Prognostic Value of Inflammation-Immunity-Nutrition Score and Inflammatory Burden Index for Hepatocellular Carcinoma Patients After Hepatectomy

Figures & data

Figure 1 Flowchart of patient enrollment.

Abbreviations: IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; CRP, C-reactive protein; ALB, albumin; LYM, lymphocyte; H, high; L, low; N, number.

Table 1 Characteristics of Enrolled Patients with Resectable Hepatocellular Carcinoma

Characteristics	Overall (n = 701)
Sex^a
Male	601(85.7)
Female	100(14.3)
Age(years)^a
<50	399(56.9)
≥50	302(43.1)
BCLC Stage^a
0-A	343(48.9)
B-C	358(51.1)
HBsAg^a
Negative	7(1.0)
Positive	694(99.0)
HBV-DNA (IU/mL)^a
<5×10^2	207(29.5)
≥5×10^2	494(70.5)
Liver cirrhosis^a
Negative	295(42.1)
Positive	406(57.9)
Tumor number^a
Single	488(69.6)
Multiple	213(30.4)
Tumor size (cm)^a
≤5	279(39.8)
>5	422(60.2)
Tumor capsule^a
Complete	685(97.7)
Incomplete	16(2.3)
AFP (ng/mL)^a
≤400	351(50.1)
>400	350(49.9)
MVI^a
Negative	317(45.2)
Positive	384(54.8)
Neu (×10^9/L)^b	3.61[2.73,4.70]
Lym (×10^9/L)^b	1.70[1.33, 2.12]
Plt (×10^9/L)^b	204.43[158, 264]
CRP (mg/L)^b	3.60[1.37,9.75]
Alb (g/L)^b	39.40[36.5,42.1]
IBI^b	6.44[2.36,24.47]
NLR^b	2.09[1.54,2.68]
PLR^b	118.37[85.37,166.30]
SII^b	427.30[263.66,675.27]
CAR^b	0.09[0.03,0.26]
PNI^b	48.19[43.95, 52.05]
IINS^a
0	276(39.4)
1	255(36.4)
2	124(17.7)
3	46(6.5)
PI^a
0	510(72.8)
1	174(24.8)
2	17(2.4)
GPS^a
0	468(66.8)
1	189(26.9)
2	44(6.3)
mGPS^a
0	534(76.2)
1	123(17.5)
2	44(6.3)

Notes: ^aCategorical variables are presented as number (percentage). ^bContinuous variables are presented as median[interquartile range].

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; HBsAg, hepatitis B surface antigen; HBV-DNA, hepatitis B virus DNA; AFP, alpha-fetoprotein; MVI, microvascular invasion; Neu, neutrophil; Lym, lymphocyte; Plt, platelet; CRP, C reactive protein; Alb, albumin; IBI, inflammatory burden index; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet- lymphocyte ratio; SII, systemic immune inflammation index; CAR, C-reactive protein/albumin ratio, PNI, prognostic nutritional index; IINS, inflammation-immunity-nutrition score; PI, prognostic index; GPS, Glasgow Prognostic Score; mGPS, modified Glasgow Prognostic Score.

Figure 2 Receiver operating characteristic curves of the following indices for overall survival in patients with hepatocellular carcinoma: (A) IINS, (B) IBI, (C) CAR, (D) PLR, (E) SII, (F) NLR, (G) PNI, (H) PI, (I) GPS, and (J) mGPS.

Abbreviations: IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; CAR, C-reactive protein/albumin ratio; PLR, platelet–lymphocyte ratio; SII, systemic immune inflammation index; NLR, neutrophil-to-lymphocyte ratio; PNI, prognostic nutritional index; PI prognostic index; GPS, Glasgow prognostic score; mGPS, modified Glasgow prognostic score; AUC, area under the curve; HCC, hepatocellular carcinoma.

