炎症标志物对早期小肝癌行射频消融术预后的预测价值

楚伟可; 吴雪; 张鹏; 冯婧; 牛斌; 周辉; 宓余强; 李萍

doi:10.3969/j.issn.1001-5256.2022.04.020

炎症标志物对早期小肝癌行射频消融术预后的预测价值

DOI: 10.3969/j.issn.1001-5256.2022.04.020

楚伟可¹,
吴雪¹,
张鹏¹,
冯婧¹,
牛斌¹,
周辉¹,
宓余强²,
李萍^2, , ,

1.
天津医科大学研究生院, 天津 300070
2.
天津市第二人民医院中西医结合肝病科, 天津市肝病研究所, 天津 300192

基金项目:

中国肝炎防治基金会王宝恩肝纤维化研究基金 (2021038)

伦理学声明：本研究于2019年12月25日通过天津市第二人民医院伦理委员会批准，批号：[2019]58。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：楚伟可负责课题设计，数据收集分析，撰写论文；吴雪、张鹏、冯婧、牛斌、周辉参与收集数据，修改论文；宓余强负责指导写作思路；李萍负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
李萍, tjlplxg@163.com

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出版历程
- 收稿日期: 2021-08-10
- 录用日期: 2021-09-24
- 出版日期: 2022-04-20

Value of inflammatory biomarkers in predicting the prognosis of early small hepatocellular carcinoma after radiofrequency ablation

Weike CHU¹,
Xue WU¹,
Peng ZHANG¹,
Jing FENG¹,
Bin NIU¹,
Hui ZHOU¹,
Yuqiang MI²,
Ping LI^{2
, ,
,}

1.
Graduate School of Tianjin Medical University, Tianjin 300070, China
2.
Tianjin Institute of Hepatology, Department of Traditional and Western Medical Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China

Research funding:

Chinese Foundation for Hepatitis Prevention and Control （2021038）

More Information

Corresponding author: LI Ping, tjlplxg@163.com (ORCID: 0000-0001-9930-6429)

