Table 1. The basic clinical characteristics of early-stage HCC patients
Clinical parameter
|
Total
(n=703)
|
FHFU cohort(n=490)
|
FHXU cohort
(n=213)
|
Sex, male/female
|
580/123
|
404/86
|
175/38
|
Age, year
|
53.7±10.9
|
53.4±11.1
|
52.8±10.5
|
BCLC staging system, (0/A)
|
45/658
|
31/459
|
13/200
|
WBC, 109/L
|
5.2±1.6
|
5.0±1.9
|
4.9±1.5
|
PLT, 109/L
|
160.3±62.5
|
158.6±58.7
|
161.6±65.3
|
Hb, g/L
|
142.4±14.9
|
139.6±15.1
|
141.6±15.5
|
Hematocrit, %
|
41.5±3.9
|
41.3±2.7
|
40.4±3.3
|
MCV, fL
|
90.7±4.8
|
92.2±5.1
|
89.9±5.0
|
MCH, pg
|
31.1±2.0
|
31.3±1.9
|
31.2±1.8
|
Neutrophil, 109/L
|
3.1±1.2
|
3.0±1.1
|
3.1±1.2
|
Lymphocyte, 109/L
|
1.6±0.6
|
1.6±0.6
|
1.6±0.6
|
Monocyte, 109/L
|
0.4±0.1
|
0.4±0.1
|
0.4±0.1
|
NR, %
|
58.3±9.3
|
59.4±9.8
|
55.4±8.9
|
LR, %
|
31.8±8.5
|
32.3±8.2
|
32.1±08.6
|
MR, %
|
7.0±2.0
|
7.0±1.9
|
7.0±2.1
|
RDW, %
|
13.2±0.9
|
13.1±0.8
|
13.1±0.8
|
RBC, 109/L
|
4.6±0.6
|
4.6±0.6
|
4.6±0.5
|
AFP, μg/L
|
339.1±484.8
|
319±480
|
364.7±491.4
|
ALT, U/L
|
35.1±28.0
|
35.3±27
|
36.4±35.5
|
HBV DNA level, <106/>106 IU/mL
|
283/420
|
197/293
|
86/127
|
Albumin, g/L
|
42.2±3.2
|
42.5±3.1
|
42.1±3.1
|
Scr, μmol/L
|
72.1±15.6
|
76.9±17.1
|
77.4±16.5
|
γ-GGT, U/L
|
78.3±102.9
|
107.1±75.0
|
75.6±97.2
|
ALP, U/L
|
86.5±45.9
|
84.1±37.4
|
84.4±39.8
|
TBil, μmol/L
|
14.7±6.1
|
13.5±6.0
|
13.3±6.7
|
DBil, μmol/L
|
5.5±3.0
|
5.5±3.0
|
5.3±3.1
|
IBil, μmol/L
|
9.2±3.8
|
9.0±3.4
|
9.7±3.3
|
TBA, μmol/L
|
9.9±13.4
|
8.8±17.1
|
9.2±15.6
|
TP, g/L
|
69.7±5.0
|
74.9±4.7
|
75.6±4.8
|
ALB, g/L
|
42.2±3.2
|
42.5±3.1
|
42.1±3.1
|
GLB, g/L
|
27.5±4.2
|
29.2±5.3
|
27.7±4.8
|
ALB/GLB
|
1.6±0.3
|
1.6±0.3
|
1.6±0.3
|
PAB, mg/L
|
233.0±71.1
|
240.2±70.4
|
235.4±70.3
|
AFU, g/L
|
27.5±11.5
|
27.3±11.3
|
26.5±9.8
|
ADA, U/L
|
6.7±2.2
|
6.6±2.2
|
6.6±2.2
|
LDH, U/L
|
168.7±63.8
|
164.6±46.9
|
168±64.2
|
Urea, mmol/L
|
5.5±1.4
|
5.4±1.4
|
5.6±1.4
|
Uric acid, μmol/L
|
320±78.5
|
325±75.5
|
333±79.9
|
GLU, mmol/L
|
5.5±1.4
|
5.4±1.3
|
5.4±1.4
|
TCHO, mmol/L
|
4.2±0.9
|
4.2±0.9
|
4.2±0.9
|
TG, mmol/L
|
1.2±0.7
|
1.2±0.7
|
1.2±0.6
|
HDL, mmol/L
|
1.2±0.3
|
1.2±0.3
|
1.2±0.3
|
LDL, mmol/L
|
2.8±0.8
|
2.8±0.8
|
2.6±0.7
|
Apo-A1, g/L
|
119.2±30.9
|
117.7±29.8
|
121.5±31.0
|
Apo-B, g/L
|
85.6±22.0
|
86.7±22.5
