A Powerful Nomogram Based on the Novel D-Index to Predict Prognosis After Surgical Resection of Hepatocellular Carcinoma

Figures & data

Table 1 Baseline Characteristics of the Study Participants in the Training and Validation Cohorts

Variables	Training Set N = 277	Validation Set N = 119	P-value
Continuous variables
Age (years)	58.0 (49.0, 64.0)	57.0 (49.0, 65.0)	0.696
BMI (kg/m2)	22.8 (20.4, 24.6)	22.3 (20.8, 24.4)	0.627
Tumor size (cm)	4.0 (2.5, 6.0)	3.5 (2.2, 5.0)	0.462
Preoperative prothrombin time (s)	13.8 (13.3, 14.6)	14.0 (13.3, 14.8)	0.378
Fibrinogen (g/L)	2.9 (2.4, 3.6)	2.8 (2.4, 3.5)	0.843
Neutrophil (×10^9/L)	3.1 (2.3, 4.1)	3.2 (2.3, 4.2)	0.992
Monocyte (×10^9/L)	0.5 (0.3, 0.6)	0.4 (0.3, 0.6)	0.449
Lymphocyte (×10^9/L)	1.4 (1.0, 1.7)	1.4 (1.0, 1.8)	0.970
Platelet count (×10^9/L)	139.0 (96.0, 191.0)	138.0 (92.0, 173.0)	0.704
Albumin (g/L)	39.9 (36.4, 43.0)	38.8 (36.2, 42.6)	0.351
TBIL (μmol/L)	11.0 (8.0, 15.0)	11.0 (8.0, 17.0)	0.364
TC (mmol/L)	4.3 (3.6, 5.0)	4.3 (3.5, 5.1)	0.525
ALT (U/L)	37.0 (28.0, 57.0)	38.0 (28.0, 54.0)	0.640
AST (U/L)	34.0 (25.0, 52.0)	36.0 (23.0, 45.0)	0.593
γ-GT (U/L)	57.0 (34.0, 106.0)	50.0 (32.0, 131.0)	0.733
RFM	0.7 (0.4, 1.1)	0.6 (0.3, 1.0)	0.151
Discrete variables
Sex			0.410
Male	235 (84.8)	97 (81.5)
Female	42 (15.2)	22 (18.5)
Drink			0.628
No	158 (57.0)	71 (59.7)
Yes	119 (43.0)	48 (40.3)
Lymph node metastasis			0.880
No	270 (97.5)	117 (98.3)
Yes	7 (2.5)	2 (1.7)
Tumor stage			0.852
Grade 1/2	205 (74.0)	87 (73.1)
Grade 3/4	72 (26.0)	32 (26.9)
Peri-cancerous invasion			1.000
No	268 (96.8)	115 (96.6)
Yes	9 (3.2)	4 (3.4)
Intrahepatic metastasis			1.000
No	274 (98.9)	117 (98.3)
Yes	3 (1.1)	2 (1.7)
Capsule			0.709
No	212 (76.5)	89 (74.8)
Yes	65 (23.5)	30 (25.2)
Satellite nodules			0.817
No	259 (93.5)	112 (94.1)
Yes	18 (6.5)	7 (5.9)
Single/multiple			0.504
No	240 (86.6)	106 (89.1)
Yes	37 (13.4)	13 (10.9)
Portal vein tumor thrombus			0.319
No	265 (95.7)	111 (93.3)
Yes	12 (4.3)	8 (6.7)
Vascular invasion			0.842
No	252 (91.0)	109 (91.6)
Yes	25 (9.0)	10 (8.4)
Adjacent invasion			0.716
No	263 (94.9)	114 (95.8)
Yes	14 (5.1)	5 (4.2)
Liver cirrhosis			0.746
No	86 (31.0)	35 (29.4)
Yes	191 (69.0)	84 (70.6)
Ascites			0.819
No	233 (84.1)	99 (83.2)
Yes	44 (15.9)	20 (16.8)
HBsAg			0.839
Negative	56 (20.2)	23 (19.3)
Positive	221 (79.8)	96 (80.7)
AFP, µg/L			0.067
< 400	217 (78.3)	83 (69.7)
≥ 400	60 (21.7)	36 (30.3)
TNM stage			0.897
I	214 (77.3)	96 (80.7)
II	25 (9.0)	8 (6.7)
IIIa	21 (7.6)	8 (6.7)
IIIb	8 (2.9)	5 (4.2)
IIIc	7 (2.5)	2 (1.7)
IV	2 (0.7)	0 (0.0)
Child–Pugh class			0.868
A	194 (70.0)	82 (68.9)
B	82 (29.6)	37 (31.1)
C	1 (0.4)	0 (0.0)
CLIP score			0.398
0	121 (43.7)	44 (37.0)
1	85 (30.7)	43 (36.1)
2	40 (14.4)	13 (10.9)
3	24 (8.7)	14 (11.8)
4	6 (2.2)	5 (4.2)
5	1 (0.4)	0 (0.0)
Okuda stage			0.475
I	219 (79.1)	90 (75.6)
II	56 (20.2)	29 (24.4)
III	2 (0.7)	0 (0.0)
BCLC stage			0.800
A	231 (83.4)	104 (87.4)
B	10 (3.6)	3 (2.5)
C	34 (12.3)	12 (10.1)
D	2 (0.7)	0 (0.0)
D-index			0.772
< 37.9	102 (36.8)	42 (35.3)
≥ 37.9	175 (63.2)	77 (64.7)
1-year survival probability (n, %)	245 (88.4)	99 (83.2)	0.156
3-year survival probability (n, %)	196 (70.8)	80 (67.2)	0.483
5-year survival probability (n, %)	156 (56.3)	70 (58.8)	0.644

