Prognostic markers affecting the early recurrence of hepatocellular carcinoma with liver cirrhosis after curative resection

Abstract

Background:

Early recurrence is associated with poor prognosis after curative resection for hepatocellular carcinoma. Thus, we studied which factors, including this inflammation-based scoring system, affect disease recurrence in single hepatocellular carcinoma patients with liver cirrhosis.

Methods:

A total of 430 consecutive hepatocellular carcinoma patients were enrolled in our institution between January 2002 and December 2015. Survival rate, univariate, and multivariate analyses were performed to identify the variables associated with recurrence and early recurrence especially.

Results:

The overall survival rate was significantly lower in the early recurrence group than in the non-early recurrence group (P<0.001). According to the multivariate analysis, protein induced by vitamin K absence or antagonist (PIVKA) greater than 200 (P=0.035), neutrophil-to-lymphocyte ratio greater than 2.0 (P<0.001), elevated Glasgow prognostic score (P=0.003), tumor size greater than 5 cm (P=0.002), and the presence of lymphovascular invasion (P=0.002) were significantly different among the groups and affected the early recurrence of hepatocellular carcinoma. The patients were categorized into five levels of risk for early recurrence according to the number of independent risk factors, and patients with no risk factors were set as the reference group.

Conclusion:

Neutrophil-to-lymphocyte ratio, Glasgow prognostic score, and serum level of PIVKA offer significant prognostic information associated with early recurrence following single lesion hepatocellular carcinoma patients with liver cirrhosis after curative resection.

Keywords

Carcinoma hepatocellular prognosis survival rate lymphocytes liver neoplasms

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide.^1–3 Although there are other treatment modalities, such as trans-arterial chemoembolization (TACE) and radiofrequency ablation for the HCC, the surgical treatment—including liver transplantation—is still considered to be the most definitive option. In hepatitis B virus (HBV) endemic areas, such as Korea, the incidence of HCC accompanied by liver cirrhosis (LC) is very common, which increases the risk of surgical treatment and affects the postoperative high recurrence rate. High recurrence rate is closely related to low survival rate, and early recurrence (ER) is known to have a very negative effect on patient survival rate.^4–6

The risk factors for postoperative tumor recurrence can be classified into three major categories: tumor factor, such as size and number of tumors; host factor, such as degree of cirrhosis and viral load of hepatitis; and surgical factor, such as positive surgical margins. The tumor and surgical factors have been identified for certain parts, whereas the host factor has not been established yet. There is increasing evidence that correlates the presence of systemic inflammation with poorer cancer-specific survival in certain tumors.^7–9 Current understanding suggests that the host’s inflammatory response to tumor and the systemic effects exerted by the tumor leads to the up-regulation of the inflammatory process. Some studies have demonstrated that HCC cells produce interleukin-6 (IL-6)—which is the principal regulator of C-reactive protein (CRP) production—and several inflammation-based scoring systems, including the Glasgow prognostic score (GPS) and the neutrophil-to-lymphocyte ratio (NLR), which have been reported as useful prognostic indicators.^10–13

In the past, only aggressive tumor biology, such as tumor number and tumor size, was considered a risk factor for ER; however, various background factors, such as chronic inflammatory liver disease and cirrhosis, are currently being investigated.¹⁴ The strategies for ER may be the key to improving the prognosis of HCC patients, and the identification of clinicopathological features and risk factors for ER may be useful for guiding the management of HCC

Thus, we studied which factors, including this inflammation-based scoring system, affect disease recurrence in single HCC patients with HBV LC. In particular, we focused on the risk factor and recurrence features of the ER.

Material and methods

This study was reviewed and approved by the Institutional Review Board of our institute. The study protocol was approved by the ethics committee of Korea Medical Center. All data were analyzed retrospectively.

Patient selection

Data of patients, who underwent curative resection of the liver at our institution between January 2002 and December 2015, were collected. During the study period, 526 cases received curative liver resection for HCC underlying HBV LC. Of the 526 cases, 66 were excluded because they were multiple tumors, and 30 cases were excluded due to lack of data. All HCCs and LC was confirmed histolopathologically after resection.

Curative resection is defined as the absence of tumor in the remnant liver after confirming R0 resection pathologically.

