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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2015 Nov 1;8(11):14853–14863.

Combined detection of preoperative serum CEA, CA19-9 and CA242 improve prognostic prediction of surgically treated colorectal cancer patients

Jingtao Wang 1, Xiao Wang 1, Fudong Yu 1, Jian Chen 1, Senlin Zhao 1, Dongyuan Zhang 1, Yang Yu 1, Xisheng Liu 1, Huamei Tang 2, Zhihai Peng 1
PMCID: PMC4713601  PMID: 26823815

Abstract

We assessed the prognostic significance of preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 242 (CA242) levels in surgically treated colorectal cancer patients. The relationship of preoperative serum CEA, CA19-9 and CA242 levels with disease characteristics was investigated in 310 patients. Correlation between tumor markers was investigated using Pearson correlation test. Univariate and multivariate survival analyses were used to study the relationship between preoperative tumor markers and prognosis [disease free survival (DFS) and overall survival (OS)]. Kaplan-Meier analysis with log rank test was used to assess the impact of tumor marker levels on survival. Positive rate of preoperative serum CEA, CA19-9 and CA242 were 54.84%, 47.42% and 37.10%, respectively. High preoperative CEA level was associated with tumor size (P = 0.038), T stage (P < 0.001) and AJCC stage (P = 0.002). High preoperative CA19-9 level was associated with tumor AJCC stage (P = 0.023). Preoperative CA242 positively correlated with CEA (P < 0.001) and CA19-9 (P < 0.001). Combining the three markers was of independent prognostic value in CRC (HR = 2.532, 95% CI: 1.400-4.579, P = 0.002 for OS; and HR = 2.366, 95% CI: 1.334-4.196, P = 0.003 for DFS). Combined detection of preoperative serum CEA, CA19-9 and CA242 is of independent prognostic value for management of CRC patients treated surgically.

Keywords: Carcinoembryonic antigen, carbohydrate antigen 19-9, carbohydrate antigen 242, prognosis, colorectal cancer

Introduction

Colorectal cancer (CRC) represents the third most common and the third most lethal cancer in the world [1]. In 2012, more than 1,360,600 individuals were diagnosed with colorectal cancer and almost 693,900 died from this malignancy worldwide [2]. Despite advances in surgical and adjuvant therapy, the long-term survival of this disease was not satisfactory because of tumor recurrence and metastasis [3]. Classification of high- and low-risk patients with colorectal cancer requires a different strategy. Early intervention is more conducive to successful treatment. Preoperative assessment and classification of patient outcomes is of great clinical significance.

Serological tumor markers play an important role in the diagnosis, monitoring, prognosis and even treatment of many cancers [4,5]. Serum tumor markers are non-invasive, low-cost, popular and convenient tools for widespread clinical application. In colorectal cancer, serum tumor assays are valuable adjuncts to clinical examination in preoperative assessment and postoperative monitoring of patients [6].

Carcinoembryonic antigen (CEA), first introduced as a tumor-associated serum biomarker by Gold and Freedman in 1965, was the most widely used tumor marker [7]. CEA occurs in malignant tissue especially gastrointestinal carcinomas, benign disease and also in normal healthy individuals. Due to low sensitivity and specificity, CEA is of no value in colorectal cancer screening [8]. Although CEA is related to poor outcome of CRC patients [9], its role as an independent prognostic factor for CRC is controversial. Some studies showed that preoperative CEA is an independent predictor of survival, whereas others reported adverse conclusions [10-12]. Carbohydrate antigen 19-9 (CA19-9)was an isolated Lewis antigen of the MUC1 protein, extracted from colon cancer cell line SW1116 in 1979 [13]. CA19-9 was used in the diagnosis and prognosis of pancreatic cancer, colorectal cancer, gastric cancer and other gastrointestinal tumors [14-16]. Compared with CEA, CA19-9 is a less sensitive marker in colorectal cancer and is often used in combination with CEA to manage CRC patients. Carbohydrate antigen 242 (CA242), first defined in 1983, was obtained by immunizing mice with a human colorectal carcinoma cell line COLO 205 and fusion with the Sp 2/0 mouse myeloma cell line [17]. A meta-analysis revealed that serum CA242 played an important role in the diagnosis of pancreatic cancer [18]. Recent studies showed that CA242 was a prognostic factor in colorectal cancer [19]. The purpose of the present investigation was to assess the significance of preoperative serum tumor markers CEA, CA19-9 and CA242 in predicting outcome [disease-free survival (DFS) and overall survival (OS)] of surgically treated CRC patients. The results showed that the combined preoperative CEA, CA19-9 and CA242 was an independent prognostic factor and improved the prognostic value in patients with colorectal cancer after surgery.