Note: D-index was calculated using TBIL, tumor size, and RFM using the formula TBIL × TS/RFM^0.5.

Abbreviations: BMI, body mass index; TBIL, total bilirubin; TC, total cholesterol; ALT, alanine transaminase; AST, aspartate transaminase; γ-GT, γ-glutamyl transpeptidase; RFM, the ratio of fat area and muscle area; AFP, alpha-fetoprotein; HBsAg, hepatitis B surface antigen; TNM, Tumor, Node, Metastasis classification; CLIP, Cancer of the Liver Italian Program; BCLC, Barcelona Clinic Liver Cancer.

Table 2 Univariate and Multivariable Cox Proportional Hazard Analyses of the Training Cohort

Variables	Univariate		Multivariate
	HR (95% CI)	P-value	AHR (95% CI)	P-value
Statistically significant factors
Preoperative prothrombin time (s)	1.373 (1.199, 1.571)	<0.001	1.268 (1.057, 1.522)	0.010
Albumin (g/L)	0.938 (0.908, 0.969)	<0.001	0.991 (0.952, 1.032)	0.659
AST (U/L)	1.002 (1.001, 1.004)	<0.001	1.002 (1.000, 1.004)	0.011
Capsule	1.501 (1.009, 2.233)	0.045	1.026 (0.665, 1.582)	0.909
Satellite nodules	2.902 (1.628, 5.173)	<0.001	1.376 (0.672, 2.817)	0.383
Single/multiple	2.030 (1.297, 3.178)	0.002	1.405 (0.842, 2.344)	0.193
Portal vein tumor thrombus	9.758 (5.122, 18.592)	<0.001	4.259 (1.547, 11.729)	0.005
Vascular invasion	3.758 (2.287, 6.174)	<0.001	1.244 (0.544, 2.844)	0.605
Adjacent invasion	3.899 (2.136, 7.118)	<0.001	2.370 (1.170, 4.800)	0.017
Ascites	1.938 (1.254, 2.994)	0.003	1.059 (0.646, 1.737)	0.819
D-index	4.863 (2.910, 8.126)	<0.001	3.262 (1.903, 5.592)	<0.001
Statistically nonsignificant factors
Age (years)	0.998 (0.983, 1.013)	0.790
BMI (kg/m2)	0.954 (0.897, 1.015)	0.139
Fibrinogen (g/L)	1.093 (0.918, 1.303)	0.318
Neutrophil (×10^9/L)	1.058 (0.995, 1.125)	0.073
Monocyte (×10^9/L)	1.877 (0.908, 3.881)	0.089
Lymphocyte (×10^9/L)	0.783 (0.572, 1.071)	0.126
Platelet count (×10^9/L)	0.998 (0.995, 1.001)	0.228
TC (mmol/L)	0.896 (0.758, 1.059)	0.196
ALT (U/L)	1.003 (1.000, 1.006)	0.086
γ-GT (U/L)	1.000 (1.000, 1.001)	0.431
Sex	0.862 (0.509, 1.458)	0.580
Drink	0.949 (0.661, 1.361)	0.775
Lymph node metastasis	2.139 (0.789, 5.796)	0.135
Tumor stage	1.296 (0.874, 1.919)	0.197
Peri-cancerous invasion	1.769 (0.722, 4.331)	0.212
Intrahepatic metastasis	0.728 (0.102, 5.205)	0.752
Liver cirrhosis	1.269 (0.847, 1.901)	0.247
HBsAg	1.143 (0.720, 1.815)	0.570
AFP (µg/L)	1.262 (0.835, 1.906)	0.270

