Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma

doi:10.3748/wjg.v27.i27.4453

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World Journal of Gastroenterology

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1007-9327

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World J Gastroenterol. Jul 21, 2021; 27(27): 4453-4467
Published online Jul 21, 2021. doi: 10.3748/wjg.v27.i27.4453

Table 1 Baseline characteristics and plasma levels of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor

Characteristic	HCC patients (n = 240)
Age, mean age ± SD, year	60.9 ± 11.2
Male sex, n (%)	193 (80.4)
BMI, mean ± SD, kg/m²	24.1 ± 3.0
Etiology, n (%)
HBV/HCV/HBV + HCV	167 (69.6)/24 (10)/2 (0.8)
Alcohol/Others	28 (11.7)/19 (7.9)
Presence of cirrhosis, n (%)	184 (76.7)
Child-Pugh score, n (%)
A/B/C	204 (85.1)/35 (14.5)/1 (0.4)
ECOG performance status, n (%)
0/1–2/3	156 (65)/80 (33.3)/4 (1.7)
Maximal tumor size, median (IQR), cm	3.6 (2.0–7.0)
Multi-nodularity of tumor, n (%)	105 (43.8)
Vascular invasion of HCC, n (%)	45 (18.8)
Presence of distant metastasis, n (%)	18 (7.5)
BCLC staging, n (%)
0/A	52 (21.7)/81 (33.8)
B/C/D	43 (17.9)/59 (24.6)/5 (2.1)
TNM staging, n (%)
I/II	115 (48.0)/42 (17.5)
III/IV	65 (27.1)/18 (7.5)
Initial treatment, n (%)
Resection	34 (14.2)
RFA/TACE	27 (11.3)/165 (69.2)
Sorafenib/BSC	2 (0.8)/11 (4.6)
Laboratory results
WBC, median (IQR), × 10³/uL	5.1 (4.0–6.6)
Hemoglobin, median (IQR), g/dL	13.6 (12.0–14.8)
Platelet count, median (IQR), × 10⁹/uL	130 (88–184)
Prothrombin time, median (IQR), INR	1.11 (1.04–1.18)
AST, median (IQR), IU/mL	45 (32–73)
ALT, median (IQR), IU/mL	38 (23–61)
Albumin; median (IQR), g/dL	4.0 (3.5–4.2)
Total bilirubin, median (IQR), mg/dL	0.8 (0.5–1.1)
Creatinine, median (IQR), mg/dL	0.8 (0.7–1.0)
AFP, median (IQR), ng/mL	17.9 (4.0–698)
Angiogenesis marker
Ang-1, median (IQR), pg/mL	3216 (1565–6266)
Ang-2, median (IQR), pg/mL	1684 (1107–3064)
Ang-2/Ang-1 ratio, median (IQR)	0.56 (0.25–1.39)
VEGF, median (IQR), pg/mL	26.5 (13.8–51.3)
NLR, mean ± SD	2.8 ± 3.5
PLR, mean ± SD	118.2 ± 119.7

AFP: α-feto protein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; BCLC: Barcelona clinic liver cancer; BSC: Best supportive care; ECOG: Eastern Cooperative Oncology Group; HCC: Hepatocellular carcinoma; IQR: Interquartile range; NLR: Neutrophil-lymphocyte ratio; SD: Standard deviation; TNM: Tumor-node-metastasis; PLR: Platelet-lymphocyte ratio; VEGF: Vascular endothelial growth factor; WBC: White blood cell.

