Systemic Inflammation Score Using Pretherapeutic Inflammatory Markers to Predict Prognosis for Hepatocellular Carcinoma Patients After Hepatic Arterial Infusion Chemotherapy

Figures & data

Table 1 Baseline Characteristics for the Training and Validation Cohorts of HCC Patients Who Underwent HAIC

Variables	Overall Cohort (n=415)	Training Cohort (n=277)	Validation Cohort (n=138)	P value
Age [years; mean ± SD]	50.75 ± 12.09	50.81 ± 11.93	50.63 ± 12.46	0.888
Sex [cases (%)]				0.261
Male	364 (87.71)	247 (89.17)	117 (84.78)
Female	51 (12.29)	30 (10.83)	21 (15.22)
HBsAg [cases (%)]				0.944
Present	375 (90.36)	251 (90.61)	124 (89.86)
Absent	40 (9.64)	26 (9.39)	14 (10.14)
Child‒Pugh classification [cases (%)]				0.830
A	391 (94.22)	260 (93.86)	131 (94.93)
B	24 (5.78)	17 (6.14)	7 (5.07)
Liver cirrhosis [cases (%)]				0.674
Present	191 (46.02)	130 (46.93)	61 (44.20)
Absent	224 (53.98)	147 (53.07)	77 (55.80)
Times of HAIC [cases (%)]				1.000
≤3	285 (68.67)	190 (68.59)	95 (68.84)
>3	130 (31.33)	87 (31.41)	41 (31.16)
WBC (×10E9/L; mean ± SD)	6.93 ± 2.45	6.99 ± 2.49	6.80 ± 2.38	0.453
NE (×10E9/L; mean ± SD)	4.68 ± 2.13	4.75 ± 2.20	4.54 ± 1.99	0.339
LY (×10E9/L; mean ± SD)	1.50 ± 0.53	1.50 ± 0.55	1.51 ± 0.50	0.806
MO (×10E9/L; mean ± SD)	0.53 ± 0.25	0.53 ± 0.25	0.52 ± 0.26	0.680
PLT (×10E9/L; mean ± SD)	235.26 ± 107.55	237.13 ± 107.46	231.50 ± 108.03	0.616
AST (U/L; mean ± SD)	85.21 ± 60.80	82.61 ± 58.81	90.42 ± 64.52	0.218
ALT (U/L; mean ± SD)	56.43 ± 41.99	55.75 ± 42.03	57.81 ± 42.03	0.639
TBIL (umol/L; mean ± SD)	16.84 ± 7.75	16.88 ± 7.80	16.76 ± 7.69	0.878
ALB (g/L; mean ± SD)	39.49 ± 4.29	39.54 ± 4.42	39.37 ± 4.02	0.688
AAR [cases (%)]				0.972
≤0.83	59 (14.22)	40 (14.44)	19 (13.77)
>0.83	356 (85.78)	237 (85.56)	119 (86.23)
L×A [cases (%)]				0.578
≤60.76	235 (56.63)	160 (57.76)	75 (54.35)
>60.76	180 (43.47)	117 (42.24)	64 (45.65)
N×M [cases (%)]				0.093
≤2.15	227 (54.70)	143 (51.62)	84 (60.87)
>2.15	188 (45.30)	134 (48.38)	54 (39.13)
AFP [ng/mL; median (IQR)]	1814.00 (44.38–52483.00)	1148.00 (43.25–49533.00)	2965.00 (52.65–63378.75)	0.488
PIVKA-II [mAU/mL; median (IQR)]	11,274.00 (1185.50–45069.50)	11,725.00 (1129.00–48342.00)	11,051.50 (1382.75–41040.50)	0.609
Tumor size [cm; median (IQR)]	10.40 (8.20–13.15)	10.30 (8.00–13.20)	10.60 (8.33–13.00)	0.618
Tumor number [case (%)]				0.150
1	157 (37.83)	112 (40.43)	45 (32.61)
>1	258 (62.17)	165 (59.57)	93 (67.39)
Vascular invasion [case (%)]				0.292
Present	233 (56.14)	150 (54.15)	83 (60.14)
Absent	182 (43.86)	127 (45.85)	55 (39.86)
Extrahepatic metastasis [case (%)]				0.985
Present	107 (25.78)	72 (25.99)	35 (25.36)
Absent	308 (74.22)	205 (74.01)	103 (74.64)
BCLC stage [case (%)]				0.579
A	23 (5.54)	15 (5.42)	8 (5.80)
B	122 (29.40)	86 (31.05)	36 (26.09)
C	270 (65.06)	176 (63.54)	94 (68.12)