Note: D-index was calculated using TBIL, tumor size, and RFM using the formula TBIL × TS/RFM^0.5.

Abbreviations: CI, confidence interval; AST, aspartate transaminase; BMI, body mass index; TC, total cholesterol; ALT, alanine transaminase; γ-GT, γ-glutamyl transpeptidase; HBsAg, hepatitis B surface antigen; AFP, alpha-fetoprotein.

Figure 1 Nomogram of the D-index for predicting the overall survival after curative resection of PHCC. The scores of each variable were added to obtain the total score, and a vertical line was drawn on the total score to obtain the corresponding survival probability.

Abbreviations: PHCC, primary hepatocellular carcinoma; PVT, portal vein tumor thrombus; AI, adjacent infiltration; PT prothrombin time; AST, aspartate transaminase.

Figure 2 Results of using X-tile analysis by total risk score calculated by the nomogram scoring system in the training cohort.

Figure 3 Survival curves stratified by total risk score (low risk: < 69.2; medium risk: 69.2–119.9; and high risk: ≥ 119.9) in the validation cohort.

Figure 4 Calibration curves for predicting the overall survival rate by nomogram scoring system in the training and validation cohorts. Calibration curves of the prognostic nomogram for (A) 1-year overall survival, (B) 3-year overall survival, and (C) 5-year overall survival in the training set, and calibration curves for (D) 1-year overall survival, (E) 3-year overall survival, and (F) 5-year overall survival in the validation set.

Figure 5 ROC curve of the D-index, prognostic nomogram, CLIP, TNM, Child–Pugh, BCLC, Okuda system, and combined group in the training cohort. ROC curve for (A) 1-year survival, (B) 3-year survival, and (C) 5-year survival. The combined group included the CLIP, TNM, Child–Pugh, BCLC, and Okuda.

Abbreviations: CLIP, Cancer of the Liver Italian Program; TNM, Tumor, Node, Metastasis classification; BCLC, Barcelona Clinic Liver Cancer; ROC, receiver operating characteristic.

Figure 6 DCA curve of the D-index, TNM, BCLC, Okuda, CLIP, and prognostic nomogram in the training cohort. The horizontal axis represents the threshold value, which is the reference probability of whether a patient receives treatment, and the vertical axis represents the net benefit rate after the advantages minus the disadvantages. Under the same threshold probability, the larger net benefit implies that patients can obtain the maximum benefit using the diagnosis of this model. The closer the curve in the DCA graph to the top, the higher the value of the model diagnosis.

Abbreviations: DCA, decision curve analysis; TNM, Tumor, Node, Metastasis classification; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program.