摘要

摘要: 目的探讨中性粒细胞/淋巴细胞比值(NLR)、红细胞分布宽度/淋巴细胞比值(RLR)及淋巴细胞/单核细胞比值(LMR)在早期小肝癌射频消融术后的预后价值。方法选取2011年9月-2020年12月在天津市第二人民医院行射频消融术的132例初诊早期肝细胞癌(HCC)患者。收集患者术前资料并随访观察复发和生存情况。运用X-tile工具以5年生存率及无复发生存率确定NLR、RLR和LMR的最佳截断值并组合成为N-R-L评分, 并据此分为N-R-L 0分组(n=92)、N-R-L 1分组(n=29)和N-R-L 2分组(n=11)。计数资料3组间比较采用χ²检验。采用Kaplan-Meier方法绘制生存曲线, 并用log-rank检验对无复发生存率及总体生存率进行组间比较。单因素分析采用log-rank检验, 并将log-rank检验分析中具有统计学意义的因素纳入多因素Cox回归分析以确定无复发生存率与总生存率的危险因素。结果 N-R-L 0分、N-R-L 1分和N-R-L 2分组的组间Child-Pugh分级、Alb比较差异均有统计学意义(χ²值分别为10.992、5.699, P值均 < 0.05)。3组的1、3和5年总体生存率分别为100%、96.3%、90.7%, 96.6%、60.4%、41.3%和81.8%、46.8%、15.6%(χ²=38.460, P < 0.000 1);3组的1、3和5年无复发生存率分别为76.9%、52.5%、33.3%, 42.9%、13.1%、0和11.1%、0、0(χ²=35.345, P < 0.000 1)。多因素Cox回归分析显示, 肿瘤直径≥ 2 cm(HR=2.10, 95%CI: 1.28~3.43, P=0.003; HR=3.67, 95%CI: 1.58~8.52, P=0.002)、N-R-L评分1分(HR=3.14, 95%CI: 1.81~5.46, P < 0.000 1; HR=8.27, 95%CI: 3.15~21.71, P < 0.000 1)以及N-R-L评分2分(HR=2.61, 95%CI: 1.06~6.42, P=0.037; HR=14.59, 95%CI: 3.96~53.78, P < 0.000 1)是无复发生存与总生存的独立预测因素。结论由NLR、RLR和LMR组合而成的全身炎症反应标志物N-R-L评分是早期小肝癌射频消融术后复发和生存的独立危险因素, 可作为有用的无创生物标志物, 与肿瘤特征联合用来预测早期HCC射频消融术后的复发和生存。
- 癌, 肝细胞 /
- 导管消融术 /
- 中性粒细胞/淋巴细胞比值 /
- 红细胞分布宽度/淋巴细胞比值 /
- 淋巴细胞/单核细胞比值
Abstract: Objective To investigate the value of neutrophil-to-lymphocyte ratio (NLR), red blood cell distribution width-to-lymphocyte ratio (RLR), and lymphocyte-to-monocyte ratio (LMR) in predicting the prognosis of early small hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Methods A retrospective analysis was performed for 132 patients newly diagnosed with early HCC who underwent RFA in Tianjin Second People's Hospital from September 2011 to December 2020. Preoperative data were collected and the patients were followed up to observe recurrence and overall survival (OS). The X-tile tool was used to determine the optimal cut-off values of NLR, RLR, and LMR based on 5-year survival rate and recurrence-free survival (RFS) rate, and then the patients were divided into N-R-L 0 group with 92 patients, N-R-L 1 group with 29 patients, and N-R-L 2 group with 11 patients. The chi-square test was used for comparison of categorical data between the three groups. The Kaplan-Meier method was used to plot the survival curve, and the log-rank test was used to compare RFS and OS rates between groups. The factors with statistical significance in the log-rank test were included in the multivariate Cox regression analysis to determine the risk factors for RFS and OS rates. Results There were significant differences in Child-Pugh class and albumin between the N-R-L 0, N-R-L 1, and N-R-L 2 groups (χ²2=10.992 and 5.699, both P < 0.05). The 1-, 3-, and 5-year OS rates of the three groups were 100%/96.3%/90.7%, 96.6%/60.4%/41.3%, and 81.8%/46.8%/15.6%, respectively (χ²=38.46, P < 0.000 1), and the 1-, 3-, and 5-year RFS rates of the three groups were 76.9%/52.5%/33.3%, 42.9%/13.1%/0, and 11.1%/0/0, respectively (χ²=35.345, P < 0.000 1). The multivariate Cox regression analysis showed that tumor diameter ≥ 2 cm (hazard ratio[HR]=2.10, 95% confidence interval[CI]: 1.28-3.43, P=0.003; HR=3.67, 95% CI: 1.58-8.52, P=0.002), N-R-L score of 1 point (HR=3.14, 95% CI: 1.81-5.46, P < 0.000 1; HR=8.27, 95% CI: 3.15-21.71, P < 0.000 1), and N-R-L score of 2 points (HR=2.61, 95% CI: 1.06-6.42, P=0.037; HR=14.59, 95% CI: 3.96-53.78, P < 0.000 1) were independent predictive factors for RFS and OS. Conclusion N-R-L, a systemic inflammatory response marker composed of NLR, RLR, and LMR, is an independent risk factor for recurrence and survival of early small HCC after RFA, and it can be used as a useful noninvasive biomarker in combination with tumor features to predict the recurrence and survival of early HCC after RFA.
- Carcinoma, Hepatocellular /
- Catheter Ablation /
- Neutrophil-to-Lymphocyte Ratio /
- Red Blood Cell Distribution Width-to-Lymphocyte Ratio /
- Lymphocyte-to-Monocyte Ratio

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图 1 对患者5年OS和RFS进行X-tile分析以确定NLR的最佳截断值

注：a，OS面板图；b，OS人数分布直方图；c，NLR组OS比较；d，RFS面板图；e，RFS人数分布直方图；f，NLR组RFS比较。

Figure 1. X-tile analysis of 5-year OS and RFS was performed to determine the best cutoff value of NLR

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图 2 对患者5年OS和RFS进行X-tile分析以确定RLR的最佳截断值

注：a，OS面板图；b，OS人数分布直方图；c，RLR组OS比较；d，RFS面板图；e，RFS人数分布直方图；f，RLR组RFS比较。

Figure 2. X-tile analysis of 5-year OS and RFS was performed to determine the best cutoff value of RLR

