10.71 | 53.03 ± 10.67 | 55.08 ± 9.18 | 0.220 | |
Sex (%) | female | 52 (34.9) | 65 (34.8) | 34 (30.9) | 0.753 |
male | 97 (65.1) | 122 (65.2) | 76 (69.1) | ||
Hepatolithiasis (%) | no | 135 (90.6) | 172 (92.0) | 99 (90.0) | 0.826 |
yes | 14 (9.4) | 15 (8.0) | 11 (10.0) | ||
Diabetes (%) | no | 139 (93.3) | 175 (93.6) | 103 (93.6) | 0.992 |
yes | 10 (6.7) | 12 (6.4) | 7 (6.4) | ||
HBsAg (+) (%) | no | 66 (44.3) | 114 (61.0) | 65 (59.1) |
0.006
|
yes | 83 (55.7) | 73 (39.0) | 45 (40.9) | ||
Anti-HCV (%) | no | 144 (96.6) | 187 (100.0) | 109 (99.1) |
0.027
|
yes | 5 (3.4) | 0 (0.0) | 1 (0.9) | ||
Child-Pugh grade (%) | A | 147 (98.7) | 184 (98.4) | 104 (94.5) | 0.066 |
B | 2 (1.3) | 3 (1.6) | 6 (5.5) | ||
TBIL, mg/dL* | 12.60 [9.80, 15.40] | 12.00 [9.20, 16.05] | 12.45 [8.95, 16.32] | 0.563 | |
ALT, IU/L* | 26.00 [17.00, 39.10] | 25.70 [17.30, 40.70] | 28.20 [17.07, 45.43] | 0.786 | |
AST, IU/L* | 25.00 [19.00, 32.00] | 27.50 [20.55, 38.80] | 28.10 [20.00, 41.77] |
0.041
| |
GGT, IU/L* | 45.00 [30.00, 71.00] | 74.00 [47.50, 140.50] | 168.00 [97.75, 275.75] |
< 0.001
| |
HgB, g/L (mean ± SD) | 138.45 ± 16.45 | 133.45 ± 17.73 | 128.15 ± 18.28 |
< 0.001
| |
PT, second* | 11.60 [11.10, 12.20] | 11.60 [11.00, 12.10] | 11.80 [11.20, 12.30] | 0.125 | |
ALB, g/L (mean ± SD) | 43.69 ± 3.60 | 42.51 ± 3.40 | 40.58 ± 4.03 |
< 0.001
| |
PLT, ×109/L* | 172.00 [132.00, 219.00] | 195.00 [147.00, 240.50] | 219.50 [175.00, 297.50] |
< 0.001
| |
WBC, ×109/L* | 5.54 [4.64, 6.97] | 6.26 [5.21, 7.58] | 7.38 [6.44, 9.34] |
< 0.001
| |
AFP, µg/L* | 3.90 [2.40, 8.50] | 3.50 [2.30, 8.75] | 4.05 [2.42, 12.42] | 0.548 | |
CEA, µg/L* | 2.30 [1.40, 3.50] | 2.60 [1.50, 5.15] | 3.25 [1.70, 9.38] |
0.004
| |
CA199, IU/mL* | 25.60 [13.30, 49.40] | 56.90 [14.80, 206.30] | 117.10 [27.62, 1000.00] |
< 0.001
| |
Perioperative transfusion (%) | no | 135 (90.6) | 157 (84.0) | 85 (77.3) |
0.013
|
yes | 14 (9.4) | 30 (16.0) | 25 (22.7) | ||
Anatomic resection (%) | no | 32 (21.5) | 27 (14.4) | 22 (20.0) | 0.213 |
yes | 117 (78.5) | 160 (85.6) | 88 (80.0) | ||
Major resection (%) | no | 124 (83.2) | 131 (70.1) | 71 (64.5) |
0.002
|
yes | 25 (16.8) | 56 (29.9) | 39 (35.5) | ||
Resection margin ≥ 10 mm (%) | yes | 21 (14.1) | 20 (10.7) | 6 (5.5) | 0.081 |
no | 128 (85.9) | 167 (89.3) | 104 (94.5) | ||