Table 2 Univariate and multivariate analysis on the factors predictive for poor overall survival in hepatocellular carcinoma patients

Variable	Univariate analysis		Multivariable analysis
Variable	HR (95%CI)	P value	HR (95%CI)	P value
Ang-2 group (cut-off: Median level)
Low Ang-2 group	Reference	–	Reference	–
High Ang-2 group	4.76 (3.15 – 7.20)	< 0.001	5.96 (1.58–22.43)	< 0.001
VEGF group (cut-off: Median level)
Low VEGF group	Reference	–	Reference	–
High VEGF group	1.39 (0.97–2.00)	0.07	0.80 (0.33–1.98)	0.63
Ang-2/Ang-1 ratio	1.02 (0.94–1.06)	0.26	–	–
AFP (≥ 20 ng/mL)	2.97 (2.02–4.37)	< 0.001	2.63 (0.85–8.09)	0.09
Age	1.00 (0.98–1.02)	0.93	–	–
Male sex	1.05 (0.68–1.64)	0.82	–	–
BMI > 25 kg/m²	0.70 (0.47–1.03)	0.07	–	–
Presence of cirrhosis	1.02 (0.67–1.57)	0.92	–	–
Child-Pugh class B or C	3.68 (2.42–5.58)	< 0.001	5.59 (2.44–12.81)	< 0.001
NLR	3.24 (1.49–7.06)	0.003	4.45 (1.77–11.23)	0.002
PLR	2.68 (1.26–5.70)	0.01	0.56 (0.24–1.33)	0.19
TNM stage
I	Reference	–	Reference	–
II	6.30 (1.15–34.42)	0.03	3.61 (0.62–21.08)	0.15
III	26.43 (6.01–116.24)	< 0.001	14.20 (2.82–71.45)	0.001
IV	70.42 (15.00–330.6)	< 0.001	41.39 (6.62–258.67)	< 0.001

Cox proportional hazards model with a backward elimination approach was used for multivariable analysis. HR: Hazard ratio; CI: Confidence interval; VEGF: Vascular endothelial growth factor; AFP: Alpha fetoprotein; BMI: Body mass index; MELD: Model for end stage liver disease; HCC: Hepatocellular carcinoma; TNM: Tumor-node-metastasis.

Table 3 Univariate and multivariate analysis on the factors predictive for progression-free survival in hepatocellular carcinoma patients

Variable	Univariate analysis		Multivariable analysis
Variable	HR (95%CI)	P value	HR (95%CI)	P value
Ang-2 group (cut-off: Median level)
Low Ang-2 group	Reference	–	Reference	–
High Ang-2 group	2.53 (1.89–3.39)	< 0.001	1.55 (1.10–2.20)	0.01
VEGF group (cut-off: Median level)
Low VEGF group	Reference	–	Reference	–
High VEGF group	1.29 (0.97–1.71)	0.08	1.08 (0.80–1.46)	0.61
Ang-2/Ang-1 ratio	1.02 (0.98–1.05)	0.32	–	–
AFP (≥ 20 ng/mL)	2.27 (1.713.04)	< 0.001	1.54 (1.13–2.11)	0.007
Age	0.99 (0.98–1.01)	0.30	–	–
Male sex	1.32 (0.91–1.92)	0.15	–	–
BMI > 25 kg/m²	0.67 (0.50–0.91)	0.01	0.72 (0.53–0.97)	0.03
Presence of cirrhosis	1.04 (0.74–1.46)	0.81	–	–
Child-Pugh class B or C	2.17 (1.48–3.18)	< 0.001	1.54 (1.01–2.35)	0.05
NLR > 4	2.13 (1.45–3.12)	< 0.001	1.95 (1.23–3.08)	0.004
PLR > 150	2.05 (1.45–2.90)	< 0.001	1.02 (0.67–1.57)	0.93
TNM stage
I	Reference	–	Reference	–
II	1.94 (1.31–2.89)	0.001	1.75 (1.16–2.63)	0.008
III	5.47 (3.81–116.24)	< 0.001	4.35 (2.91–6.50)	< 0.001
IV	70.42 (15.00–330.6)	< 0.001	9.35 (5.00–17.46)	< 0.001

Citation: Choi GH, Jang ES, Kim JW, Jeong SH. Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma. World J Gastroenterol 2021; 27(27): 4453-4467
URL: https://www.wjgnet.com/1007-9327/full/v27/i27/4453.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i27.4453