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图 3 对患者5年OS和RFS进行X-tile分析以确定LMR的最佳截断值

注：a，OS面板图；b，OS人数分布直方图；c，LMR组OS比较；d，RFS面板图；e，RFS人数分布直方图；f，LMR组RFS比较。

Figure 3. X-tile analysis of 5-year OS and RFS was performed to determine the best cutoff value of LMR

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图 4 RFA术后N-R-L分组的RFS率和OS率比较

Figure 4. Comparison of RFS and OS in N-R-L group after RFA

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表 1 N-R-L评分的计分及分组方式

Table 1. Scoring and grouping of N-R-L score

变量	得分
NLR
＜4.1	0
≥4.1	1
RLR
＜18.3	0
≥18.3	1
LMR
＜6	0
≥6	1
N-R-L
NLR+RLR+LMR=0	0
NLR+RLR+LMR=1	1
NLR+RLR+LMR=2	2
注：N-R-L，NLR、RLR和LMR三项评分之和。

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表 2 术前N-R-L分组患者的临床特征

Table 2. Clinical characteristics of patients in preoperative N-R-L group

临床特征	N-R-L 0分组(n=92)	N-R-L 1分组(n=29)	N-R-L 2分组(n=11)	χ²值	P值
性别[例(%)]				0.545	0.762
男	66(71.7)	21(72.4)	9(81.8)
女	26(28.3)	8(27.6)	2(18.2)
年龄[例(%)]				0.371	0.831
＜60岁	48(52.2)	17(58.6)	6(54.5)
≥ 60岁	44(47.8)	12(41.4)	5(45.5)
BMI[例(%)]				2.024	0.363
＜24 kg/m²	42(45.7)	9(31.0)	5(45.5)
≥24 kg/m²	50(54.3)	20(69.0)	6(54.5)
Child-Pugh分级[例(%)]				10.992	0.001
A级	81(88.0)	26(89.7)	4(36.4)
B级	11(12.0)	3(10.3)	7(63.6)
BCLC分期[例(%)]				3.640	0.056
0期	18(19.6)	3(10.3)	0
A期	74(80.4)	26(89.7)	11(100)
肿瘤直径[例(%)]				3.876	0.144
＜2 cm	53(57.6)	17(58.6)	3(27.3)
≥2 cm	39(42.4)	12(41.4)	8(72.7)
HBV感染[例(%)]				1.601	0.449
否	22(23.9)	5(17.2)	4(36.4)
是	70(76.1)	24(82.8)	7(63.6)
HCV感染[例(%)]				1.029	0.598
否	76(82.6)	22(75.9)	8(71.7)
是	16(17.4)	7(24.1)	3(27.3)
MAFLD[例(%)]				0.367	0.832
否	56(60.9)	16(55.2)	7(63.6)
是	36(39.1)	13(44.8)	4(36.4)
AFP[例(%)]				1.266	0.531
＜15 ng/mL	59(64.1)	21(72.4)	6(54.5)
≥15 ng/mL	33(35.9)	8(27.6)	5(45.5)
ALBI分级[例(%)]				2.845	0.092
1级	54(58.7)	16(55.2)	5(45.4)
2级	36(39.1)	13(44.8)	3(27.3)
3级	2(2.2)	0	3(27.3)
TBil[例(%)]				0.904	0.636
≤20 μmol/L	55(59.8)	16(55.2)	5(45.5)
＞20 μmol/L	37(40.2)	13(44.8)	6(54.5)
Alb[例(%)]				5.699	0.017
≥35 g/L	82(89.1)	23(79.3)	7(63.6)
＜35 g/L	10(10.9)	6(20.7)	4(36.4)
ALT[例(%)]				0.109	0.741
≤50 U/L	76(82.6)	28(96.6)	7(63.6)
＞50 U/L	16(17.4)	1(3.4)	4(36.4)
AST[例(%)]				1.572	0.456
≤40 U/L	71(77.2)	24(82.8)	7(63.6)
＞40 U/L	21(22.8)	5(17.2)	4(36.4)
MELD评分[例(%)]				3.022	0.221
＜9分	65(70.7)	18(62.1)	5(45.5)
≥9分	27(29.3)	11(37.9)	6(54.5)
注：ALBI分级，白蛋白-胆红素分级。