Cirrhosis (%) | no | 107 (71.8) | 150 (80.2) | 95 (86.4) |
0.015
|
yes | 42 (28.2) | 37 (19.8) | 15 (13.6) | ||
Tumor diameter, cm (mean ± SD) | 5.41 ± 2.47 | 7.04 ± 2.81 | 8.08 ± 2.92 |
< 0.001
| |
Multiple tumors (%) | no | 142 (95.3) | 178 (95.2) | 105 (95.5) | 0.994 |
yes | 7 (4.7) | 9 (4.8) | 5 (4.5) | ||
Satellite nodules (%) | no | 122 (81.9) | 135 (72.2) | 67 (60.9) |
0.001
|
yes | 27 (18.1) | 52 (27.8) | 43 (39.1) | ||
Tumor capsule (%) | no | 133 (89.3) | 171 (91.4) | 106 (96.4) | 0.282 |
complete | 10 (6.7) | 8 (4.3) | 2 (1.8) | ||
incomplete | 6 (4.0) | 8 (4.3) | 2 (1.8) | ||
Tumor differentiation (%) | low | 7 (4.7) | 8 (4.3) | 7 (6.4) | 0.655 |
median | 140 (94.0) | 178 (95.2) | 103 (93.6) | ||
high | 2 (1.3) | 1 (0.5) | 0 (0.0) | ||
Adjacent tissue invasion (%) | no | 145 (97.3) | 177 (94.7) | 98 (89.1) |
0.019
|
yes | 4 (2.7) | 10 (5.3) | 12 (10.9) | ||
MVI (%) | no | 141 (94.6) | 163 (87.2) | 94 (85.5) |
0.030
|
yes | 8 (5.4) | 24 (12.8) | 16 (14.5) | ||
LNM (%) | no | 140 (94.0) | 158 (84.5) | 78 (70.9) |
< 0.001
|
yes | 9 (6.0) | 29 (15.5) | 32 (29.1) |
Survival analysis
Independent prognostic factors for OS and RFS
Univariable | Multivariable | |||||
---|---|---|---|---|---|---|
Variables | HR | 95%CI | P value | HR | 95%CI | P value |
Age, year | 1.005 | 0.993–1.017 | 0.453 | |||
Sex, male vs. female | 1.055 | 0.808–1.377 | 0.694 | |||
Hepatolithiasis, yes vs. no | 1.266 | 0.824–1.945 | 0.282 | |||
Diabetes, yes vs. no | 0.921 | 0.555–1.530 | 0.751 | |||
HBsAg (+), yes vs. no | 0.816 | 0.633–1.052 | 0.116 | |||
Anti-HCV, yes vs. no | 0.749 | 0.239–2.343 | 0.619 | |||
Child-Pugh grade, B vs. A | 0.446 | 0.143–1.394 | 0.165 | |||
TBIL, mg/dL | 0.999 | 0.993–1.005 | 0.761 | |||
ALT, IU/L | 1.001 | 0.999–1.002 | 0.081 | |||
AST, IU/L | 1.001 | 1.000-1.002 | 0.042 | |||
GGT, IU/L | 1.001 | 1.000-1.002 | 0.011 | |||
HgB, g/L | 0.991 | 0.984–0.998 | 0.009 | |||
PT, second | 1.058 | 0.956–1.172 | 0.274 | |||
ALB, g/L | 0.950 | 0.92–0.981 | 0.002 | |||
PLT, ×109/L | 1.002 | 1.000-1.003 | 0.034 | |||
WBC, ×109/L | 1.075 | 1.014–1.139 | 0.015 | |||
AFP, µg/L | 1.000 | 0.999–1.001 | 0.615 | |||
CEA, µg/L | 1.000 | 0.999–1.001 | 0.142 | |||
CA19-9, IU/mL | 1.001 | 1.000-1.002 | < 0.001 | 1.000 | 1.0001–1.001 | 0.010 |
Perioperative transfusion, yes vs. no | 1.354 | 0.974–1.883 | 0.071 | |||
