A Systemic Inflammation Response Score for Prognostic Prediction in Hepatocellular Carcinoma Patients After Hepatectomy

Figures & data

Table 1 Baseline Clinicopathological Characteristics of the Patients

Variables	Median (Range) or Number (Proportion, %)				P value
		Total Cohort (n=1001)	Training Cohort (n =751)	Validation Cohort (n =250)
Age, years		55.8 ± 11. 9	55.8 ± 11. 8	56.0 ± 12.2	0.906
Gender (male/female, %)		859 (85.8)/142 (14.2)	649 (86.4)/102 (13.6)	210 (84.0)/40 (16.0)	0.398
HBsAg (±, %)	Unknown	726 (72.5)/170 (17.0)/105 (10.5)	550 (73.2)/125 (16.6)/76 (10.1)	176 (70.4)/45 (18.0)/29 (11.6)	0.612
HCV-Ab (±, %)	Unknown	23 (2.3)/873 (87.2)/105 (10.5)	15 (2.0)/660 (87.9)/76 (10.1)	8 (3.2)/213 (85.2)/29 (11.6)	0.371
Child-Pugh classifications (A/B/C, %)		991 (90.0)/10 (10.0)/0 (0)	745 (99.2)/6 (0.8)/0 (0)	246 (98.4)/4 (1.6)/0 (0)	0.278
PLT (x10^9/L)		200.1 ± 72.9	147.8 ± 15.8	148.4 ± 15.5	0.352
ALB (g/L)		43.7 ± 3.2	43.6 ± 3.2	43.8 ± 3.3	0.622
HGB (g/L)		148.0 ± 15.7	147.8 ± 15.8	148.4 ± 15.5	0.352
WBC (109/L)		6.0 ± 1.7	6.0 ± 1.7	6.1 ± 1.7	0.307
NE (109/L)		3.5 ± 1.3	3.5 ± 1.3	3.6 ± 1.4	0.129
LYM (109/L)		1.8 ± 0.6	1.9 ± 0.6	1.8 ± 0.6	0.391
MONO (109/L)		0.4 ± 0.2	0.4 ± 0.2	0.4 ± 0.2	0.765
ALT (U/L)		39.7 ± 29.9	39.2 ± 29.5	41.3 ± 30.8	0.790
AST (U/L)		36.7 ± 25.9	36.6 ± 26.2	36.9 ± 25.0	0.525
TBIL (umol/L)		13.8 ± 11.4	13.9 ± 12.8	13.3 ± 5.3	0.757
PT (s)		11.9 ± 0.8	11.9 ± 0.8	11.9 ± 0.8	0.840
APTT (s)		27.2 ± 3.7	27.3 ± 3.8	26.9 ± 3.3	0.382
NLR (<1.30/≥1.30)		199 (19.9)/802 (80.1)	155 (20.6)/596 (79.4)	44 (17.6)/206 (82.4)	0.341
PLR (<106.03/≥106.03)		504 (50.3)/497 (49.7)	381 (50.7)/370 (49.3)	123 (49.2)/127 (50.8)	0.729
M×C (<1.92/≥1.92)		779 (77.8)/222 (22.2)	585 (77.9)/166 (22.1)	194 (77.6)/56 (22.4)	0.992
CEA (5 ng/mL)		4.1 ± 30.7	4.5 ± 35.4	2.8 ± 1.8	0.156
DCP (40mAU/mL)		5030.7 ± 14,250.4	5141.6 ± 14,290.2	4697.3 ± 14,153.5	0.758
AFP (25 ng/mL)		6202.8 ± 20,385.6	6191.7 ± 20,239.5	6236.0 ± 20,859.5	0.353
CA19-9 (35 U/mL)		27.8 ± 36.7	27.5 ± 37.5	28.7 ± 34.1	0.828
CEA (<5 ng/mL/≥5 ng/mL)		876 (87.5)/125 (12.5)	652 (86.8)/99 (13.2)	224 (89.6)/26 (10.4)	0.297
DCP (<40mAU/mL/≥40mAU/mL)		213 (21.3)/718 (71.7)	164 (21.8)/587 (78.2)	49 (19.6)/201 (80.4)	0.510
AFP (<25 ng/≥25 ng)		449 (44.9)/551 (55.1)	333 (44.3)/418 (55.7)	116 (46.4)/134 (53.6)	0.622
CA19-9 (<35 U/mL/≥35 U/mL)	Unknown	726 (72.5)/229 (22.9)/46 (4.6)	538 (71.6)/174 (23.2)/39 (5.2)	188 (75.2)/55 (22.0)/7 (2.8)	0.630
Tumor size (<5.0cm/≥5.0 cm, %)		651 (65.0)/350 (35.0)	488 (65.0)/263 (35.0)	163 (65.2)/87 (34.8)	1.000
Tumor numbers (one/two/more/than two, %)		493 (49.3)/176 (17.6)/332 (33.2)	372 (49.5)/124 (16.5)/255 (34.0)	121 (48.4)/52 (20.8)/77 (30.8)	0.276
Presence vascular invasion (±, %)		26 (2.5)/975 (97.4)	17 (2.3)/734 (97.7)	9 (3.6)/241 (96.4)	0.357
Barcelona Clinic Liver Cancer staging (A/B/C, %)		561 (56.0)/376 (37.6)/64 (6.4)	419 (55.8)/285 (37.9)/47 (6.3)	142 (56.8)/91 (36.4)/17 (6.8)	0.887
Tumor differentiation (High/Medium/Low, %)	Unknown	32 (3.2)/490 (49.0)/428 (42.8)/51 (5.1)	25 (3.3)/368 (49.0)/325 (43.3)/33 (4.4)	7 (2.8)/122 (48.8)/103 (41.2)/18 (7.2)	0.904
ALBI grade (I/II/III, %)		961 (96.0)/85 (8.5)/0 (0)	689 (91.7)/62 (8.3)/0 (0)	227 (90.8)/23 (9.2)/0 (0.4)	0.739