Combined HCC and cholangiocarcinoma (CCC) is excluded in this study. Recurrence within 2 years after hepatic resection was defined as the ER group. Clinicopathologic factors that were potentially associated with survival and recurrence were selected in this study, including age, sex, tumor markers (serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist (PIVKA)), type of resection (anatomical resection (AR) or non-anatomical resection (non-AR)), aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, albumin, HBV DNA titer, NLR, GPS, tumor size, tumor differentiation, and pathological microvascular invasion (MVI).

Operative procedure

In non-AR, we dissected the liver along a line to secure the surgical margin of at least 2 cm. The final decision to perform non-AR was based on factors such as hardness of the liver, tumor location by ultrasound, and degree of collateral vessels around the liver. In AR, each hepatic pedicle, including the anterior, posterior, and left Glissonian pedicles, was always isolated to enable performance of the pringle maneuver, as needed. The hepatic pedicle was systematically encircled with a tourniquet to allow for intermittent clamping if necessary. Liver parenchymal transection was performed using a Cavitron Ultrasonic Surgical Aspirator (CUSA Excel; Integra Lifescience, Plainsboro, NJ, US) and an energy device (Thunderbeat; Olympus Medical Systems Corp., Tokyo, Japan). Before the introduction of Thunderbeat, a harmonic scalpel (Ultracision; Ethicon Endo-surgery, Cincinnati, OH, US) was used as an energy device.

In certain cases, an intermittent Pringle maneuver was used, consisting of repeated cycles of 15 min of ischemia followed by 5 min of reperfusion. Intra-parenchymal control of the vessels was obtained using Hem-o-lok (Weck Closure System, Research Triangle Park, NC, US) or metal clips. Hemostasis was achieved by mono-polar electrocoagulation, argon beam, or non-absorbable sutures. Systemic routine placement of an abdominal drain was performed during surgery.

Follow-up

After discharge from the hospital, all patients were followed up at hepatobiliary clinics and have 2-monthly abdominal computed tomography (CT) and 4-monthly chest CT performed during the first postoperative year with tumor markers (AFP and PIVKA). After that, the examination was performed every 3 to 6 months. In addition, liver magnetic resonance imaging (MRI) was used to define suspicious lesions demonstrated on CT and/or a raised tumor maker. A positron emission tomography-CT (PET-CT) scan was performed every 2 years to check for systemic recurrence.

If suspected recurrence was seen during follow-up, liver MRI, chest CT, bone scan, and PET-CT were performed, and when multiple recurrence sites were found after the screening exam, each site was counted for recurrence.

GPS and NLR

Blood samples were collected within 1 month before surgery and all blood test results, including inflammation-related blood tests, were checked in a stable state before the preoperative examination, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous trans-hepatic biliary drainage (PTBD). Patients with neither an elevated CRP level (>1.0 mg/dL) nor hypoalbuminemia (<3.5 g/dL) were assigned a GPS of 0. Patients with either one or the other of these biochemical abnormalities were assigned a GPS of 1. Patients with both elevated CRP and albumin levels were assigned a GPS of 2. The NLR was calculated from the differential leukocyte count by dividing the absolute neutrophil count by the absolute lymphocyte count.

Statistical analysis

Data with a normal distribution were reported as means (SD). Variables not fitting a normal distribution were presented as medians (range). Continuous variables were compared using the Student’s t-test if normally distributed; otherwise, the Mann–Whitney U-test was used.

Categorical variables were compared using the chi-square test. The patient overall survival (OS) was estimated using the Kaplan–Meier method and compared with log-rank tests. Data were considered statistically significant at P < 0.05. Multivariate models were manually built using a forward strategy. Statistical analysis was conducted with SPSS 22.0 for Windows (SPSS, Chicago, IL, US). Receiver operating characteristic (ROC) analysis was used to choose the optimal cut-off value of NLR, HBV DNA, AFP, and PIVKA.

Results

During the follow-up period, 196 cases recurred and were divided into the ER group (n=78) and the late recurrence (LR) group (n=118). The mean follow-up period of the ER group (n=78) was 34.76 ± 28.65 months, and the mean follow-up period of the non-ER (n=352) group was 69.15 ± 29.47 months. In the ER group, the follow-up period of less than 1 year was 18 cases, of which 12 died and 6 were lost to follow-up. During the follow-up period, 39 cases died in the ER group and 22 were lost to follow-up. In the non-ER group, 34 cases died and 25 were lost to follow-up. In-hospital mortality was not observed in either group.

