Development and Validation of Novel Models Including Tumor Micronecrosis for Predicting the Postoperative Survival of Patients with Hepatocellular Carcinoma

Figures & data

Table 1 Baseline Characteristics of the Training and Validation Cohorts

Variables	Training Cohort n (%)	Validation Cohort n (%)	P value
Sample size	n=536	n=229
Age, years			0.271
≤60	334(62.3)	133(58.1)
>60	202(37.7)	96(41.9)
Sex			0.748
Male	436(81.3)	184(80.3)
Female	100(18.7)	45(19.7)
HBsAg			0.781
Negative	91(17.0)	37(16.2)
Positive	445(83.0)	192(83.8)
MVI			0.924
Negative	388(72.4)	165(72.1)
Positive	148(27.6)	64(27.9)
Tumor micronecrosis			0.168
0	307(57.3)	118(51.5)
1	155(28.9)	82(35.8)
2	74(13.8)	29(12.7)
Cirrhosis			0.501
No	95(17.7)	36(15.7)
Yes	441(82.3)	193(84.3)
Tumor number			0.113
1	480(89.6)	203(88.6)
2	46(8.6)	16(7.0)
≥3	10(1.9)	10(4.4)
Tumor size, cm			0.438
≤2	138(25.7)	50(21.8)
2–5	289(53.9)	134(58.5)
>5	109(20.3)	45(19.7)
AFP, ng/mL			0.292
≤20	242(45.1)	100(43.7)
20–400	187(34.9)	72(31.4)
>400	107(20.0)	57(24.9)
NLR			0.995
≤2	281(52.4)	120(52.4)
>2	255(47.6)	109(47.6)
PLT, 10^9/L			0.285
≥100	402(75.0)	180(78.6)
<100	134(25.0)	49(21.4)
ALBI grade			0.428
1	401(74.8)	176(76.9)
2	133(24.8)	53(23.1)
3	2(0.4)	0(0.0)
PT, second			0.991
≤13.5	494(92.2)	211(92.1)
>13.5	42(7.8)	18(7.9)

Abbreviations: MVI, microvascular invasion; AFP, alpha-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; PLT, platelet count; ALBI, albumin-bilirubin; PT, prothrombin time.

Table 2 Univariate and Multivariate Analyses for RFS and OS in the Training Cohort

Variables	RFS				OS
	Univariate		Multivariate		Univariate		Multivariate
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Age, years		0.143				0.038		0.132
≤60	ref				ref		ref
>60	1.20(0.94–1.52)				1.54(1.03–2.31)		1.37(0.91–2.07)
Sex		0.203				0.747
Male	ref				ref
Female	0.81(0.59–1.12)				1.09(0.64–1.87)
HBsAg		0.778				0.171
Negative	ref				ref
Positive	0.96(0.69–1.31)				0.71(0.43–1.16)
MVI		0.01		0.285		0.039		0.643
Negative	ref		ref		ref		ref
Positive	1.40(1.08–1.80)		1.16(0.89–1.52)		1.56(1.02–2.38)		1.11(0.71–1.74)
Tumor micronecrosis		<0.001		0.035		<0.001		<0.001
0	ref		ref		ref		ref
1	1.30(1.00–1.70)		1.10(0.84–1.45)		1.85(1.13–3.05)		1.57(0.94–2.63)
2	2.06(1.49–2.86)		1.57(1.12–2.21)		4.83(2.96–7.90)		3.37(2.03–5.61)
Cirrhosis		0.061				0.117
No	ref				ref
Yes	1.38(0.99–1.94)				1.65(0.88–3.10)
Tumor number		0.027		0.014		0.140
1	ref		ref		ref
2	1.35(0.92–1.98)		1.14(0.77–1.68)		1.74(0.95–3.19)
≥3	2.81(1.32–5.98)		3.09(1.44–6.63)		2.15(0.68–6.83)
Tumor size, cm		<0.001		<0.001		<0.001		<0.001
≤2	ref		ref		ref		ref
2–5	1.69(1.22–2.35)		1.66(1.19–2.31)		3.28(1.48–7.25)		2.82(1.27–6.28)
>5	3.58(2.49–5.15)		3.03(2.04–4.50)		8.09(3.62–18.09)		5.98(2.59–13.8)
AFP, ng/mL		0.493				0.162
≤20	ref				ref
20–400	0.90(0.69–1.17)				1.24(0.77–1.98)
>400	1.09(0.80–1.49)				1.65(0.99–2.77)
NLR		0.725				0.158
≤2	ref				ref
>2	0.96(0.76–1.21)				1.34(0.89–2.02)
PLT, 10^9/L		0.677				0.527
≥100	ref				ref
<100	0.95(0.72–1.23)				0.86(0.53–1.39)
ALBI grade		0.026		0.033		0.002		0.043
1	ref		ref		ref		ref
2	1.42(1.10–1.84)		1.41(1.09–1.83)		2.09(1.38–3.16)		1.76(1.13–2.73)
3	–		–		–		–
PT, second		0.063				0.008		0.006
≤13.5	ref				ref		ref
>13.5	1.47(0.98–2.20)				2.21(1.23–3.97)		2.43(1.29–4.56)