Table 2 Optimal Cut-Off Values for Inflammatory and Nutritional Indicators

Variable	High	N%	Low	N%
IBI	>7.20	334(47.7)	≤7.20	367(52.3)
CAR	>0.12	281(40.0)	≤0.12	420(60.0)
PLR	>148.43	225(32.0)	≤148.43	476(68.0)
SII	>1038.54	87(12.4)	≤1038.54	614(87.6)
NLR	>2.58	223(31.8)	≤2.58	478(68.2)
PNI	>43.95	525(74.8)	≤43.95	176(25.2)

Abbreviations: IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; CAR, C-reactive protein/albumin ratio; PLR, platelet–lymphocyte ratio; SII, systemic immune inflammation index; NLR, neutrophil-to-lymphocyte ratio; PNI, prognostic nutritional index.

Table 3 Associations of IINS and IBI with Clinicopathological Characteristics in Patients with Hepatocellular Carcinoma

Variable	IINS					IBI
	0 (N = 276)	1 (N = 255)	2 (N = 124)	3 (N = 46)	P	Low (N = 367)	High (N = 334)	P
Sex					0.156			0.021
Male	228	226	105	42		304	297
Female	48	29	19	4		63	37
Age (years)					<0.001			0.866
≤50	181	142	53	23		210	189
>50	95	113	71	23		157	145
BCLC stage					<0.001			<0.001
0-A	183	105	40	15		233	110
B-C	93	150	84	31		134	224
HBsAg					0.634			0.613
Negative	3	4	0	0		3	4
Positive	273	251	124	46		364	330
HBV-DNA (IU/mL)					0.025			<0.001
<5×10^2	98	71	27	11		129	78
≥5×10^2	178	184	97	35		238	256
Liver cirrhosis					0.034			0.208
Negative	130	106	44	15		146	149
Positive	146	149	80	31		221	185
Tumor number					<0.001			0.001
Single	214	174	68	32		275	213
Multiple	62	81	56	14		92	121
Tumor size (cm)					<0.001			<0.001
≤5	149	98	29	3		213	66
>5	127	157	95	43		154	268
Tumor capsule					0.931			0.087
Complete	274	247	119	45		362	323
Incomplete	2	8	5	1		5	11
AFP (ng/mL)					0.033			0.045
≤400	153	126	56	16		197	154
>400	123	129	68	30		170	180
MVI					0.034			<0.001
Negative	138	118	44	17		191	126
Positive	138	137	80	29		176	208

Abbreviations: HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; HBsAg, hepatitis B surface antigen; HBV-DNA, hepatitis B virus DNA; AFP, alpha-fetoprotein; MVI, microvascular invasion; Neu, neutrophil; Lym, lymphocyte; IINS, inflammation-immunity-nutrition; IBI, inflammatory burden index.

Figure 3 Kaplan–Meier survival curves of HCC patients after hepatectomy, stratified by (A and B) inflammation-immunity-nutrition score (IINS) or (C and D) inflammatory burden index (IBI).

Table 4 Univariate Analysis to Identify Clinicopathological Characteristics Associated with Poor DFS and OS

Variable	Disease-Free Survival			Overall Survival
	HR	95CI%	P	HR	95CI%	P
Sex (M)	1.559	1.161–2.093	0.003	1.365	1.015–1.835	0.039
Age (>50 years)	1.100	0.913–1.324	0.317	1.057	0.869–1.284	0.580
HBsAg (Positive)	0.631	0.282–1.412	0.263	0.675	0.280–1.632	0.383
HBV-DNA (≥5×10^2 IU/mL)	1.368	1.107–1.691	0.004	1.452	1.158–1.820	0.001
Liver cirrhosis (Positive)	1.114	0.923–1.346	0.260	0.994	0.818–1.209	0.955
Tumor number (Multiple)	1.797	1.482–2.178	<0.001	1.557	1.272–1.906	<0.001
Tumor size (>5cm)	1.921	1.573–2.344	<0.001	2.316	1.864–2.876	<0.001
Tumor capsule (Incomplete)	1.281	0.704–2.332	0.417	1.561	0.857*2.844	0.146
AFP (>400 ng/mL)	1.431	1.188–1.723	<0.001	1.455	1.198–1.768	<0.001
MVI (Positive)	1.873	1.546–2.270	<0.001	2.077	1.696–2.544	<0.001
IINS
1	1.554	1.239–1.949	<0.001	2.344	1.827–3.007	<0.001
2	2.727	2.110–3.525	<0.001	4.118	3.109–5.456	<0.001
3	4.051	2.811–5.838	<0.001	7.023	4.900–10.067	<0.001
IBI (H)	1.960	1.624–2.366	<0.001	2.799	2.288–3.425	<0.001

