Clinical significance and usefulness of soluble heparin binding-epidermal growth factor in gastric cancer

Table 1 Baseline characteristics of subjects in each group

Groups	Control2 (n = 60)	High-risk3 (n = 30)	EGC (n = 37)	AGC (n = 30)	P value4
Clinical features
Age (mean ± SD, yr)	56.5 ± 11.1	66.2 ± 7.6	58.3 ± 10.6	56.3 ± 10.3	0.856
Sex (male:female, n)	37:23	19:11	22:15	17:13	0.953
H. pylori infection (-/+, n)	35:25	17:13	22:15	20:10	0.857
Histopathological features
Histology (well:mod:poorly:signet)	NS	NS	14:9:7:7	2:6:16:6	0.006
Tumor location (lower:middle:upper)1	NS	NS	20:13:4	18:9:3	0.884
Size of tumor (mean ± SD, cm)	NS	NS	3.9 ± 1.2	5.0 ± 1.3	0.010
T-stage (T1a:T1b:T2:T3:T4)	NS	NS	31:6:0:0:0	0:0:15:4:11	< 0.001
N-stage (N0:N1:N2:N3)	NS	NS	35:2:0:0	15:2:4:9	< 0.001
Distant metastasis (M0:M1)	NS	NS	37:0	25:5	< 0.001
Overall stage (I:II:III:IV)	NS	NS	37:0:0:0	7:12:6:5	< 0.001

¹Tumor location is divided into three areas: lower third (antrum-angle), middle third (low body-middle body), and upper third (upper body-cardia).

²Control group includes individuals with normal mucosa or patients with simple chronic superficial gastritis and chronic atrophic gastritis.

³High-risk group included patients with intestinal metaplasia and dysplasia.

⁴Continuous data were compared by ANOVA test and nominal data by χ² test. P < 0.05 (two-tailed) was considered statistically significant. AGC: Advanced gastric cancer; EGC: Early gastric cancer; H. pylori: Helicobacter pylori; Mod: Moderate-differentiated carcinoma; Poorly: Poorly-differentiated carcinoma; SD: Standard deviation; Signet: Signet ring cell carcinoma; Well: Well-differentiated carcinoma.

Table 2 Serum levels of soluble heparin-binding epidermal growth factor-like growth factor and carcinoembryonic antigen according to disease groups

Groups	Control2 (n = 60)	High-risk3 (n = 30)	EGC (n = 37)	AGC (n = 30)	P value4
Serum sHB-EGF1 (pg/mL)	94.7 ± 83.6	98.7 ± 67.3	165.3 ± 123.2	314.4 ± 127.5	< 0.001
Serum CEA1 (ng/mL)	1.8 ± 1.5	2.2 ± 1.1	2.4 ± 1.4	4.5 ± 5.1	0.001

¹All tested values are expressed as the mean ± standard deviation.

²Control group includes individuals with normal mucosa or patients with simple chronic superficial gastritis and chronic atrophic gastritis.

³High-risk group included patients with intestinal metaplasia and dysplasia.

⁴One-way analysis of variance (ANOVA) test with the multiple comparisons by the post-hoc Bonferroni method is applied to compare the differences in means among disease groups. P < 0.05 (two-tailed) was considered statistically significant. AGC: Advanced gastric cancer; EGC: Early gastric cancer; CEA: Carcinoembryonic antigen; sHB-EGF: Soluble heparin-binding EGF-like growth factor.

Table 3 Serum levels of soluble heparin-binding epidermal growth factor-like growth factor between normal mucosa/chronic superficial gastritis and chronic atrophic gastritis or between normal mucosa and chronic superficial gastritis

Groups	Serum sHB-EGF1 (pg/mL)
Normal mucosa/CSG (n = 30)	86.4 ± 73.5
CAG (n = 30)	102.9 ± 93.1
P value2	0.449
Normal mucosa (n = 15)	83.1 ± 59.0
CSG (n = 15)	89.7 ± 87.6
P value2	0.811

¹Tested value is expressed as the mean ± SD.

²An independent sample t-test is applied to compare the differences of means between two groups. P < 0.05 (two-tailed) was considered statistically significant. sHB-EGF: Soluble heparin-binding EGF-like growth factor. CSG: Chronic superficial gastritis; CAG: Chronic atrophic gastritis.