Validation of the optimal cutoff value of AFP, PIVKA, HBV DNA, and NLR

The recommended cutoff value for each parameter was determined at the most prominent points on the ROC curves for sensitivity and specificity. According to the ROC curve, the optimal cutoff value of HBV DNA was 2.0 (Log₁₀ value) (IU/mL), AFP was 40 (ng/mL), PIVKA was 200 (mAU/mL), and NLR was 2.0. Among these, the value confirmed for NLR and PIVKA, was statistically significant (NLR: AUC 0.792, 95% CI 0.709, 0.874, sensitivity 80.39%, specificity 72.84%, P=0.001; PIVKA: AUC 0.757, 95% CI 0.723, 0.854, sensitivity 75.12%, specificity 70.42%, P=0.001).

Demographic features and survival rate of the ER and non-ER groups

When comparing the ER group with the non-ER group, significant differences were observed in the serum level of PIVKA (P=0.007), NLR (P=0.001), GPS (P=0.001), Edmondson–Steiner (ES) grading (P=0.002), tumor necrosis (P=0.004), and MVI (P=0.001). However, HBV DNA and type of resection did not show a significant difference between the two groups. Unlike the comparison between the recur and the non-recur groups, there was no difference between ER and non-ER group in male ratio and operation time; however, in ES grading, there was a significant difference between the two groups. Table 1 summarizes the demographic data and postoperative outcomes of the ER and the non-ER groups.

Table 1.

Demographic data of the ER and non-ER group.

	ER (N = 78)	Non-ER (N = 352)	P-value
Age			0.911
<60	54 (66.7)	227 (64.6)
⩾60	24 (33.3)	125 (35.4)
Sex, n (%)			0.834
male	63 (80.4)	274 (77.8)
female	15 (19.6)	78 (22.2)
BMI (kg/m²)	24.4±3.1	24.0±2.9	0.394
Preoperative laboratory data
Child-Pugh			0.030
A	61 (78.4)	319 (90.6)
B	17 (21.6)	33 (9.4)
Platelet count (x10³/uL)			0.882
<100	32 (41.1)	141 (40.5)
⩾100	46 (58.9)	211 (59.5)
AST	48.45±33.57	55.90±49.47	0.422
ALT	46.47±33.38	55.97±49.23	0.271
Total bilirubin (mg/dl)			0.537
< 1.0	47 (72.5)	274 (77.8)
⩾ 1.0	31 (27.5)	78 (22.2)
Albumin	4.08±0.45	4.12±0.33	0.328
HBV DNA (Log₁₀ value)			0.227
<2.0	31 (43.1)	189 (53.8)
⩾2.0	47 (56.9)	163 (46.2)
AFP (ng/mL)			0.206
<40.0	44 (56.9)	238 (67.5)
⩾40.0	34 (43.1)	114 (32.5)
PIVKA (mAU/mL)			0.001
<200	46 (58.8)	309 (87.7)
⩾200	32 (41.2)	43 (12.3)
NLR			0.001
<2.0	44 (21.6)	280 (79.7)
⩾2.0	34 (78.4)	72 (20.3)
GPS			0.001
0	50 (64.7)	326 (92.6)
1 and 2	28 (35.3)	26 (7.4)
Peri- and postoperative data
Type of resection			0.617
AR	37 (47.1)	148 (42.0)
Non-AR	41 (52.9)	204 (58.0)
Amount of bleeding (mL)	871.57±756.72	819.75±795.87	0.711
Operating time (min)	200.23±80.12	179.01±90.01	0.177
Tumor size (cm)			0.001
<5	40 (50.9)	297 (84.4)
⩾5	38 (49.1)	55 (15.6)
Edmondson–Steiner grading			0.003
1 and 2	9 (11.8)	125 (35.4)
3 and 4	69 (88.2)	227 (64.6)
Tumor necrosis			0.003
absent	35 (45.1)	243 (68.9)
present	43 (54.9)	109 (31.1)
MVI			0.001
absent	15 (19.6)	274 (77.8)
present	63 (80.4)	78 (22.2)
Perioperative complication
Overall complications	17 (21.6)	61 (17.3)	0.782
Ascites	2 (2.6)	6 (1.7)
Pleural effusion	3 (3.8)	9 (2.5)
Fluid collection at op site	4 (5.1)	15 (4.2)
Bile leakage	3 (3.8)	12 (3.4)
Wound problem	3 (3.8)	12 (3.4)
Postoperative bleeding	2 (2.6)	6 (1.7)