Anatomic resection, yes vs. no | 1.704 | 1.175–2.472 | 0.005 | 1.578 | 1.085–2.295 | 0.017 |
Major resection, yes vs. no | 1.553 | 1.186–2.033 | 0.001 | |||
Resection margin < 10 mm, yes vs. no | 1.833 | 1.134–2.963 | 0.012 | |||
Cirrhosis, yes vs. no | 0.854 | 0.623–1.171 | 0.327 | |||
Tumor diameter, cm | 1.117 | 1.074–1.162 | < 0.001 | |||
Multiple tumors, yes vs. no | 0.816 | 0.433–1.538 | 0.530 | |||
Satellite nodules, yes vs. no | 1.997 | 1.537–2.595 | < 0.001 | 1.448 | 1.095–1.915 | 0.009 |
Tumor capsule, yes vs. no | 0.620 | 0.421–0.914 | 0.016 | |||
Tumor differentiation, high vs. median vs. low | 1.410 | 0.809–2.458 | 0.225 | |||
Adjacent tissue invasion, yes vs. no | 1.570 | 0.944–2.611 | 0.082 | |||
MVI, yes vs. no | 1.794 | 1.254–2.566 | 0.001 | 1.587 | 1.101–2.291 | 0.014 |
LNM, yes vs. no | 2.179 | 1.618–2.935 | < 0.001 | 1.422 | 1.038–1.949 | 0.028 |
IFS, high vs. median vs. low | 2.320 | 1.955–2.753 | < 0.001 | 2.106 | 1.682–2.637 | < 0.001 |
Univariable | Multivariable | |||||
---|---|---|---|---|---|---|
Variables | HR | 95%CI | P value | HR | 95%CI | P value |
Age, year | 0.997 | 0.986–1.008 | 0.586 | |||
Sex, male vs. female | 0.938 | 0.745–1.180 | 0.583 | |||
Hepatolithiasis, yes vs. no | 0.995 | 0.675–1.467 | 0.980 | |||
Diabetes, yes vs. no | 0.770 | 0.479–1.240 | 0.283 | |||
HBsAg (+), yes vs. no | 0.859 | 0.688–1.071 | 0.177 | |||
Anti-HCV, yes vs. no | 0.313 | 0.078–1.257 | 0.101 | |||
Child-Pugh grade, B vs. A | 0.754 | 0.374–1.523 | 0.432 | |||
TBIL, mg/dL | 1.001 | 0.997–1.004 | 0.655 | |||
ALT, IU/L | 0.999 | 0.996–1.001 | 0.335 | |||
AST, IU/L | 1.000 | 0.998–1.001 | 0.656 | |||
GGT, IU/L | 1.000 | 0.999–1.001 | 0.070 | |||
HgB, g/L | 0.994 | 0.988-1.000 | 0.049 | |||
PT, second | 1.036 | 0.940–1.141 | 0.479 | |||
ALB, g/L | 0.986 | 0.959–1.013 | 0.311 | |||
PLT, ×109/L | 1.002 | 1.000-1.003 | 0.037 | |||
WBC, ×109/L | 1.064 | 1.010–1.122 | 0.019 | |||
AFP, µg/L | 1.001 | 0.999–1.002 | 0.151 | |||
CEA, µg/L | 1.000 | 0.999–1.001 | 0.110 | |||
CA19-9, IU/mL | 1.001 | 1.0006–1.0012 | < 0.001 | 1.001 | 1.000-1.008 | 0.011 |
Perioperative transfusion, yes vs. no | 1.152 | 0.857–1.548 | 0.348 | |||
Anatomic resection, yes vs. no | 1.289 | 0.966–1.720 | 0.085 | |||
Major resection, yes vs. no | 1.299 | 1.017–1.658 | 0.036 | |||
