Inflammation-Related Marker NrLR Predicts Prognosis in AFP-Negative HCC Patients After Curative Resection

Figures & data

Table 1 The Definition and Cut-off Value of Inflammation-Related Marker

Inflammation-Related Marker	Formula	Cut-off Value
NrLR	Neutrophil (10^9/L) × GGT (U/L) ÷ lymphocyte (10^9/L)	120
LMR	Lymphocyte (10^9/L) ÷ monocyte (10^9/L)	5
PLR	Platelet (10^9/L) ÷ lymphocyte (10^9/L)	142
PNI	Albumin (g/L) + 5 × lymphocyte (10^9/L)	50
SII	Platelet (10^9/L) × neutrophil (10^9/L) ÷ lymphocyte (10^9/L)	580

Abbreviations: GGT, γ-glutamyl transpeptidase; NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; PLR, platelet to lymphocyte ratio; PNI, prognostic nutritional index; SII, systemic immune-inflammation index.

Figure 1 The flow chart in the study.

Abbreviations: HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein.

Table 2 Univariate Cox Regression Analysis of Factors Associated with OS and RFS in AFP-Negative HCC Patients

Variables	OS		RFS
	HR (95% CI)	p-value	HR (95% CI)	p-value
Patient factors/Surgical factors
Age, ≥50 years vs <50 years	0.993 (0.815–1.209)	0.942	0.958 (0.817–1.124)	0.597
Gender, male vs female	1.146 (0.803–1.637)	0.453	1.254 (0.937–1.679)	0.127
Hepatitis, yes vs no	1.009 (0.765–1.331)	0.950	0.974 (0.777–1.222)	0.821
AFP, ng/mL	1.036 (1.016–1.057)	<0.001	1.046 (1.029–1.062)	<0.001
ALBI, >2.63 vs ≤2.63	1.458 (1.169–1.818)	0.001	1.459 (1.217–1.749)	<0.001
Blood transfusion, yes vs no	1.393 (1.028–1.888)	0.033	1.590 (1.238–2.043)	<0.001
Operative bleeding loss, >800mL vs ≤800mL	1.558 (1.140–2.129)	0.005	1.715 (1.325–2.221)	<0.001
Resection margin, ≥1cm vs <1cm	0.654 (0.503–0.849)	0.001	0.735 (0.598–0.904)	0.004
Inflammation-related markeres
NrLR, >120 vs ≤120	1.895 (1.563–2.297)	<0.001	1.796 (1.538–2.099)	<0.001
LMR, >5 vs ≤5	0.751 (0.620–0.909)	0.003	0.712 (0.610–0.832)	<0.001
PLR, >142 vs ≤142	1.541 (1.228–1.933)	<0.001	1.466 (1.213–1.770)	<0.001
PNI, >50 vs ≤50	0.668 (0.552–0.807)	<0.001	0.749 (0.641–0.874)	<0.001
SII, >580 vs ≤580	1.533 (1.199–1.960)	0.001	1.492 (1.215–1.832)	<0.001
Tumor factors
Tumor size, ≥5cm vs <5cm	2.840 (2.290–3.522)	<0.001	3.091 (2.605–3.667)	<0.001
Tumor number, multiple vs solitary	2.013 (1.597–2.536)	<0.001	2.463 (2.037–2.978)	<0.001
Microvascular invasion, presence vs absence	1.924 (1.577–2.348)	<0.001	1.926 (1.634–2.271)	<0.001
Edmondson-Steiner grade, III–IV vs I–II	2.036 (1.570–2.641)	<0.001	1.843 (1.506–2.257)	<0.001
Liver cirrhosis, presence vs absence	1.044 (0.854–1.277)	0.672	1.072 (0.910–1.263)	0.406

Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval; ALBI, albumin-bilirubin; NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; PLR, platelet to lymphocyte ratio; PNI, prognostic nutritional index; SII, systemic immune-inflammation index.

Table 3 Multivariable Cox Regression Analysis of Factors Associated with OS and RFS in AFP-Negative HCC Patients

Variables	OS		RFS
	HR (95% CI)	p-value	HR (95% CI)	p-value
NrLR, >120 vs ≤120	1.390 (1.133–1.704)	0.002	1.228 (1.038–1.452)	0.017
PNI, >50 vs ≤50	0.790 (0.651–0.960)	0.018	-	-
AFP, ng/mL	-	-	1.030 (1.013–1.452)	0.001
Tumor size, ≥5cm vs <5cm	2.674 (2.126–3.362)	<0.001	2.892 (2.417–3.461)	<0.001
Tumor number, multiple vs solitary	1.857 (1.471–2.345)	<0.001	2.295 (1.894–2.781)	<0.001
Microvascular invasion, presence vs absence	2.028 (1.651–2.493)	<0.001	1.910 (1.614–2.260)	<0.001
Edmondson-Steiner grade, III–IV vs I–II	1.466 (1.120–1.918)	0.005	1.267 (1.026–1.563)	0.028

Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; CI, confidence interval; OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio; PNI, prognostic nutritional index; NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; GPR, γ-glutamyl transpeptidase to platelet ratio.