AFP: alpha-fetoprotein AR: anatomical resection; AST: aspartate transaminase; BMI: body mass index; GPS: Glasgow prognostic score; MVI: microvascular invasion; NLR: neutrophil-to-lymphocyte ratio; PIVKA: protein induced by vitamin K absence or antagonist.

Kaplan–Meier survival analysis of patients with ER revealed a significantly poor OS compared to the patient with non-ER. Survival rates of 1, 3, and 5 years were 79.1%, 52.4%, and 49.3%, respectively, in the ER group and 98.7%, 93.6%, and 86.2%, respectively, in the non-ER group (Figure 1).

Figure 1.

Comparison of overall survival rate between the ER and the non-ER group.

Risk factor analysis affecting ER

In the univariate analysis, the following variables affecting survival were statistically significant: PIVKA (⩾200), NLR (⩾2.0), GPS (1 & 2), ES grading (3 & 4), tumor size (⩾5), the presence of tumor necrosis, and the presence of MVI. Additionally, analysis of the prognostic factors using multivariate analysis revealed PIVKA, NLR, GPS, tumor size, and the presence of MVI as independent risk factors predicting ER (Table 2).

Table 2.

Risk factor analysis affecting the early recurrence of hepatocellular carcinoma.

Variables	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (⩾ 60 vs. <60)	1.33 (0.73, 2.39)	0.351
Gender (male vs. female)	0.76 (0.38, 1.51)	0.425
CTP score ( B vs. A)	1.80 (0.92, 3.52)	0.084
Total bilirubin (⩾ 1.0 vs. < 1.0)	0.91 (0.49, 1.69)	0.767
Platelet count (⩾ 100k vs. < 100k)	0.97 (0.71, 1.21)	0.911
AFP (⩾ 40.0 vs. < 40.0)	1.51 (0.87, 2.64)	0.141
PIVKA (⩾ 200 vs. < 200)	2.11 (1.51, 3.69)	0.008	1.85 (1.29, 2.42)	0.035
NLR (⩾ 2.0 vs. < 2.0)	5.91 (2.95, 11.83)	<0.001	3.84 (1.86, 7.93)	<0.001
HBV DNA (⩾ 2.0 vs. < 2.0)	1.53 (0.87, 2.68)	0.138
GPS ( 1 & 2 vs. 0 )	3.39 (1.91, 6.05)	<0.001	2.50 (1.35, 4.62)	0.003
Type of resection (AR vs. non AR)	1.04 (0.60, 1.81)	0.882
ES grading (3&4 vs. 1&2)	3.32 (1.42, 7.79)	0.006	1.32 (0.52, 3.38)	0.56
Tumor size (⩾ 5 vs. <5)	2.71 (1.56, 4.70)	0.001	1.96 (1.44, 2.57)	0.002
Tumor necrosis (present vs. absent)	2.35 (1.35, 4.08)	0.002	1.26 (0.63, 2.49)	0.516
MVI (present vs. absent)	5.82 (2.91, 11.66)	<0.001	3.29 (1.57, 6.91)	0.002

AFP: serum alpha-fetoprotein; AR: anatomical resection; CI: confidence interval; CTP: GPS: Glasgow prognostic score; HBV: hepatitis B virus; HR: hazard ratio; MVI: microvascular invasion; NLR: neutrophil-to-lymphocyte ratio; PIVKA: protein induced by vitamin K absence or antagonist.

The patients were categorized into five levels of risk for ER according to the number of independent risk factors, and the patients with no risk factors were set as the reference group. The ER rates were stratified according to the number of risk factors for ER (P<0.0001) (Figure 2).

Figure 2.