|
82.3±20.5
|
Calcium, mmol/L
|
2.3±0.1
|
2.3±0.1
|
2.3±0.1
|
Phosphorus, mmol/L
|
1.1±0.2
|
1.1±0.2
|
1.1±0.2
|
Magnesium, mmol/L
|
0.9±0.1
|
0.9±0.1
|
0.9±0.1
|
Kalium, mmol/L
|
4.1±0.3
|
4.1±0.3
|
4.3±0.3
|
Natrium, mmol/L
|
141±2.4
|
141±2.3
|
141±2.4
|
Chlorine, mmol/L
|
103.0±2.9
|
103.1±2.7
|
103.0±3.1
|
TT, second
|
20.0±1.5
|
20.1±1.5
|
20.0±1.8
|
FIB, g/L
|
2.4±0.8
|
2.4±0.7
|
2.4±0.8
|
APTT, second
|
28.0±4.2
|
27.8±4.1
|
28.0±3.7
|
PT, second
|
11.7±1.1
|
11.9±1.0
|
12.3±1.2
|
Tumor size, centimiter
|
5.4±3.6
|
5.2±3.3
|
5.4±3.8
|
Tumor number, single/multiple
|
670/33
|
467/23
|
203/10
|
Satellite nodules, yes/no
|
389/314
|
276/214
|
113/100
|
MVI, M0/M1/M2
|
428/173/102
|
294/121/75
|
134/52/27
|
Tumor capsule, yes/no
|
328/375
|
228/262
|
100/113
|
Cirrhosis, yes/no
|
208/495
|
142/348
|
66/147
|
Follow-up time (months)
|
18.8±10.2
|
19.0±10.2
|
18.3±10.3
|
Recurrence/metastasis rates (%)
(8-month/1-year/2-year/3-year)
|
5.8/8.1/
11.8/12.7
|
6.5/9.2/
11.7/12.5
|
4.2/5.6/
9.5/10.4
|
Survival rate (%)
(8-month/1-year/2-year/3-year)
|
1.7/2.4/
3.9/4.2
|
1.9/2.5/
4.1/4.4
|
1.8/2.2/
3.6/4.0
|
FHFU, the first affiliated hospital of Fujian Medical University; FHXU, the first affiliated hospital of Xiamen University; BCLC staging system, Barcelona Clinic Liver Cancer staging system; WBC, white blood cell; PLT, platelet; Hb, hemoglobin; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; NR, neutrophil ratio; LR, lymphocyte ratio; MR, monocyte ratio; RDW, red blood cell distribution width; RBC, red blood cell; AFP, α-fetoprotein; ALT, alanine aminotransferase; HBV DNA level, hepatitis B virus deoxyribonucleic acid level; Scr, Serum creatinine; γ-GTT, γ-glutamyl transpeptidase; ALP, alkaline phophatase; TBil, total bilirubin; DBil, direct bilirubin; IBil, indirect bilirubin; TBA, total bile acid; TP, total protein; ALB, albumin; GLB, globumin; PAB, prealbumin; AFU, α-fucosidase; ADA, adenosine deaminase; LDH, lactate dehydrogenase; GLU, Glucose; TCHO, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Apo-A1, apolipoprotein A1; Apo-B, apolipoprotein B; TT, thrombin time; FIB, fibrinogen; APTT, activated partial thromboplastin time; PT, prothrombin time; MVI, microvascular invasion.