Table 4 Baseline Characteristics of Patients

	Before PSM			After PSM
Variables	Low NrLR (n=628)	High NrLR (n=551)	p-value	Low NrLR (n=435)	High NrLR (n=435)	p-value
Age, years	53.3 (10.4)	54.0 (10.3)	0.227	53.5 (10.6)	54.0 (10.2)	0.498
Gender			0.016			0.522
Female	67 (10.7%)	36 (6.5%)		36 (8.3%)	30 (6.9%)
Male	561 (89.3%)	515 (93.5%)		399 (91.7%)	405 (93.1%)
Hepatitis			0.079			0.283
No	80 (12.7%)	91 (16.5%)		55 (12.6%)	67 (15.4%)
Yes	548 (87.3%)	460 (83.5%)		380 (87.4%)	368 (84.6%)
AFP, ng/mL	5.56 (4.26)	6.47 (4.43)	<0.001	6.05 (4.50)	6.24 (4.20)	0.515
ALBI grade			<0.001			0.868
Grade 1	527 (83.9%)	407 (73.9%)		342 (78.6%)	345 (79.3%)
Grade 2	101 (16.1%)	144 (26.1%)		93 (21.4%)	90 (20.7%)
Resection margin			0.024			0.663
<1cm	488 (77.7%)	458 (83.1%)		357 (82.1%)	351 (80.7%)
≥1cm	140 (22.3%)	93 (16.9%)		78 (17.9%)	84 (19.3%)
Blood transfusion			<0.001			0.888
No	601 (95.7%)	479 (86.9%)		409 (94.0%)	407 (93.6%)
Yes	27 (4.3%)	72 (13.1%)		26 (6.0%)	28 (6.4%)
Operative bleeding loss			<0.001			0.662
<800mL	605 (96.3%)	485 (88.0%)		412 (94.7%)	408 (93.8%)
≥800mL	23 (3.7%)	66 (12.0%)		23 (5.3%)	27 (6.2%)
Tumor size, cm	4.81 (2.58)	6.82 (3.61)	<0.001	5.48 (2.75)	5.79 (2.90)	0.108
Tumor number			0.155			0.777
Solitary	546 (86.9%)	462 (83.8%)		371 (85.3%)	367 (84.4%)
Multiple	82 (13.1%)	89 (16.2%)		64 (14.7%)	68 (15.6%)
Microvascular invasion			0.889			0.750
Absence	474 (75.5%)	413 (75.0%)		329 (75.6%)	334 (76.8%)
Presence	154 (24.5%)	138 (25.0%)		106 (24.4%)	101 (23.2%)
Edmondson-Steiner grade			0.024			0.936
I–II	165 (26.3%)	113 (20.5%)		103 (23.7%)	101 (23.2%)
III–IV	463 (73.7%)	438 (79.5%)		332 (76.3%)	334 (76.8%)
Liver cirrhosis			0.516			0.432
No	211 (33.6%)	196 (35.6%)		143 (32.9%)	155 (35.6%)
Yes	417 (66.4%)	355 (64.4%)		292 (67.1%)	280 (64.4%)

Abbreviations: Mean (standard deviation, SD) was presented for continuous variables. PSM, propensity score matching; AFP, alpha-fetoprotein; ALBI grade, albumin-bilirubin grade; NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio.

Figure 2 Comparison of prognosis between Low NrLR and High NrLR Groups. (A) OS before PSM; (B) RFS before PSM; (C) OS after PSM; (D) RFS after PSM.

Abbreviations: OS, overall survival; RFS, recurrence-free survival; NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; PSM, propensity score matching.

Figure 3 Comparison of overall survival between Low NrLR and High NrLR Groups in different subgroups.

Abbreviations: NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; ALBI grade, albumin-bilirubin grade.

Figure 4 Comparison of recurrence-free survival between Low NrLR and High NrLR Groups in different subgroups.

Abbreviations: NrLR, neutrophil times γ-glutamyl transpeptidase to lymphocyte ratio; ALBI grade, albumin-bilirubin grade.