Abbreviations: DFS, disease-free survival; OS, overall survival; M, male; HBsAg, hepatitis B surface antigen; HBV-DNA, hepatitis B virus DNA; AFP, alpha-fetoprotein; MVI, microvascular invasion; IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; H, high.

Table 5 Multivariate Analysis of the Three Models to Predict DFS and OS

Variable	Model1			Model2			Model3
	HR	95CI%	P	HR	95CI%	P	HR	95CI%	P
Model for disease-free Survival
Sex (M)	1.485	1.099–2.005	0.010	1.522	1.128–2.053	0.006	1.478	1.094–1.997	0.011
Tumor number (Multiple)	1.506	1.236–1.835	<0.001	1.530	1.257–1.862	<0.001	1.505	1.235–1.833	<0.001
Tumor size (>5cm)	1.493	1.212–1.839	<0.001	1.511	1.219–1.871	<0.001	1.454	1.170–1.807	0.001
AFP (>400 ng/mL)	1.346	1.113–1.628	0.002	1.361	1.125–1.646	0.001	1.350	1.116–1.634	0.002
MVI (Positive)	1.593	1.309–1.939	<0.001	1.569	1.290–1.908	<0.001	1.586	1.304–1.930	<0.001
IINS
1	1.370	1.088–1.724	0.006				1.318	1.029–1.687	0.028
2	2.170	1.666–2.827	<0.001				2.034	1.503–2.754	<0.001
3	3.064	2.098–4.475	<0.001				2.843	1.877–4.306	<0.001
IBI (H)				1.524	1.245–1.865	<0.001	1.111	0.873–1.413	0.391
Model for Overall Survival
Tumor number (Multiple)	1.231	1.001–1.513	0.048	1.327	1.081–1.629	0.007	1.236	1.005–1.519	0.044
Tumor size (>5cm)	1.625	1.296–2.037	<0.001	1.580	1.252–1.993	<0.001	1.496	1.181–1.895	0.001
AFP (>400 ng/mL)	1.321	1.081–1.614	0.006	1.348	1.104–1.647	0.003	1.334	1.091–1.630	0.005
MVI (Positive)	1.804	1.466–2.221	<0.001	1.750	1.424–2.151	<0.001	1.789	1.454–2.202	<0.001
IINS
1	2.081	1.615–2.680	<0.001				1.848	1.406–2.430	<0.001
2	3.328	2.493–4.443	<0.001				2.752	1.979–3.827	<0.001
3	5.118	3.519–7.443	<0.001				4.116	2.718–6.232	<0.001
IBI (H)				2.173	1.750–2.699	<0.001	1.361	1.052–1.761	0.019

Notes: Model 1, prognostic model based on IINS; Model 2, prognostic model based on IBI; Model 3, prognostic model based on IINS and IBI.

Abbreviations: DFS, disease-free survival; OS, overall survival; M, male; AFP, alpha-fetoprotein; MVI, microvascular invasion; IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; H, high.

Figure 4 Model 1 for predicting OS of HCC patients after hepatectomy. (A) Nomogram of the model. (B–D) Calibration curves for OS at (B) 1 year, (C) 3 years and (D) 5 years. The light gray line indicates the ideal, where predictions match observations. The red dots were calculated by bootstrapping (1000 resamplings) and describe the performance of the nomogram: the closer the solid red line is to the light gray line, the more accurately the model predicts survival.

Note: Model 1, prognostic model based on IINS.

Abbreviations: IINS, inflammation-immunity-nutrition score; MVI, microvascular invasion; AFP, alpha-fetoprotein; OS, overall survival.