Table 2. Univariate multivariate of clinical parameters associated with DFS and OS in early-stage HCC patients after R0 resection
Clinical parameter
|
DFS
|
OS
|
HR (95% CI)
|
p-value
|
HR (95% CI)
|
p-value
|
Univariate analysis
|
|
Age, year
|
0.25(0.08-0.77)
|
0.015
|
0.98 (0.95-1)
|
0.091
|
Sex, male/female
|
0.81(0.45-1.46)
|
0.998
|
0.88 (0.41-1.9)
|
0.741
|
BCLC staging system, (0/A)
|
3.04(0.75-12.33)
|
0.122
|
2.74 (0.68-11.29)
|
0.995
|
WBC, ≤3.7/>3.7×109/L
|
2.41(0.98-6.02)
|
0.055
|
1.21(1.06-1.5.2)
|
0.013
|
PLT, ≤160/>160×109/L
|
1.76(1.12-2.77)
|
0.018
|
1.00(1.00-1.00)
|
0.027
|
Hb, ≤125/>125×109/L
|
2.05(0.81-5.06)
|
0.133
|
0.99(0.97-1.12)
|
0.312
|
Hematocrit, ≤42.2/>42.2%
|
1.56(0.67-2.32)
|
0.073
|
0.98(0.91-1.12)
|
0.692
|
MCV, ≤87/>87fL
|
0.66(0.42-1.03)
|
0.061
|
0.95(0.90-1.01)
|
0.055
|
MCH, ≤31.5/>31.5pg
|
0.45(0.28-0.72)
|
<0.001
|
0.85(0.76-0.96)
|
0.007
|
Lymphocyte, ≤1.5/>1.5×109/L
|
0.93(0.60-1.45)
|
0.732
|
0.86(0.52-1.55)
|
0.585
|
Neutrophil, ≤3.3/>3.3×109/L
|
2.02(1.01-3.80)
|
0.045
|
1.43(1.14-1.72)
|
0.002
|
Monocyte, ≤0.5/>0.5×109/L
|
1.54(0.89-2.60)
|
0.126
|
7.51(1.63-15.86)
|
0.012
|
LR, ≤41.6/>41.6%
|
0.56(0.33-0.96)
|
0.036
|
0.95(0.92-0.99)
|
0.011
|
NR, ≤47.8/>47.8%
|
1.60(0.97-2.52)
|
0.068
|
1.05(1.00-1.10)
|
0.033
|
RDW, ≤13.6/>13.6%
|
1.81(1.12-3.01)
|
0.016
|
1.12(0.89-1.56)
|
0.292
|
RBC, ≤4.5/>4.5×109/L
|
1.35(0.86-2.63)
|
0.152
|
1.22(0.66-2.24)
|
0.533
|
AFP, <400/≥400μg/L
|
2.01(1.20-3.26)
|
0.005
|
1.00(1.00-1.00)
|
<0.001
|
ALT, <61/≥61 U/L
|
13.12(1.85-5.40)
|
<0.001
|
1.00(0.99-1.00)
|
1.000
|
HBV DNA,
<50/≥50×109 IU/mL
|
1.74(1.12-2.96)
|
0.016
|
1.00(1.00-1.00)
|
0.971
|
Albumin, <50/≥50g/L
|
0.47(0.23-0.93)
|
0.031
|
0.89(0.82-0.97)
|
0.008
|
Scr, <76/≥76μmol/L
|
0.62(0.34-1.12)
|
0.123
|
0.98(0.96-1.02)
|
0.240
|
γ-GGT, <34/≥34U/L
|
2.10(1.12-3.95)
|
0.021
|
1.00(1.00-1.00)
|
0.541
|
ALP, <76/≥76&<117≥117U/L
|
4.75(2.61-8.56)
|
<0.001
|
1.00(1.00-1.00)
|
0.182
|
TBil, <16.4/≥16.4μmol/L
|
1.44(0.88-2.12)
|
0.169
|
0.97 (0.93-1.24)
|
0.313
|
DBil, <5.6/≥5.6μmol/L
|
1.52(0.97-2.30)
|
0.065
|
0.95 (0.83-1.10)
|
0.415
|
IBil, <6.6/≥6.6μmol/L
|
1.55(0.83-2.70)
|
0.178
|
0.94 (0.86-1.00)
|
0.182
|
TBA, <7.2/≥7.2μmol/L
|
2.33(1.20-4.32)
|
0.011
|
0.95 (0.89-1.01)
|
0.061
|
TP, <77 /≥77g/L
|
0.26(0.07-1.01)
|
0.049
|
1.00 (0.95-1.10)
|
0.706
|
ALB, <37/≥37g/L
|
1.40(0.23-0.93)
|
0.031
|
0.89 (0.82-0.97)
|
0.008
|
GLB, <28.2/≥28.2g/L
|
1.42(0.88-2.10)
|
0.168
|
1.00(0.96-1.06)
|
0.727
|
ALB/GLB <2.2/≥2.2
|
0.39(0.19-0.82)
|
0.013
|
1.73 (0.26-1.30)
|