Materials and methods

Patients and inclusion criteria

This retrospective study enrolled 310 patients admitted to Department of General Surgery, First People’s Hospital, Shanghai Jiao Tong University from January 2003 to December 2010 and was approved by the Institutional Review Boards of Shanghai Jiao Tong University Affiliated Shanghai First People’s Hospital Medical Center. All patients received tumor resection in this hospital under the same surgical team and provided informed consents in advance. The inclusion criteria were: (i) Patients received curative tumor resection, (ii) Tumor histopathology indicated colorectal adenocarcinoma, (iii) Patients had not received any chemotherapy or radiotherapy before surgery, (iv) Preoperative serum was available and CEA, CA19-9 and CA242 levels were detected, (v) Patients were available for follow-up. The clinicopathological features and staging were determined according to the American Joint Committee on Cancer TNM (AJCC) classification guidelines [20].

Serum CEA, CA19-9, and CA242 level evaluation

A total of 5 ml fasting peripheral venous blood was obtained from each patient the day before surgery. Using C12 protein biochip system (Shanghai Health-Digit Co, Ltd, China), the serum levels of CEA, CA19-9 and CA242 were detected [21-23]. According to the manufacturer’s instructions, the cutoff values for CEA, CA19-9 and CA242 were 5 ng/ml, 35 U/ml and 20 U/ml, respectively, and a value lower than the cutoff was considered negative.

Follow-up

All patients were followed up at 3-month intervals for the first 2 years, and then at 6-month intervals thereafter. Follow-up evaluation included patient’s history, physical examination, laboratory test, ultrasonic inspection, X-rays and computed tomography (CT) as needed. The last follow-up was performed in January 2014 via telephone, with a median follow-up time of 71 months (range, 37-129 months). Overall survival (OS) was determined from the time of surgery to death from CRC or to the last follow-up time. Disease-free survival (DFS) was defined as the time from surgery until tumor recurrence (local or metastatic) or death due to CRC.

Statistical analysis

The IBM SPSS version 20.0 software for Windows (IBM, Armonk, NY, USA) was used for data analysis. The precise level of tumor markers were expressed as median, mean and ran-ge value. Relationship between serum tumor markers and CRC clinicopathological variables was determined using Pearson’s Chi-square test or Fisher exact test. Pearson correlation analysis was used in correlation analysis of CEA, CA19-9 and CA242. Survival curves were plotted using Kaplan-Meier method and analyzed by log rank test. The Cox proportional hazards model was performed for univariate and multivariate analyses of OS and DFS. The confidence intervals (CIs) were set at 95% and a P-value of < 0.05 (two-sided) was considered statistically significant.

Results

Patient demographics

From January 2003 to December 2010, 2825 CRC patients received surgical resection in our medical center. Based on our strict inclusion criteria, 310 patients were enrolled in our retrospective study finally. Of these, 152 patients were men (49.0%) and 158 patients were women (51.0%). The median age was 65.90 years (range: 24-89 years). Distribution of the patients based on the American Joint Committee on Cancer TNM classification (AJCC) by stage of the primary CRC was as follows: 64 (20.6%) with stage I disease, 127 (41.0%) with stage II disease and 119 (38.4%) with stage III disease (Table 1).

Table 1.