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表 3 Cox回归分析RFS率的影响因素

Table 3. Results of RFS by Cox regression analysis

变量	单因素分析		多因素分析
变量	HR(95%CI)	P值	HR(95%CI)	P值
性别(男/女)	1.97(1.14~3.40)	0.015	1.55(0.87~2.76)	0.136
BMI(≥24 kg/m²/＜24 kg/m²)	1.22(0.77~1.92)	0.402
MAFLD(是/否)	1.03(0.65~1.61)	0.916
Child-Pugh分级(B级/A级)	2.58(1.50~4.45)	0.001	1.28(0.56~2.91)	0.564
肿瘤直径(≥2 cm/＜2 cm)	2.28(1.43~3.62)	0.001	2.10(1.28~3.43)	0.003
BCLC分期(A期/0期)	2.06(0.89~4.75)	0.090
ALT(＞50 U/L/≤50 U/L)	1.41(0.78~2.57)	0.260
AST(＞40 U/L/≤40 U/L)	1.63(0.98~2.70)	0.058
TBil(≤20 μmol/L/＞20 μmol/L)	1.69(1.07~2.65)	0.024	1.60(0.96~2.67)	0.074
Alb(＜35 g/L/≥35 g/L)	2.45(1.45~4.12)	0.001	1.01(0.44~2.32)	0.974
AFP(＞400 ng/mL/≤400 ng/mL)	0.81(0.33~2.01)	0.650
ALBI分级(ref: 1级)
2级	1.25(0.79~2.00)	0.341	0.92(0.49~1.70)	0.781
3级	4.15(1.61~10.70)	0.003	1.91(0.48~7.59)	0.356
MELD评分(＞9分/≤9分)	1.44(0.91~2.28)	0.124
N-R-L得分(ref: 0分)
1分	3.13(1.89~5.20)	＜0.000 1	3.14(1.81~5.46)	＜0.000 1
2分	4.99(2.40~10.37)	＜0.000 1	2.61(1.06~6.42)	0.037

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表 4 Cox回归分析OS率的影响因素

Table 4. Results of OS by Cox regression analysis

变量	单因素分析		多因素分析
变量	HR(95%CI)	P值	HR(95%CI)	P值
性别(男/女)	2.17(0.88~5.33)	0.093
BMI(≥24 kg/m²/＜24 kg/m²)	1.64(0.78~3.44)	0.191
MAFLD(是/否)	1.20(0.58~2.51)	0.620
Child-Pugh分级(B级/A级)	3.54(1.52~8.25)	0.003	0.99(0.28~3.52)	0.987
肿瘤直径(≥2 cm/＜2 cm)	2.89(1.36~6.14)	0.006	3.67(1.58~8.52)	0.002
BCLC分期(A期/0期)	1.10(0.33~3.63)	0.880
ALT(＞50 U/L/≤50 U/L)	1.21(0.46~3.17)	0.705
AST(＞40 U/L/≤40 U/L)	1.30(0.58~2.94)	0.530
TBil(≤20 μmol/L/＞20 μmol/L)	2.27(1.08~4.76)	0.030	1.97(0.82~4.77)	0.132
Alb(＜35 g/L/≥35 g/L)	3.49(1.58~7.74)	0.002	1.36(0.36~5.09)	0.649
AFP(＞400 ng/mL/≤400 ng/mL)	1.35(0.41~4.50)	0.621
ALBI分级(ref: 1级)
2级	1.67(0.78~3.56)	0.184	0.97(0.35~2.65)	0.950
3级	12.94(2.55~65.68)	0.002	2.11(0.25~17.94)	0.495
MELD评分(＞9分/≤9分)	1.59(0.75~3.33)	0.224
N-R-L得分(ref: 0分)
1分	6.92(2.82~17.00)	＜0.000 1	8.27(3.15~21.71)	＜0.000 1
2分	13.50(4.68~38.91)	＜0.000 1	14.59(3.96~53.78)	＜0.000 1

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