Resection margin < 10 mm, yes vs. no | 1.439 | 0.987–2.096 | 0.057 | |||
Cirrhosis, yes vs. no | 0.788 | 0.596–1.043 | 0.096 | |||
Tumor diameter, cm | 1.117 | 1.079–1.158 | < 0.001 | 1.059 | 1.015–1.105 | 0.008 |
Multiple tumors, yes vs. no | 1.039 | 0.637–1.694 | 0.879 | |||
Satellite nodules, yes vs. no | 1.970 | 1.557–2.494 | < 0.001 | 1.419 | 1.098–1.834 | 0.007 |
Tumor capsule, yes vs. no | 0.750 | 0.568–0.989 | 0.042 | |||
Tumor differentiation, high vs. median vs. low | 1.019 | 0.662–1.569 | 0.93 | |||
Adjacent tissue invasion, yes vs. no | 1.810 | 1.160–2.825 | 0.009 | |||
MVI, yes vs. no | 1.955 | 1.400–2.730 | < 0.001 | 1.664 | 1.182–2.342 | 0.003 |
LNM, yes vs. no | 1.998 | 1.511–2.643 | < 0.001 | 1.406 | 1.040–1.901 | 0.027 |
IFS, high vs. median vs. low | 1.857 | 1.603–2.153 | < 0.001 | 1.572 | 1.322–1.87 | < 0.001 |
Comparison of different scoring systems
Clinical staging systems | C-index (95%CI) | Change (95%CI) | P value | AIC value |
---|---|---|---|---|
IFS | 0.684 (0.654–0.714) | 2646.467 | ||
AJCC 7th TNM Stage | 0.607 (0.574–0.641) | -0.077 (-0.111 — -0.035) |
< 0.0001
| 2701.532 |
AJCC 8th TNM Stage | 0.614 (0.581–0.648) | -0.070 (-0.106 — -0.027) |
0.0005
| 2697.023 |
Child-Pugh Stage | 0.505 (0.494–0.516) | -0.179 (-0.212 — -0.144) |
< 0.0001
| 2740.608 |
The validation of IFS system
Variables | level | Low IFS score | Median IFS score | High IFS score | P value |
---|---|---|---|---|---|
N = 42 | N = 110 | N = 23 | |||
Age, year (mean ± SD) | 58.12 ± 9.78 | 56.56 ± 10.68 | 58.87 ± 10.80 | 0.521 | |
Sex (%) | female | 14 (33.3) | 34 (30.9) | 6 (26.1) | 0.833 |
male | 28 (66.7) | 76 (69.1) | 17 (73.9) | ||
Hepatolithiasis (%) | no | 42 (100.0) | 106 (96.4) | 22 (95.7) | 0.436 |
yes | 0 (0.0) | 4 (3.6) | 1 (4.3) | ||
Diabetes (%) | no | 38 (90.5) | 101 (91.8) | 22 (95.7) | 0.758 |
yes | 4 (9.5) | 9 (8.2) | 1 (4.3) | ||
HBsAg (+) (%) | no | 22 (52.4) | 67 (60.9) | 15 (65.2) | 0.526 |
yes | 20 (47.6) | 43 (39.1) | 8 (34.8) | ||
Anti-HCV (%) | no | 42 (100.0) | 110 (100.0) | 22 (95.7) |
0.036
|
yes | 0 (0.0) | 0 (0.0) | 1 (4.3) | ||
Child-Pugh grade (%) | A | 37 (88.1) | 104 (94.5) | 17 (73.9) |
0.027
|
B | 2 (4.8) | 4 (3.6) | 4 (17.4) | ||
TBIL, mg/dL* | 12.45 [10.03, 16.17] | 11.90 [9.83, 14.35] | 10.30 [8.85, 12.25] | 0.153 | |
ALT, IU/L* | 18.50 [14.00, 25.90] | 21.90 [14.00, 31.08] | 28.00 [15.75, 46.00] | 0.151 | |
