The median follow-up duration was 50 months, and 15 cases eventually died. The 1-, 3-, and 5-year OS rates after surgical resection were 87.2%, 61.7%, and 43.7%, respectively (Figure 1A). According to the univariate analysis, high intratumoral LC3 expression, microvascular invasion, tumor number, and tumor size were remarkably associated with OS (Table 3).
Table 3
Univariate and multivariate Cox regression analyses LC3 for overall survival and disease-free survival of patients in the cohort
Univariate analysis
|
Overall survival
|
|
Disease-free survival
|
|
|
Hazard ratio (95% CI)
|
P-value
|
Hazard ratio (95% CI)
|
P-value
|
LC3 in tumor (low vs. high)
|
3.81 (1.35-10.8)
|
0.012
|
5.15 (1.47-17.9)
|
0.01
|
Sex ( male vs. female)
|
0.47 (0.10-2.20)
|
0.34
|
4.85 (1.19-19.7)
|
0.027
|
Age (≥60 vs. <60 years)
|
2.46 (0.73-8.24)
|
0.145
|
2.33 (0.64-8.38)
|
0.195
|
Alcohol use (absent vs. present)
|
0.43 (0.15-1.20)
|
0.108
|
3.64 (0.98-13.1)
|
0.053
|
HBV (negative vs. positive)
|
3.16 (0.89-11.8)
|
0.078
|
0.76 (0.21-2.73)
|
0.674
|
HCV (negative vs. positive)
|
2.98 (0.37-23.8)
|
0.303
|
0.03 (0.01-52.2)
|
0.36
|
Cirrhosis (absent vs. present)
|
1.68 (0.57-4.99)
|
0.349
|
0.20 (0.04-1.02)
|
0.054
|
Child-Pugh class A
|
|
|
|
|
Edmondson-Steiner Grades (I-II vs. III-IV)
|
0.88 (0.20-3.95)
|
0.878
|
3.93 (0.96-16.0)
|
0.057
|
Tumor size (<5 vs. ≥5 cm)
|
3.08 (1.19-13.7)
|
0.037
|
43.6 (0.18-173)
|
0.174
|
Tumor number (single vs. multiple)
|
0.33 (1.02-1.33)
|
0.039
|
0.04 (0.01-12.9)
|
0.547
|
AFP (<200 vs. ≥200 ng/ml)
|
0.32 (0.08-1.22)
|
0.095
|
4.32 (0.94-19.6)
|
0.059
|
Resection (R0 vs. R1/2)
|
1.14 (0.39-3.31)
|
0.808
|
3.29 (0.91-11.8)
|
0.069
|
Microvascular invasion (absent vs. present)
|
0.24 (0.08-0.70)
|
0.009
|
1.55 (0.42-5.64)
|
0.506
|
Macrovascular invasion (absent vs. present)
|
0.53 (0.11-2.61)
|
0.44
|
0.37 (0.00-189)
|
0.45
|
Lympho nodules metastasis (absent vs. present)
|
1.69 (0.46-6.22)
|
0.425
|
3.92 (0.96-16.0)
|
0.057
|
Distal metastasis (absent vs. present)
|
|
|
|
|
AJCC stage (I-II vs. III-IV)
|
1.69 (0.46-6.22)
|
0.425
|
3.92 (0.96-16.0)
|
0.057
|
BCLC stage (A/B vs. C)
|
0.92 (0.30-2.75)
|
0.883
|
2.71 (0.67-10.9)
|
0.161
|
Recurrence (absent vs. present)
|
1.56 (0.47-5.20)
|
0.466
|
|
|
|
|
|
|
|
Multivariate analysis
|
Overall survival
|
|
Disease-free survival
|
|
|
Hazard ratio (95% CI)
|
P-value
|
Hazard ratio (95% CI)
|
P-value
|
LC3 in tumor (low vs. high)
|
6.74 (1.68-26.9)
|
0.007
|
51.3 (2.85-922)
|
0.008
|
Tumor number (single vs. multiple)
|
0.03 (0.00-0.34)
|
0.004
|
|
|
Microvascular invasion (absent vs. present)
|
0.07 (0.01-0.46)
|
0.006
|
|
|
Tumor size (<5 vs. ≥5 cm)
|
3.78 (0.39-36.1)
|
0.248
|
|
|
Sex ( male vs. female)
|
|
|
15.8 (0.77-322)
|
0.073
|
Cirrhosis (absent vs. present)
|
|
|
17.9 (1.05-306)
|
0.046
|
Resection (R0 vs. R1/2)
|
|
|
0.77 (0.11-5.05)
|
0.789
|
HR: Hazard ratio; CI: Confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; INR: International normalize ratio; AFP: Alpha-fetoprotein; AJCC: American Joint Committee on Cancer. BCLC: Barcelona clinic liver cancer.
|
The multivariate regression analysis presented that high intratumoral LC3 expression remarkably correlated with improved OS (hazard ratio [HR]: 6.74, 95% Confidence interval [CI]: 1.68–26.9, p = 0.007), but multiple tumors and microvascular invasion remarkably correlated with poor OS (HR: 0.03, 95% CI: 0.01–0.34, p = 0.004 and HR: 0.07, 95% CI: 0.01–0.46, p = 0.006, respectively), as shown in Table 3.
Patients with high intratumoral LC3 expression had a remarkably better OS than those with low LC3 expression, as revealed by Kaplan–Meier analysis. The 1-, 3-, and 5-year OS rates were 90.7%, 66.8%, and 61.2% in high LC3 patients and 71.4%, 35.8%, and 0% in low LC3 patients, respectively (Figure 2A). Furthermore, patients with microvascular invasion had a remarkably poorer OS than those without microvascular invasion. The 1-, 3-, and 5-year OS rates were 70.9%, 30.4%, and 0% in patients with microvascular invasion and 96.0%, 75.4%, and 51.4% in those without microvascular invasion, respectively (Figure 2B). However, tumor numbers were not remarkably associated with OS (p = 0.08, Figure 2C).
Prognostic factors correlated with DFS in cHCC-CC patients underwent surgical resection
Tumor recurrence was observed in 10 patients. The 1-, 3-, and 5-year DFS rates after surgical resection were 87.5%, 71.8%, and 57.4%, respectively (Figure 1B). According to the univariate analysis, those factors remarkably correlated with DFS: female, cirrhosis, R0 resection, and high intratumoral LC3 expression.
The multivariate regression analysis revealed that patients with high intratumoral LC3 expression had higher DFS rate (HR: 51.3, 95% CI: 2.85–922, p = 0.008) followed by cirrhosis (HR: 17.9, 95% CI: 1.05–306, p = 0.046), as presented in Table 3.
Patients with high intratumoral LC3 expression had remarkably higher DFS rates than those with low LC3 expression. The 1-, 3-, and 5-year DFS rates were 93.9%, 74.6%, and 74.6% in high LC3 patients and 57.1%, 57.1%, and 0% in low LC3 patients, respectively (Figure 3A). In addition, patients with cirrhosis had remarkably higher DFS rates than those without cirrhosis. The 1-, 3-, and 5-year DFS rates were 100%, 100%, and 71.4% in patients with cirrhosis and 81.5%, 40.7%, and 0% in those without cirrhosis, respectively (Figure 3B).