ST2, PIVKA-II, CEA, CA125 and their combinations in elderly liver metastases cancers: Development of a diagnostic scoring model

Table 1 Comparison of clinical data between the two groups, n (%)

Variable	Construct group (n = 336)	Validation group (n = 144)	χ2/t	P value
Age (years), mean ± SD	68.03 ± 8.45	68.15 ± 8.33	0.711	0.477
Gender			0.731	0.392
Male	194 (57.74)	76 (52.78)
Female	142 (42.26)	68 (47.22)
Blood type			1.140	0.767
A	86 (25.60)	39 (27.08)
B	84 (25.00)	33 (22.92)
O	81 (24.10)	35 (24.31)
AB	85 (25.30)	37 (25.69)
Diet			1.454	0.228
Low-fat and low-cholesterol	178 (52.98)	81 (56.25)
High fat and high cholesterol	158 (47.02)	63 (43.75)
Nature of work			1.449	0.229
Brainpower	123 (36.61)	48 (33.33)
Physical strength	213 (63.39)	96 (66.67)
Course of illness (months)			0.726	0.394
< 3	170 (50.60)	77 (53.47)
≥ 6	166 (49.40)	67 (46.53)
BMI (kg/m2)			1.977	0.160
20-25	243 (72.32)	109 (75.69)
≥ 25	93 (27.68)	35 (24.31)
Installments			0.93	0.531
Phase I-II	168 (50.00)	69 (47.92)
Phase III	168 (50.00)	75 (52.08)
History of hepatitis B			2.216	0.137
Have	83 (24.70)	29 (20.14)
None	253 (75.30)	115 (79.86)
ST2 (pg/mL)	58.92 (44.36, 198.74)	62.34 (45.88, 215.47)	1.619	0.106
PIVKA-II (mAU/mL)	45.23 (24.67, 415.78)	48.15 (26.33, 398.72)	1.702	0.089
CEA (ng/mL)	8.91 (3.12, 89.45)	9.45 (3.34, 85.12)	1.720	0.086
CA125 (U/mL)	31.25 (21.08, 65.44)	32.17 (22.10, 68.95)	1.804	0.072
Fatty liver			0.651	0.420
Have	60 (17.86)	30 (20.83)
None	276 (82.14)	114 (79.17)

BMI: Body mass index; ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.

Table 2 Univariate analysis of liver metastasis in the construct group, n (%)

Variable	Liver metastasis group (n = 84)	Liver metastasis-free group (n = 252)	χ2/t	P value
Age (years), mean ± SD	67.94 ± 8.51	68.07 ± 8.44	0.055	0.956
Gender			0.162	0.687
Male	50 (59.52)	144 (57.14)
Female	34 (40.48)	108 (42.86)
Blood type			0.380	0.944
A	23 (27.38)	63 (25.00)
B	18 (21.43)	66 (26.19)
O	21 (25.00)	60 (23.81)
AB	22 (26.19)	63 (25.00)
Diet			0.726	0.394
Low-fat and low-cholesterol	47 (55.95)	131 (51.98)
High fat and high cholesterol	37 (44.05)	121 (48.02)
Nature of work			0.481	0.488
Brainpower	34 (40.48)	89 (35.32)
Physical strength	50 (59.52)	163 (64.68)
Course of illness (months)			3.505	0.061
< 3	39 (46.43)	131 (51.98)
≥ 6	45 (53.57)	121 (48.02)
BMI (kg/m2)			0.407	0.524
20-25	59 (70.24)	184 (73.02)
≥ 25	25 (29.76)	68 (26.98)
Installments			0.632	0.427
Phase I-II	40 (47.62)	128 (50.79)
Phase III	44 (52.38)	124 (49.21)
History of hepatitis B			0.258	0.611
Have	23 (27.38)	60 (23.81)
None	61 (72.62)	192 (76.19)
ST2 (pg/mL)	396.45 (332.18, 472.15)	49.87 (42.15, 58.64)	85.077	< 0.001
PIVKA-II (mAU/mL)	752.18 (682.34, 830.47)	28.92 (20.15, 38.74)	160.464	< 0.001
CEA (ng/mL)	320.45 (305.80, 337.22)	3.52 (2.65, 4.41)	325.563	< 0.001
CA125 (U/mL)	105.67 (92.14, 128.35)	25.08 (19.87, 31.65)	63.921	< 0.001
Fatty liver			84.183	< 0.001
Have	40 (47.62)	20 (7.94)
None	44 (52.38)	232 (92.06)

BMI: Body mass index; ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.