Figure 5 Model 2 for predicting OS of HCC patients after hepatectomy. (A) Nomogram of the model. (B–D) Calibration curves for OS at (B) 1 year, (C) 3 years and (D) 5 years.

Note: Model 2, prognostic model based on IBI.

Abbreviations: IBI, inflammation-immunity-nutrition score; MVI, microvascular invasion; AFP, alpha-fetoprotein; OS, overall survival.

Figure 6 Model 3 to predict OS of HCC patients after hepatectomy. (A) Nomogram of the model. (B–D) Calibration curves for OS at (B) 1 year, (C) 3 years and (D) 5 years.

Note: Model 3, prognostic model based on IINS and IBI.

Abbreviations: IBI, inflammation-immunity-nutrition score; IINS, inflammation-immunity-nutrition score; MVI, microvascular invasion; AFP, alpha-fetoprotein; OS, overall survival.

Table 6 Comparison of Concordance Indices for Different Models to Predict Disease-Free Survival and Overall Survival

Model	Disease-Free Survival					Overall Survival
	C-Index (95% CI)	NRI	P	IDI	P	C-Index (95% CI)	NRI	P	IDI	P
Model 1^a	0.692 (0.665–0.719)					0.717 (0.692–0.742)
Model 2	0.677 (0.652–0.702)	−0.059	0.013	−0.020	<0.001	0.701 (0.676–0.726)	−0.176	<0.001	−0.046	<0.001
Model 3	0.692 (0.665–0.719)	0	0.998	0	0.925	0.722 (0.698–0.746)	0.023	0.225	0.005	0.078
BCLC stage	0.628 (0.603–0.653)	−0.205	<0.001	−0.088	<0.001	0.645 (0.619–0.670)	−0.324	<0.001	−0.116	<0.001
AJCC TNM (8th)	0.613 (0.588–0.638)	−0.225	<0.001	−0.105	<0.001	0.611 (0.583–0.366)	−0.332	<0.001	−0.156	<0.001
Model 2^b
Model 3		0.059	0.013	0.020	<0.001		0.198	<0.001	0.050	<0.001
BCLC stage		−0.145	<0.001	−0.068	<0.001		−0.245	<0.001	−0.070	<0.001
AJCC TNM (8th)		−0.166	<0.001	−0.063	<0.001		−0.273	<0.001	−0.110	<0.001
Model 3^c
BCLC stage		−0.205	<0.001	−0.088	<0.001		−0.346	<0.001	−0.120	<0.001
AJCC TNM (8th)		−0.225	<0.001	−0.083	<0.001		−0.355	<0.001	−0.161	<0.001

Notes: ^aComparison of NRI and IDI values between the Model 1 and other models; ^bComparison of NRI and IDI values between the Model 2 and other models; ^cComparison of NRI and IDI values between the Model 3 and other models; Model 1, prognostic model based on IINS; Model 2, prognostic model based on IBI; Model 3, prognostic model based on IINS and IBI.

Abbreviations: IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; BCLC, Barcelona Clinic Liver Cancer; AJCC TNM, American Joint Committee on Cancer/Tumor-Node-Metastasis; NRI, net reclassification index; IDI, integrated discrimination improvement.

Figure 7 Comparison of models and traditional clinical staging systems for predicting prognosis. (A and B) Decision curve analysis (DCA) of nomogram models. The horizontal solid black line represents the hypothesis that no patients reached the endpoint, and the solid pink line represents the hypothesis that all patients met the endpoint. Model 1 showed the highest area under the curve and emerged as the optimal decision-making tool for maximal net benefit in HCC patients after hepatectomy. (C) Time-dependent C -index. (D) Time-dependent AUCs. The red nodes represent C-index or AUC values of Model 1 for 1 year, 3 years and 5 years.

Notes: Model 1, prognostic model based on IINS; Model 2, prognostic model based on IBI; Model 3, prognostic model based on IINS and IBI.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; AJCC TNM, American Joint Committee on Cancer/Tumor-Node-Metastasis; AUC, area under the curve; IINS, inflammation-immunity-nutrition score; IBI, inflammatory burden index; OS, overall survival.