Characteristic of 310 colorectal cancer patients

Variable n CEA- CEA+ P-value CA19-9- CA19-9+ P-value CA242- CA242+ P-value
(n = 140) (n = 170) (n = 163) (n = 147) (n = 195) (n = 115)
Age (year)
    < 65 138 71 67 0.051 81 57 0.067 94 44 0.098
    ≥ 65 172 69 103 82 90 101 71
Sex
    Male 152 61 91 0.088 83 69 0.497 99 53 0.481
    Female 158 79 79 80 78 96 62
Location
    Colon 176 76 100 0.490 89 87 0.424 109 67 0.723
    Rectum 134 64 70 74 60 86 48
Size (cm)
    < 5 174 88 86 0.038* 88 86 0.492 105 69 0.343
    ≥ 5 136 52 84 75 61 90 46
T stage
    T1 20 12 8 < 0.001* 14 6 0.164 15 5 0.384
    T2 58 39 19 35 23 39 19
    T3 166 68 98 83 83 104 62
    T4 66 21 45 31 35 37 29
N stage
    N0 191 88 103 0.906 108 83 0.111 125 66 0.400
    N1 86 38 48 37 49 49 37
    N2 33 14 19 18 15 21 12
AJCC stage
    I 64 41 23 0.002* 43 21 0.023* 46 18 0.214
    II 127 47 80 65 62 79 48
    III 119 52 67 55 64 70 49
Differentiation
    Well 51 26 25 0.648 26 25 0.182 33 18 0.628
    Moderate 190 83 107 107 83 122 68
    Poor 69 31 38 30 39 40 29
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*

P < 0.05.

Correlation between tumor markers and clinicopathological variables

The median preoperative CEA, CA19-9 and CA242 levels were 5.08 ng/ml (mean, 17.56; range, 0.20-1171.11), 11.08 U/ml (mean, 32.46; range, 0.60-555.22) and 12.36 U/ml (mean, 21.53; range, 0.10-200.00), respectively. Of the 310 patients, 170 (54.84%) showed positive preoperative serum CEA levels (≥ 5 ng/ml), 147 (47.42%) contained positive preoperative serum CA19-9 levels (≥ 35 U/ml) and 115 (37.10%) manifested high positive preoperative serum CA242 levels (≥ 20 U/ml) (Table 1). The positive rate for CEA, CA19-9 and CA242 was 54.84%, 47.42% and 37.10%, respectively. Positive serum CEA levels significantly correlated with tumor size (P = 0.038), T stage (P < 0.001) and AJCC stage (P = 0.002). Positive preoperative serum CA19-9 levels were significantly correlated with AJCC stage (P = 0.023).

Correlation between tumor markers

Pearson Correlation revealed that CEA was positively correlated with CA242 (P < 0.001, r = 0.368), but not with CA19-9 (P = 0.208, r = 0.072) while CA19-9 positively correlated with CA242 (P < 0.001, r = 0.612). Additional statistics is presented in Table 2.

Table 2.

Correlation between tumor markers CEA, CA19-9 and CA242

CEA CA19-9 CA242
CEA
    Pearson correlation 1 0.072 0.368**
    significance (two-tailed) 0.208 0.000
    N 310 310 310
CA19-9
    Pearson correlation 0.072 1 0.612**
    significance (two-tailed) 0.208 0.000
    N 310 310 310
CA242
    Pearson correlation 0.368** 0.612** 1
    significance (two-tailed) 0.000 0.000
    N 310 310 310
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**

Significant at level of P = 0.01 (two-tailed).

Combined detection of CEA, CA19-9 and CA242

The combined effect was assessed by considering the combined value as negative when all the three markers were negative, otherwise rated as positive. The combination of the three biomarkers increased positive rate from 54.84% to 71.61%. Combined detection of the three markers appeared to be significantly correlated with patient age (P = 0.006), T stage (P < 0.001) and AJCC stage (P = 0.001) (Table 3).

Table 3.

Correlation between clinicopathologic factors and combined tumor markers

Variable n Combined 3 markers P-value
Negative Positive
Sum 310
Age (year)
    < 65 138 50 88 0.006*
    ≥ 65 172 38 134
Sex
    Male 152 37 115 0.121
    Female 158 51 107
Location
    Colon 176 47 129 0.451
    Rectum 134 41 93
Size (cm)
    < 5 174 53 121 0.360
    ≥ 5 136 35 101
T stage
    T1 20 10 10 < 0.001*
    T2 58 25 33
    T3 166 46 120
    T4 66 7 59
N stage
    N0 191 91 130 0.113
    N1 86 22 64
    N2 33 5 28
AJCC stage
    I 64 30 34 0.001*
    II 127 31 96
    III 129 27 92
Differentiation
    Well 51 14 37 0.983
    Moderate 190 54 136
    Poor 69 20 49
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*

P < 0.05.