AST, IU/L* | 22.15 [17.00, 27.88] | 22.95 [17.25, 31.75] | 31.80 [23.05, 42.00] |
0.012
| |
GGT, IU/L* | 49.00 [28.25, 86.25] | 73.50 [38.25, 154.75] | 92.00 [55.00, 199.00] | 0.079 | |
HgB, g/L (mean ± SD) | 136.05 ± 15.16 | 134.75 ± 13.86 | 124.65 ± 18.64 |
0.007
| |
PT, second* | 11.55 (1.17) | 11.65 (0.90) | 12.22 (1.19) |
0.027
| |
ALB, g/L (mean ± SD) | 42.69 ± 5.27 | 42.36 ± 3.37 | 40.00 ± 3.78 |
0.021
| |
PLT, ×109/L* | 162.00 [133.50, 199.00] | 186.50 [146.25, 242.50] | 185.00 [136.50, 223.00] | 0.054 | |
WBC, ×109/L* | 5.98 [4.66, 6.82] | 6.08 [5.03, 7.46] | 6.13 [5.04, 8.27] | 0.428 | |
AFP, µg/L* | 3.50 [1.90, 6.05] | 3.05 [2.12, 5.70] | 6.60 [2.40, 21.00] | 0.208 | |
CEA, µg/L* | 2.30 [1.40, 3.65] | 2.90 [2.00, 6.10] | 3.30 [1.55, 4.70] |
0.024
| |
CA199, IU/mL* | 36.45 [18.35, 124.85] | 69.75 [24.20, 670.12] | 45.20 [16.65, 171.60] | 0.104 | |
Perioperative transfusion (%) | no | 37 (88.1) | 96 (87.3) | 19 (82.6) | 0.804 |
yes | 5 (11.9) | 14 (12.7) | 4 (17.4) | ||
Anatomic resection (%) | no | 30 (71.4) | 71 (64.5) | 13 (56.5) | 0.472 |
yes | 12 (28.6) | 39 (35.5) | 10 (43.5) | ||
Major resection (%) | no | 30 (71.4) | 74 (67.3) | 18 (78.3) | 0.559 |
yes | 12 (28.6) | 36 (32.7) | 5 (21.7) | ||
Cirrhosis (%) | no | 31 (73.8) | 89 (80.9) | 15 (65.2) | 0.223 |
yes | 11 (26.2) | 21 (19.1) | 8 (34.8) | ||
Tumor diameter, cm (mean ± SD) | 5.55 ± 3.54 | 6.58 ± 3.60 | 8.02 ± 3.76 |
0.031
| |
Multiple tumors (%) | no | 34 (81.0) | 70 (63.6) | 18 (78.3) | 0.073 |
yes | 8 (19.0) | 40 (36.4) | 5 (21.7) | ||
Satellite nodules (%) | no | 27 (64.3) | 58 (52.7) | 16 (69.6) | 0.203 |
yes | 15 (35.7) | 52 (47.3) | 7 (30.4) | ||
Tumor capsule (%) | no | 40 (95.2) | 100 (90.9) | 21 (91.3) | 0.747 |
complete | 1 (2.4) | 7 (6.4) | 2 (8.7) | ||
incomplete | 1 (2.4) | 3 (2.7) | 0 (0.0) | ||
Tumor differentiation (%) | low | 3 (7.1) | 9 (8.2) | 3 (13.0) | 0.466 |
median | 37 (88.1) | 96 (87.3) | 17 (73.9) | ||
high | 2 (4.8) | 5 (4.5) | 3 (13.0) | ||
Adjacent tissue invasion (%) | no | 40 (95.2) | 105 (95.5) | 20 (87.0) | 0.267 |
yes | 2 (4.8) | 5 (4.5) | 3 (13.0) | ||
MVI (%) | no | 35 (83.3) | 88 (80.0) | 21 (91.3) | 0.425 |
yes | 7 (16.7) | 22 (20.0) | 2 (8.7) | ||
LNM (%) | no | 40 (95.2) | 96 (87.3) | 19 (82.6) | 0.242 |
yes | 2 (4.8) | 14 (12.7) | 4 (17.4) |