Note: P value < 0.05 is statistically significant.

Abbreviations: SD, standard deviation; IQR, interquartile range; HBsAg, hepatitis B surface antigen; HAIC, hepatic arterial infusion chemotherapy; WBC, white blood cell; NE, neutrophil; LY, lymphocyte; MO, monocyte; PLT, platelet; AST, aspartate transaminase; ALT, alanine aminotransferase; TBIL, total bilirubin; ALB, albumin; AAR, aspartate transaminase-to-alanine aminotransferase ratio; L × A, lymphocyte × albumin; N × M, neutrophil × monocyte; AFP, alpha fetoprotein; PIVKA-II, protein induced by vitamin K absence/antagonist-II; BCLC, Barcelona Clinic Liver Cancer.

Figure 1 SIS is associated with OS in patients with hepatocellular carcinoma. (a and b) Univariate Cox regression analysis (a) and multivariate Cox regression analysis (b) between blood indicators and overall survival in the training cohort. The indicators with statistical significance (p < 0.05) are presented in bold text. (c) The calculation formula of SIS. (d and e) Kaplan–Meier estimates of overall survival in the training cohort (d) and the validation cohort (e) of patients in the low- and high- SIS groups.

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LCR, lymphocyte to C-reactive protein ratio; LMR, lymphocyte-to-monocyte ratio; CAR, C-reactive protein-to-albumin ratio; AAR, aspartate transaminase to alanine aminotransferase ratio; ALR, aspartate aminotransferase-to-lymphocyte ratio; NAR, neutrophil-to-albumin ratio; MAR, monocyte-to-albumin ratio; PAR, platelet-to-albumin ratio; N × M, neutrophil × monocyte; N × P, neutrophil × platelet; N × C, neutrophil × C-reactive protein; M × P, monocyte × platelet; M × C, monocyte × C-reactive protein; P × C, platelet × C-reactive protein; L × A, lymphocyte × albumin.

Table 2 Cox Regression Analysis for OS Among Clinical Characteristics and SIS in the Training Cohort

Variable	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age, y (≤/>50)	0.790 (0.605–1.033)	0.085
Sex (male/female)	0.861 (0.558–1.327)	0.497
HBsAg (No/Yes)	0.934 (0.589–1.479)	0.770
Extrahepatic metastasis (No/Yes)	1.423 (1.050–1.929)	0.023	1.521 (1.025–2.260)	0.037
Vascular invasion (No/Yes)	1.400 (1.068–1.834)	0.015	2.017 (1.150–3.540)	0.014
Times of HAIC (≤/>3)	0.750 (0.561–1.003)	0.053
Liver cirrhosis (No/Yes)	0.812 (0.620–1.064)	0.131
Tumor size, cm (≤/>10)	1.671 (1.270–2.197)	<0.001	1.671 (1.258–2.220)	<0.001
Tumor number (1/>1)	1.239 (0.939–1.633)	0.129
SIS (≤/>-0.227)	1.706 (1.110–2.610)	0.014	1.579 (1.018–2.450)	0.042
BCLC stage (A-B/C)	1.393 (1.051–1.845)	0.021
Child‒Pugh classification (A/B)	0.889 (0.497–1.590)	0.692
ALT, U/L (≤/>50)	1.192 (0.912–1.560)	0.199
AST, U/L (≤/>40)	1.216 (0.865–1.710)	0.260
ALB, U/L (≤/>40)	0.728 (0.556–0.953)	0.021
TBIL, umol/L (≤/>17.1)	1.320 (1.008–1.736)	0.044
AFP, ng/mL (≤/>400)	1.659 (1.252–2.198)	<0.001	1.506 (1.132–2.000)	0.005
PIVKA-II, mAU/mL (≤/>40)	1.119 (0.497–2.521)	0.785