0.186
|
PAB, ≤200/>200mg/L
|
0.32(0.14-0.73)
|
0.007
|
0.99 (0.99-1.00)
|
0.0014
|
AFU, <38/≥38g/L
|
4.12(1.62-10.04)
|
0.003
|
1.02 (1.00-1.03)
|
0.032
|
ADA, <7/≥7U/L
|
1.92(1.25-3.04)
|
0.008
|
1.12 (0.99-1.32)
|
0.063
|
LDH, <212/≥212U/L
|
2.02(1.12-3.76)
|
0.033
|
1.00 (1.00-1.00)
|
<0.001
|
Urea, <4/≥4&<6.9/≥6.9mmol/L
|
0.22 (0.08-0.59)
|
0.003
|
0.95 (0.76-1.22)
|
0.623
|
Uric acid, <379/≥379μmol/L
|
1.64(0.99-2.62)
|
0.053
|
1.01(0.99-1.03)
|
0.192
|
GLU, <4.9/≥4.9mmol/L
|
0.60(0.38-0.94)
|
0.025
|
0.97(0.78-1.22)
|
0.821
|
TCHO, <3.4/≥3.4mmol/L
|
1.95(0.74-4.78)
|
0.184
|
1.02(0.75-1.40)
|
0.990
|
TG, <1.1/≥1.1mmol/L
|
0.60(0.37-0.98)
|
0.043
|
0.51(0.24-1.18)
|
0.081
|
HDL, <1/≥1mmol/L
|
0.70(0.43-1.12)
|
0.156
|
1.25(0.48-3.05)
|
0.702
|
LDL, <3/≥3mmol/L
|
2.08(1.22-3.16)
|
0.005
|
0.98(0.65-1.52)
|
0.905
|
Apo-A1, <83/≥83g/L
|
0.45(0.22-0.91)
|
0.028
|
1.00(0.99-1.01)
|
0.760
|
Apo-B, <113/≥113g/L
|
2.01(1.14-3.66)
|
0.027
|
1.00(0.99-1.01)
|
0.708
|
Calcium, <2.5/≥2.5mmol/L
|
1.75(0.24-12.4)
|
0.590
|
2.01(0.09-4.01)
|
0.660
|
Phosphorus, <1.1/≥1.1mmol/L
|
1.72(1.03-3.01)
|
0.043
|
10.01(1.82-20.14)
|
0.008
|
Magnesium, <0.8/≥0.8mmol/L
|
0.70(0.38-1.25)
|
0.212
|
2.1(0.02-4.24)
|
0.751
|
Kalium, <4.5/≥4.5mmol/L
|
1.84(1.01-3.23)
|
0.044
|
3.72(1.65-8.62)
|
0.003
|
Natrium, <141/≥141mmol/L
|
0.57(0.36-0.89)
|
0.014
|
0.99(0.87-1.15)
|
0.860
|
Chlorine, <102/≥102mmol/L
|
0.46(0.29-0.73)
|
<0.001
|
0.93(0.84-1.02)
|
0.151
|
TT, <20/≥20second
|
0.46(0.22-0.95)
|
0.035
|
0.75(0.59-0.96)
|
0.025
|
FIB, <2.8/≥2.8g/L
|
2.10(1.34-3.37)
|
0.002
|
1.81(1.40-2.34)
|
<0.001
|
APTT, <25.7/≥25.7second
|
0.59(0.37-0.92)
|
0.020
|
1.01(0.93-1.15)
|
0.960
|
PT, <11.3/≥11.3second
|
1.52(0.94-2.57)
|
0.092
|
1.00(0.76-1.41)
|
0.933
|
Tumor size,
<5/≥5&<10/≥10centimiter
|
3.82(2.12-6.84)
|
<0.001
|
1.22 (1.14-1.35)
|
<0.001
|
Tumor number, single/multiple
|
0.62(0.20-12.0)
|
0.415
|
1.55(0.55-4.36)
|
0.408
|
Satellite nodules, yes/no
|
1.72(1.13-2.61)
|
0.022
|
1.2 (0.69-2.1)
|
0.525
|
MVI, M0/M1/M2
|
2.60(1.51-4.45)
|
<0.001
|
2.20(1.61-3.05)
|
<0.001
|
Tumor capsule, yes/no
|
0.87(0.67-1.15)
|
0.308
|
0.62(0.20-2.01)
|
0.415
|
Cirrhosis, yes/no
|
0.77(0.46-1.32)
|
0.313
|
0.54(0.25-1.15)
|
0.107
|
Multivariate analysis
|
|
|
|
|
Neutrophil
|
0.34(0.19-0.60)
|
<0.001
|
|
|
ALP
|
4.41(2.05-9.62)
|
<0.001
|
-
|
-
|
Urea
|
0.46(0.26-0.80)
|
0.007
|
-
|
-
|
LDL
|
2.15(1.34-3.67)
|
0.003
|
-
|
-
|
Apo-A1
|
0.32(0.16-0.66)
|
0.002
|
-
|
-
|
TT
|
0.34(0.16-0.70)
|
0.003
|
0.92(0.87-0.97)
|
0.003
|
Tumor size
|
2.20(1.29-3.82)