Abbreviations: HBsAg, hepatitis B surface antigen; HCV-Ab, hepatitis C virus antibody; PLT, platelet; ALB, albumin; HGB, hemoglobin; WBC, white blood cell; NE, neutrophil; LYM, lymphocyte; MONO, monocyte; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; PT, prothrombin time; APTT, Activated partial thromboplastin time; CEA, carcinoembryonic antigen; DCP, des-gamma-carboxyprothrombin; AFP, alpha-fetoprotein; CA19-9, cancer antigen 199; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; M×C, monocyte×c reactive protein; ALBI, albumin-bilirubin.

Figure 1 SIRS is associated with OS in patients with hepatocellular carcinoma. (A and B). Results of the univariate Cox regression analysis and multivariate Cox regression analysis between hematological markers of inflammation and overall survival in the training cohort. (C). The computational formula of SIRS. (D). Kaplan–Meier curves for the overall survival of patients in the high- and low-SIRS groups in the training cohort. (E). Kaplan–Meier curves for the overall survival of patients in the high- and low-SIRS groups in the validation cohort.

Abbreviations: ALB, serum albumin; CRP, C-reactive protein; PLR, platelet-lymphocyte ratio; NLR, neutrophil-lymphocyte ratio; PMR, platelet-monocyte ratio; NMR, neutrophil-monocyte ratio; LMR, lymphocyte-monocyte ratio; LCR, lymphocyte-CRP ratio; NAR, neutrophil-albumin ratio; MAR, monocyte-albumin ratio; PAR, platelet-albumin ratio; CAR, CRP-albumin ratio; N×M, neutrophil×monocyte; N×P, neutrophil×platelet; N×C, neutrophil×CRP; M×P, monocyte×platelet; M×C, monocyte×CRP; P×C, platelet×CRP; L×A, lymphocyte×albumin.

Table 2 Results of the Univariate Cox Regression Analysis and Multivariate Cox Regression Analysis for OS Among the Clinical Characteristics and SIRS