Table 4 Serum levels of soluble heparin-binding epidermal growth factor-like growth factor and carcinoembryonic antigen between non-cancer and cancer groups

Groups	Non-cancer2(n = 90)	Cancer3(n = 67)	P value4
Serum sHB-EGF1 (pg/mL)	96.0 ± 78.2	232.1 ± 144.9	< 0.001
Serum CEA1 (ng/mL)	1.9 ± 1.4	3.3 ± 3.7	0.004

¹All tested values are expressed as the mean ± SD.

²Non-cancer groups include normal/gastritis group and IM/dysplasia group.

³Cancer groups include early gastric cancer (EGC) and advanced gastric cancer (AGC) groups.

⁴An independent sample t-test is applied to compare the differences of means between non-cancer and cancer groups. P < 0.05 (two-tailed) was considered statistically significant. CEA: Carcinoembryonic antigen; sHB-EGF: Soluble heparin-binding EGF-like growth factor.

Table 5 Correlations between serum soluble heparin-binding epidermal growth factor-like growth factor and clinicopathological characteristics of each group

Clinicopathological characteristics	Serum sHB-EGF	Serum CEA
	γs (P value)	γs (P value)
Age (yr)1	-0.265 (0.001)	-0.087 (0.275)
Sex (male:female)	0.138 (0.076)	-0.021 (0.792)
H. pylori infection (-/+)	-0.054 (0.486)	-0.114 (0.151)
Histology (well:mod:poorly:signet)	0.214 (0.078)	0.090 (0.465)
Tumor location (lower:middle:upper)	-0.052 (0.652)	-0.048 (0.691)
T-stage (T1a:T1b:T2:T3:T4)	0.669 (< 0.001)	0.201 (0.101)
N-stage (N0:N1:N2:N3)	0.407 (0.001)	0.073 (0.552)
Distant metastasis (M0:M1)	0.261 (0.030)	0.328 (0.006)
Overall stage (I:II:III:IV)	0.570 (< 0.001)	0.229 (0.060)
Size of tumor (< 3 cm; 3-5 cm and > 5 cm)2	0.237 (0.048)	0.362 (0.002)

¹This value is continuous variable. Thus, correlation is evaluated by Pearson’s correlation (γ_p).

²Subjects were classified into three groups according to primary GC size: < 3 cm, 3-5 cm, and > 5 cm to analyze the relationship between serum HB-EGF levels and primary GC size. CEA: Carcinoembryonic antigen; H. pylori: Helicobacter pylori; Mod: Moderate-differentiated carcinoma; Poorly: Poorly-differentiated carcinoma; Signet: Signet ring cell carcinoma; sHB-EGF: Soluble heparin-binding EGF-like growth factor; Well: Well-differentiated carcinoma; γ_s: Spearman’s correlation coefficient. P < 0.05 (two-tailed) was considered statistically significant. Statistically significant values are given in bold print.

Table 6 Pearson’s correlation between serum soluble heparin-binding epidermal growth factor-like growth factor and age in non-cancer groups vs cancer groups

Groups		Serum sHB-EGF	Serum CEA
		γp (P value)	γp (P value)
Non-cancer groups1	Age	-0.108 (0.313)	0.122 (0.265)
Cancer groups2	Age	-0.314 (0.010)	-0.187 (0.133)

¹Non-cancer groups include normal/gastritis and IM/dysplasia groups.

²Cancer groups include EGC and AGC groups. γ_p: Pearson’s correlation coefficient. Statistically significant values are given in bold print. AGC: Advanced gastric cancer; EGC: Early gastric cancer; sHB-EGF: Soluble heparin-binding epidermal growth factor-like growth factor; CEA: Carcinoembryonic antigen.

Table 7 Logistic regression determination of the diagnostic accuracy of serum soluble heparin-binding epidermal growth factor-like growth factor compared with those of serum carcinoembryonic antigen for prediction of gastric cancer

Markers1	Cut-off point2	Sensitivity	Specificity
Serum sHB-EGF	0.38	76.1%	76.5%
Serum CEA	0.38	62.1%	51.8%
Serum sHB-EGF + CEA	0.38	77.3%	76.5%

¹Each marker is included as a linear term and evaluated as a panel from one to two markers combination.

²Cut-off point means the probability cut-off point to classify subjects as having gastric cancer (GC) or not in binary logistic regression. CEA: Carcinoembryonic antigen; sHB-EGF: Soluble heparin-binding epidermal growth factor-like growth factor.