Early recurrence (ER) rates after hepatectomy according to the number of risk factors for ER. The ER rates were significantly higher with a greater number of risk factors (P< 0.0001).

The area under the curve (AUC) of ROC was 0.898 (95% CI 0.849, 0.946), and the sensitivity of our scoring system was 82.5%, specificity was 90.2%, positive predictive value was 44.5%, and negative predictive value was 2.8%. The Youden index reached a maximum when the risk factor was more than 2 in the scoring system

Comparison of recurrence site and post-recurrence treatment of the ER and LR groups

In both groups, the liver was the most common site followed by lung and lymph node in the ER group, followed by lymph node and lung in the LR group. In the LR group, liver recurrence was shown more often (72.9% vs. 53.8%) than in the ER group, and the extra-hepatic metastasis was more frequent in the ER group. TACE was the most frequent treatment for recurrence in both groups, followed by surgical resection (Table 3).

Table 3.

Recurrence site and post-recurrence treatment.

Recur site	ER group (n = 78)	LR group (n = 118)
Liver	42 (53.8)	86 (72.9)
Lung	15 (19.2)	10 (8.5)
Bone	3 (3.8)	2 (1.7)
Lymph node	10 (12.8)	12 (10.2)
Peritoneum	5 (6.4)	5 (4.2)
Others	3 (3.8)	3 (2.5)
Treatment after recurrence
Surgical resection	15 (19.2)	25 (21.1)
TACE	35 (44.8)	65 (55.1)
RFA	8 (10.2)	12 (10.2)
Chemotherapy	10 (12.8)	10 (8.5)
No treatment	10 (12.8)	6 (5.1)

ER: early recurrence; LR: late recurrence; RFA: radiofrequency ablation; TACE: trans-arterial chemoembolization.

Discussion

Surgical treatment for HCC is the most basic method for its curative treatment, but the postoperative high recurrence rate is a stumbling block to the survival rate of HCC. In particular, HCC with LC has a higher recurrence rate than those without LC, leading to a lower survival rate. Several studies have shown that ER is associated with poorer prognosis.^1,3,15 The definition of the ER period varies from 6 months to 2 years according to several papers, but we defined it as 2 years and then proceeded with the study. Many studies have reported the factors affecting ER, and factors such as AFP, PIVKA, MVI, tumor size, tumor number, and tumor differentiation are currently known. Also, we identified that the survival rate of ER group is significantly lower compared to the non-ER group in this study.

Zhu et al.¹⁶ showed that the level of AFP (>800 ng/mL), multiple tumor, and microvascular invasion were risk factors for HBV-related ER HCC (less than 1 year). Du et al.⁵ also revealed that independent risk factors for ER HCC (less than 2 years) were the multiplicity of tumors and venous infiltration. The authors identified five variables that showed significant differences between non-ER and ER groups by using the logistic regression method: PIVKA, NLR, GPS, tumor size, and MVI. In addition to these risk factors, the presence of an association between systemic inflammation and ER has been discussed and published, especially in cases of colorectal carcinoma.^17–19

Recently, inflammation-based assessment tools, such as GPS and NLR based on CRP, have been developed and recommended in various institutions. In particular, HBV DNA titers are considered as risk factors in HCC patients.^12,20–22

In this study, HBV DNA titer was identified as a factor affecting recurrence but is not a significant factor in ER. However, systemic inflammation markers, such as NLR and GPS, as well as PIVKA, tumor size, and MVI, showed significant differences in ER as well as recurrence. Furthermore, by confirming that the cutoff value of 200 for the serum level of PIVKA and 2.0 for NLR is an independent prognostic factor for ER, the authors recommend to establish a strategy for HCC treatment as well as traditional tumor node metastasis staging.

AFP and PIVKA are routinely measured in the diagnosis of HCC, detecting recurrence and predicting prognosis, and high levels of AFP and PIVKA are known to be associated with tumor size and degree of differentiation. In this study, however, only PIVKA greater than 200 showed significant results, except AFP. Postoperative HCC recurrence is thought to occur in two ways: intrahepatic metastasis in the residual liver, and multicentric hepato-carcinogenesis based on hepatitis.⁴ MVI is known to be one of the important factors of intrahepatic metastasis. The three factors identified in the multivariate analysis indicate that both of the above pathways are related to the ER of single HCC with HBV LC.