Variables	Univariate Cox Analysis		Multivariate Cox Analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age		0.319
≤65	Reference
>65	1.172 (0.858–1.601)
CRP		<0.001*		0.652
≤5.78	Reference		Reference
>5.78	2.350 (1.726–3.201)		1.092 (0.741–1.610)
ALB		0.154
≤45.9	Reference
>45.9	0.770 (0.538–1.103)
HBsAg		0.162
Negative	Reference
Positive	1.346 (0.888–2.041)
HCV-Ab		0.478
Negative	Reference
Positive	0.661 (0.211–2.071)
SIRS		<0.001*		0.001*
Low	Reference		Reference
High	2.302 (1.713–3.095)		1.806 (1.268–2.573)
Gender		0.087
Male	Reference
Female	1.498 (0.942–2.382)
Tumor size		<0.001*		0.005*
≤5cm	Reference		Reference
>5cm	2.241 (1.686–2.980)		1.604 (1.145–2.246)
Tumor number		0.142
1	Reference
2	1.114 (0.744–1.668)	0.600
≥3	1.373 (1.003–1.878)	0.048
AFP		<0.001*		0.108
<25	Reference		Reference
≥25	1.802 (1.332–2.438)		1.315 (0.939–1.842)
CA19-9		0.007*		0.003*
<35	Reference		Reference
≥35	1.533 (1.125–2.090)		1.625 (1.181–2.236)
DCP		<0.001*		0.164
<40	Reference		Reference
≥40	2.540 (1.598–4.038)		1.438 (0.872–2.370)
CEA		0.189
<5	Reference
≥5	1.304 (0.878–1.936)
Grade		<0.001*		0.001*
I, II	Reference		Reference
III	2.254 (1.671–3.041)		1.754 (1.269–2.424)
Vascular invasion		<0.001*		0.001*
No	Reference		Reference
Yes	3.912 (2.269–6.746)		2.468 (1.376–4.423)
Child-Pugh score		0.008*		0.196
A	Reference		Reference
B	3.332 (1.370–8.106)	0.019	1.947 (0.710–5.339)
ALBI		0.154
I	Reference
II	0.770 (0.538–1.103)

Note: *P-value < 0.05 is statistically significant in both univariate and multivariate analyses.

Abbreviations: CRP, c reactive protein; HBsAg, hepatitis B surface antigen; HCV-Ab, hepatitis C virus antibody; CEA, carcinoembryonic antigen; DCP, des-gamma-carboxyprothrombin; AFP, alpha-fetoprotein; CA19-9, cancer antigen 199; ALBI, albumin-bilirubin.

Table 3 Relationship Between SIRS and Clinical Characteristics

Variables	Median (Range) or Number (Proportion, %)				P value
		Total (n=1001)	SIRS High (n =456)	SIRS Low (n =545)
CA19-9 (<35 U/mL/≥35 U/mL)	Unknown	726 (72.5)/229 (22.9)/46 (4.6)	326 (71.5)/110 (24.1)/20 (4.4)	400 (73.4)/119 (21.8)/26 (4.8)	0.407
Tumor size (≤5.0cm/>5.0 cm, %)		651 (65.0)/350 (35.0)	258 (56.6)/198 (43.4)	393 (72.1)/152 (27.9)	<0.001*
Presence vascular invasion (±, %)		26 (2.5)/975 (97.4)	17 (3.7)/439 (96.3)	9 (1.7)/536 (98.3)	0.040*
Barcelona Clinic Liver Cancer staging (A/B/C, %)		561 (56.0)/376 (37.6)/64 (6.4)	237 (52.0)/182 (39.9)/37 (8.1)	324 (59.4)/194 (35.6)/27 (5.0)	0.023*
Tumor differentiation (High, Medium/Low, %)	Unknown	522 (52.2)/428 (42.8)/51 (5.1)	226 (49.6)/213 (46.7)/17 (3.7)	296 (54.3)/215 (39.4)/34 (6.2)	0.047*

Note: *P-value < 0.05 is statistically significant.

Abbreviation: CA19-9, cancer antigen 199.

Figure 2 Nomogram predicting the overall survival for patients with hepatocellular carcinoma. (A). Nomogram for predicting OS of hepatocellular carcinoma patients after surgery. (B and C). Calibration plot of the nomogram for 1-year survival in the training cohort and validation cohort. (D and E). Calibration plot of the nomogram for 3-year survival in the training cohort and validation cohort. Calibration plot of the nomogram for 5-year survival in the training cohort and validation cohort. (F and G).

Figure 3 The predictive performance of the nomogram is better than that of traditional prognostic factors. (A). AUC of time-dependent ROC curves verified the prognostic accuracy of the nomogram in the training cohort. (B). AUC of time-dependent ROC curves verified the prognostic accuracy of the nomogram in the validation cohort. (C and D). AUC of ROC curves compared the prognostic accuracy for 1-year survival of the nomogram and traditional prognostic factors in the training cohort and validation cohort. (E and F). AUC of ROC curves compared the prognostic accuracy for 3-year survival of the nomogram and traditional prognostic factors in the training cohort and validation cohort. (G and H). AUC of ROC curves compared the prognostic accuracy for 5-year survival of the nomogram and traditional prognostic factors in the training cohort and validation cohort.

Figure 4 Decision-curve analysis (DCA) plot depicting the standardized net benefit. (A). Training cohort at 12, 36, and 60 months. (B). Validation cohort at 12, 36, and 60 months.