Note: P value < 0.05 is statistically significant.

Abbreviations: HBsAg, hepatitis B surface antigen; HAIC, hepatic arterial infusion chemotherapy; SIS, systemic inflammation score; BCLC, Barcelona Clinic Liver Cancer; ALT, alanine aminotransferase; AST, aspartate transaminase; ALB, albumin; TBIL, total bilirubin; AFP, alpha fetoprotein; PIVKA-II, protein induced by vitamin K absence/antagonist-II.

Table 3 Relationship Between SIS and Clinical Characteristics

Variable	SIS High (n=300)	SIS Low (n=115)	P value
AFP (≤400 ng/mL/>400 ng/mL)	113 (37.67)/187 (62.33)	48 (41.74)/67 (58.26)	0.446
PIVKA (≤40mAU/mL/>40mAU/mL)	12 (4.00)/288 (96.00)	3 (2.61)/112 (97.39)	0.769
Tumor size (≤10 cm/>10 cm)	124 (41.33)/176 (58.67)	69 (60.00)/46 (40.00)	<0.001
Vascular invasion (-/+)	123 (41.00)/177 (59.00)	59 (51.30)/56 (48.70)	0.058
Metastasis (-/+)	211 (70.33)/89 (29.67)	97 (84.35)/18 (15.65)	0.003
Tumor number (1/>1)	103 (34.33)/197 (65.67)	54 (46.96)/61 (53.04)	0.018
BCLC stage (A/B/C)	8 (2.67)/84 (28.00)/208 (69.33)	15 (13.04)/38 (33.04)/62 (53.91)	<0.001

Notes: Values are presented as n (%). P value < 0.05 is statistically significant.

Abbreviations: SIS, systemic inflammation score; AFP, alpha fetoprotein; PIVKA-II, protein induced by vitamin K absence/antagonist-II; BCLC, Barcelona Clinic Liver Cancer.

Figure 2 Nomogram depicting 2- and 3-year overall survival probability for patients with hepatocellular carcinoma.

Abbreviations: SIS, systemic inflammation score; AFP, alpha fetoprotein.

Figure 3 Calibration plots of overall survival in the training and validation cohorts. (a and b) Calibration plot of the nomogram for 2-year survival in the training cohort (a) and validation cohort (b). (c and d) Calibration plot of the nomogram for 3-year survival in the training cohort (c) and validation cohort (d).

Figure 4 Nomogram has better predict ability than other prognostic factors. (a and b) ROC analysis of 2- and 3-year overall survival for nomogram in the training cohort (a) and validation cohort (b). (c and d) AUC of ROC curves compared the prognostic accuracy for 2-year survival of the nomogram and other prognostic factors in the training cohort (c) and validation cohort (d). (e and f) AUC of ROC curves compared the prognostic accuracy for 3-year survival of the nomogram and other prognostic factors in the training cohort (e) and validation cohort (f).

Figure 5 Decision-curve analysis (DCA) of nomogram in the training and validation cohorts. (a and b) DCA curves compared the standardized net benefit for 2-year survival of the nomogram and other prognostic factors in the training cohort (a) and validation cohort (b). (c and d) DCA curves compared the standardized net benefit for 3-year survival of the nomogram and other prognostic factors in the training cohort (c) and validation cohort (d).