In the last decade, several retrospective studies have been conducted on the clinical efficacy of the systemic inflammation-based scoring system, such as NLR and GPS. Since albumin and CRP production could be decreased in this population due to impaired liver function, Ishizuka et al.²³ proposed new cutoff values for hepatic GPS. However, we applied conventional GPS rather than hepatic GPS because of the concern that 80%–90% of our cohort is composed of child A patients and that the liver function impairment is not likely to occur in cohort. In the present study, elevated GPS was significantly different in the ER group than in the non-ER group, and it was confirmed that the survival rate of the ER group was a statistically significant factor.

NLR is a useful predictor of postoperative mortality in patients with different types of cancer and is easy to use. Since 2008, several reports revealed that the preoperative NLR level was a prognostic factor for recurrence-free survival and OS after curative resection and liver transplantation of HCC.^22,24–26 We confirmed that NLR is a predictor of ER with a cutoff value set to 2.0, and that it was an independent factor affecting the survival rate of the ER group as well as elevated GPS. As far as the authors are aware, there have been no studies suggesting the cutoff value of NLR in the ER of single HCC in the hepatitis B environment.

The relationship between systemic inflammation and carcinogenesis has been recognized, although the detailed mechanism underlying how inflammation influences cancer progression. One possible explanation is that the host’s immune response to tumor is lymphocyte dependent. High NLR levels mean absolutely less lymphocyte counts than neutrophils, which also mean relative lymphocytopenia. This circumstance may result in exhibiting a poorer lymphocyte-mediated immune response to malignancy, thereby worsening their prognosis and increasing the risk of tumor recurrence.^27–29 Among the many cytokines produced during a lymphocyte-mediated immune response, some cytokines, such as IL-6 and vascular endothelial growth factor, are known to play an important role in the progression of HCC.^10,11,30

Another point to consider regarding the low survival rate of the ER group is that extra-hepatic metastasis is more common than in the non-ER group. Considering that modalities, such as TACE and resection, can be considered as an additional treatment for hepatic recurrence, the high tendency of extra-hepatic metastasis in the ER group may affect the low survival rate.

When the recurrence rate was calculated according to the number of risk factors that were found to affect ER, we identified a recurrence rate of more than 30% in patients with two or more risk factors. In patients with more than four risk factors, they had an ER rate of 100%, although this was only small number of patients.

Therefore, we recommended that it should be performed systematic examination including the PET, bone scan and chest CT within 1 year after surgery in patients with risk factors for early recurrence identified through our study, especially those who have more than two. Several studies have been attempted to validate the aggressiveness of the tumor biology by responding to some preoperative treatment modalities, such as TACE and immunotherapy, in a group with a high risk of recurrence. In this study, the Edmondson–Steiner grading, the extent of tumor necrosis, and the MVI were significantly different in the ER group compared to the non-ER group. Additionally, in the case of patients with high GPS, NLR, and PIVKA, if these parameters improved and consequently survival rate and recurrence improved, comprehensively considering these parameters would be a great help in establishing a strategy for patient treatment. The authors believe that more research is needed in the future.

Our study has some limitations. First, the sample size was small, because this was a retrospective single-center study. Future huge prospective cohort studies involving multiple institutions should be performed. Second, the cohort of this study was performed as a single disease entity in a single underlying disease. It may be necessary to extend the study to other liver tumors, including HCC exposed to various environments including hepatitis C.

Conclusion

Our study validated the prognostic factors that affect ER of single lesion HCC with HBV LC after curative resection, and identified the ideal cutoff values of the risk factors. GPS and NLR may be used as important tools for predicting ER if further research has been conducted on their relationship with HCC progression. An additional treatment modality, such as TACE and chemotherapy, should be considered to improve the survival rate of patients with elevated GPS, NLR, and PIVKA preoperatively.

Footnotes

Author contributions

WJK developed the concept and designed the study. TWL and PJP analyzed and interpreted the data. SBC, WBK, and WJK drafted and revised the manuscript. All of authors approved the final version of the manuscript.

Declaration of conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

This study was approved by the Ethics Committee of the Korea University Guro Hospital (No. 2018GR0106).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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