|
0.008
|
-
|
-
|
MVI grade
|
2.31(1.25-4.16)
|
0.009
|
0.80(0.64-0.99)
|
0.023
|
MCH
|
-
|
-
|
0.67(0.54-0.83)
|
<0.001
|
Monocyte
|
-
|
-
|
4.67(2.37-9.68)
|
<0.001
|
PAB
|
-
|
-
|
0.56(0.38-0.84)
|
0.005
|
AFU
|
-
|
-
|
0.71(0.61-0.82)
|
<0.001
|
BCLC staging system, Barcelona Clinic Liver Cancer staging system; WBC, white blood cell; PLT, platelet; Hb, hemoglobin; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; LR, lymphocyte ratio; NR, neutrophil ratio; MR, monocyte ratio; RDW, red blood cell distribution width; MPC, Mean platelet volume; RBC, red blood cell; AFP, α-fetoprotein; ALT, alanine aminotransferase; HBV DNA level, hepatitis B virus deoxyribonucleic acid level; Scr, Serum creatinine; γ-GTT, γ-glutamyl transpeptidase; ALP, alkaline phophatase; TBil, total bilirubin; DBil, direct bilirubin; IBil, indirect bilirubin; TBA, total bile acid; TP, total protein; ALB, albumin; GLB, globumin; PAB, prealbumin; AFU, α-fucosidase; ADA, adenosine deaminase; LDH, lactate dehydrogenase; GLU, Glucose; TCHO, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Apo-A1, apolipoprotein A1; Apo-B, apolipoprotein B; TT, thrombin time; FIB, fibrinogen; APTT, activated partial thromboplastin time; PT, prothrombin time; MVI, microvascular invasion.
Table 3. The C-index of the nomograms and classical staging systems
Prognostic system
|
Training cohort
|
Internal validation cohort
|
External validation cohort
|
DFS
|
OS
|
DFS
|
OS
|
DFS
|
OS
|
C-index
|
95%CI
|
C-index
|
95%CI
|
C-index
|
95%CI
|
C-index
|
95%CI
|
C-index
|
95%CI
|
C-index
|
95%CI
|
Nomograms
|
0.775
|
0.720-0.830
|
0.812
|
0.732-0.892
|
0.865
|
0.806-0.924
|
0.839
|
0.675-1.00
|
0.957
|
0.763-0.951
|
0.842
|
0.708-0.970
|
AJCC
|
0.591
|
0.558-0.628
|
0.588
|
0.546-0.611
|
0.622
|
0.581-0.662
|
0.615
|
0.572-0.649
|
0.586
|
0.544-0.607
|
0.578
|
0.533-0.599
|
BCLC
|
0.601
|
0.563-0.648
|
0.599
|
0.550-0.641
|
0.602
|
0.568-0.651
|
0.608
|
0.575-0.655
|
0.574
|
0.534-0.622
|
0.571
|
0.530-0.619
|
JIS
|
0.589
|
0.543-0.632
|
0.592
|
0.548-0.637
|
0.606
|
0.552-0.639
|
0.599
|
0.554-0.643
|
0.581
|
0.535-0.622
|
0.574
|
0.528-0.616
|
HKLC
|
0.595
|
0.562-0.629
|
0.612
|
0.568-0.632
|
0.625
|
0.581-0.649
|
0.619
|
0.577-0.638
|
0.558
|
0.528-0.580
|
0.541
|
0.512-0.568
|
C-index, concordance index; DFS, disease-free survival; OS, overall survival; CI, confidence interval; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer staging system; JIS, the Japan Integrated Staging Score; HKLC, the Hong Kong Liver Cancer prognostic classification scheme.