Abbreviations: MVI, microvascular invasion; AFP, alpha-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; PLT, platelet count; ALBI, albumin-bilirubin; PT, prothrombin time; HR, hazard ratio; CI, confidence interval.

Figure 1 The recurrence-free survival (RFS) nomogram (A) and overall survival nomogram (OS) nomogram (B) for predicting postoperative recurrence and death in HCC patients.

Figure 2 The calibration curves for predicting the 1-, 3- and 5-year recurrence-free survival (RFS) in the training (A–C) and validation (D–F) cohorts.

Figure 3 The calibration curves for predicting the 1-, 3- and 5-year overall survival (OS) in the training (A–C) and validation (D–F) cohorts.

Figure 4 The receiver operating characteristics curves (AUROC) of 1-, 2-, 3-, 4- and 5-year recurrence-free survival (RFS) in the training (A) and validation (B) cohorts, and the AUROCs of 1-, 2-, 3-, 4- and 5-year overall survival (OS) in the training (C) and validation (D) cohorts.

Table 3 C-Indexes of Different Prognostic Models for RFS and OS in the Training and Validation Cohorts

Model	Training Cohort	P value	Validation Cohort	P value
	C Index (95% CI)		C Index (95% CI)
Part I: RFS
Our model	0.66(0.62–0.69)	NA	0.66(0.62–0.71)	NA
TNM stage	0.61(0.58–0.64)	<0.001	0.62(0.57–0.66)	0.029
BCLC stage	0.58(0.56–0.61)	<0.001	0.59(0.55–0.62)	<0.001
CUPI score	0.52(0.49–0.55)	<0.001	0.53(0.48–0.57)	<0.001
HKLC stage	0.59(0.56–0.62)	<0.001	0.58(0.54–0.62)	<0.001
JIS score	0.57(0.55–0.60)	<0.001	0.58(0.55–0.62)	<0.001
Tokyo score	0.60(0.57–0.63)	<0.001	0.61(0.56–0.65)	0.012
CLIP score	0.55(0.52–0.58)	<0.001	0.56(0.52–0.61)	0.001
Part II: OS
Our model	0.74(0.69–0.79)	NA	0.77(0.70–0.83)	NA
TNM stage	0.61(0.56–0.67)	<0.001	0.64(0.57–0.71)	0.004
BCLC stage	0.61(0.57–0.65)	<0.001	0.61(0.56–0.66)	<0.001
CUPI score	0.53(0.48–0.58)	<0.001	0.58(0.51–0.66)	<0.001
HKLC stage	0.61(0.56–0.66)	<0.001	0.69(0.62–0.77)	0.038
JIS score	0.59(0.55–0.63)	<0.001	0.59(0.54–0.64)	<0.001
Tokyo score	0.62(0.57–0.68)	<0.001	0.71(0.65–0.78)	0.094
CLIP score	0.57(0.51–0.62)	<0.001	0.61(0.53–0.69)	0.002

Abbreviations: TNM, tumor node metastasis; BCLC, Barcelona Clinic Liver Cancer; CUPI, Chinese University Prognostic Index; HKLC, Hong Kong Liver Cancer; JIS, Japan Integrated Staging; CLIP, Cancer of the Liver Italian Program.

Figure 5 The time-dependent area under the receiver operating characteristic curves (td AUROC) of recurrence-free survival (RFS) nomogram and other staging systems (TNM, BCLC, CUPI, HKLC, JIS, Tokyo score and CLIP) since hepatic resection over time in the training (A) and validation (B) cohorts, and the td AUROCs of overall survival (OS) nomogram and other staging systems in the training (C) and validation (D) cohorts.

Data Sharing Statement

The datasets used during the current study are available from the corresponding authors on reasonable request.