Table 3 Explanation and values of independent variables in logistic regression analysis

Variable	Variable description	Assignment status
ST2	Continuous variables	Value
PIVKA-II	Continuous variables	Value
CEA	Continuous variables	Value
CA125	Continuous variables	Value
Fatty liver	Binary variable	Present = 1, absent = 2

ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.

Table 4 Multivariate analysis of liver metastasis in patients in the construct group

Variable	Regression coefficient	SE	Wald	P value	OR value	95%CI
ST2	1.254	0.310	16.333	< 0.001	3.503	1.958-6.630
PIVKA-II	1.829	0.354	26.694	< 0.001	6.220	2.951-9.169
CEA	1.311	0.291	20.287	< 0.001	3.708	2.096-6.559
CA125	1.570	0.337	17.341	< 0.001	4.808	2.312-10.054
Fatty liver	0.765	0.283	7.287	0.007	2.148	1.233-3.743

CI: Confidence interval; OR: Odds ratio; ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.

Table 5 Positive rates of different combinations of soluble growth-stimulating gene 2, protein Induced by vitamin K absence or antagonist-II, carcinoembryonic antigen, and carbohydrate antigen 125, n (%)

Project portfolio	Liver metastasis group (n = 84)	Liver metastasis-free group (n = 252)
ST2 + PIVKA-II	35 (41.67)	5 (1.98)
ST2 + CEA	40 (47.62)	7 (2.78)
ST2 + CA125	45 (53.57)	5 (1.98)
PIVKA-II + CEA	42 (50.00)	5 (1.98)
PIVKA-II + CA125	43 (51.19)	6 (2.38)
CEA + CA125	41 (48.81)	6 (2.38)
ST2 + PIVKA-II + CEA	39 (46.43)	4 (1.59)
ST2 + PIVKA-II + CA125	37 (44.05)	5 (1.98)
ST2 + CEA + CA125	36 (42.86)	4 (1.59)
PIVKA-II + CEA + CA125	42 (50.00)	2 (0.79)
ST2 + PIVKA-II + CEA + CA125	47 (55.95)	2 (0.79)

ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.

Table 6 Receiver operating characteristic curves analysis of soluble growth-stimulating gene 2, protein induced by vitamin K absence or antagonist-II, carcinoembryonic antigen, and carbohydrate antigen 125 individually and in combination

Project portfolio	AUC	Optimal cutoff value	Youden index	SE	95%CI	P value	Sensitivity (%)	Specificity (%)
ST2	0.641	32.48 pg/mL	0.276	0.045	0.553-0.729	0.003	72.46	55.19
PIVKA-II	0.668	42.02 mAU/mL	0.268	0.043	0.584-0.752	< 0.001	69.48	57.30
CEA	0.650	5.81 ng/mL	0.347	0.047	0.558-0.742	0.001	72.91	61.75
CA125	0.657	37.53 U/mL	0.251	0.046	0.567-0.747	< 0.001	65.36	59.72
ST2 + PIVKA-II	0.689	0.45	0.336	0.041	0.609-0.769	< 0.001	55.42	78.14
ST2 + CEA	0.624	0.42	0.342	0.049	0.528-0.720	< 0.001	56.34	77.89
ST2 + CA125	0.704	0.44	0.300	0.040	0.626-0.782	< 0.001	58.44	71.53
PIVKA-II + CEA	0.741	0.48	0.272	0.037	0.668-0.814	0.004	57.16	70.06
BEER-II + CA125	0.715	0.46	0.428	0.040	0.636-0.794	< 0.001	58.67	84.11
CEA + CA125	0.734	0.47	0.377	0.038	0.659-0.809	0.002	54.96	82.74
ST2 + PIVKA-II + CEA	0.660	0.52	0.420	0.041	0.580-0.740	< 0.001	49.37	92.66
ST2 + PIVKA-II + CA125	0.794	0.58	0.410	0.044	0.708-0.880	< 0.001	47.20	93.78
ST2 + CEA + CA125	0.817	0.62	0.402	0.047	0.725-0.909	< 0.001	46.05	94.19
PIVKA-II + CEA + CA125	0.863	0.65	0.409	0.049	0.767-0.959	< 0.001	44.42	96.47
ST2 + PIVKA-II + CEA + CA125	0.896	0.75	0.315	0.037	0.823-0.969	< 0.001	33.04	98.42

AUC: Area under the curve; ST2: Soluble growth-stimulating gene 2; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125.