Survival and tumor markers

Kaplan-Meier survival analysis was based on different preoperative serum CEA, CA19-9 and CA242 levels. Log rank test was used to evaluate their significance in OS and DFS. Compared with low serum levels, high levels of serum CEA, CA19-9 CA242 and combined markers appear to have decreased the OS (P = 0.027, 0.031, 0.002 and 0.001, respectively) (Figure 1A-D). Compared with low serum levels, high levels of serum CEA, CA19-9, CA242 and combined markers appear to have decreased the DFS (P=0.002, 0.002, 0.002 and 0.001, respectively) (Figure 2A-D).

Figure 1.

Figure 1

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Kaplan-Meier survival curves depicting outcomes according to the level of preoperative CEA, CA19-9 and CA242 levels. A. Preoperative CEA levels with overall survival; B. Preoperative CA19-9 levels with overall survival; C. Preoperative CA242 levels with overall survival; D. Combined Preoperative CEA, CA19-9 and CA242 levels with overall survival.

Figure 2.

Figure 2

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Kaplan-Meier survival curves depicting outcomes according to the level of preoperative CEA, CA19-9 and CA242 levels. A. Preoperative CEA levels with disease free survival; B. Preoperative CA19-9 levels with disease free survival; C. Preoperative CA242 levels with disease free survival; D. Combined Preoperative CEA, CA19-9 and CA242 levels with disease free survival.

Univariate and multivariate analysis of OS and DFS

We performed Cox proportional hazards regression analysis to determine the prognostic value of clinicopathological factors including preoperative tumor markers. We first studied preoperative tumor markers individually, and then simultaneously. Factors that showed prognostic significance (P < 0.05) in the univariate analysis were included in the multivariate analysis.

In univariate analysis, tumor size, N stage, AJCC stage, differentiation, CEA level, CA19-9 level, CA242 level and the combined markers showed significant association with OS (P = 0.007, P = 0.001, P =0.016, P = 0.001, P = 0.001, P = 0.002, P = 0.001 and P = 0.002, respectively) (Table 4). In multivariate analysis, only tumor size, N stage, differentiation and the three markers combined, were independent prognostic factors (HR 1.634, 95% CI 1.065-2.507, P = 0.024; HR 1.528, 95% CI 1.163-2.007, P=0.002; HR 2.129, 95% CI 1.488-3.046, P < 0.001 and HR 2.532, 95% CI 1.400-4.579, P = 0.002, respectively) (Table 4).

Table 4.

Univariate and multivariate analysis of overall survival and disease free survival

OS DFS
Variable Univariate P-value Mutivariate P-value Univariate P-value Mutivariate P-value
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)
Age
    < 65 1 0.053 1 0.070
    ≥ 65 1.543 (0.995-2.393) 1.486 (0.968-2.281)
Sex
    Male 1 0.114 1 0.085
    Female 0.710 (0.465-1.085) 0.693 (0.457-1.052)
Location
    Colon 1 0.660 1 0.762
    Rectum 0.909 (0.593-1.392) 0.937 (0.617-1.425)
Size
    < 5 cm 1 0.007* 1.634 (1.065-2.507) 0.024* 1 0.004* 1.696 (1.113-2.584) 0.014*
    ≥ 5 cm 1.789 (1.169-2.738) 1.852 (1.218-2.815)
T stage
    T1 1 0.053 1 0.037* 1.129 (0.781-1.631) 0.520
    T2 1.795 (0.393-8.193) 1.801 (0.395-8.221)
    T3 3.578 (0.872-14.692) 3.855 (0.940-15.807)
    T4 3.962 (0.934-16.809) 4.009 (0.945-17.007)
N stage
    N0 1 0.001* 1.528 (1,163-2.007) 0.002* 1 0.001* 1.514 (1.158-1.978) 0.002*
    N1 1.324 (0.810-2.164) 1.413 (0.877-2.277)
    N2 2.881 (1.663-4.991) 2.805 (1.622-4.850)
AJCC stage
    I 1 0.016* 1.027 (0.611-1.726) 0.919 1 0.009* 1.004 (0.529-1.904) 0.991
    II 1.824 (0.901-3.692) 1.906 (0.944-3.849)
    III 2.627 (1.320-5.229) 2.796 (1.409-5.548)
Differentiation
    Well 1 0.001* 2.129 (1.488-3.046) < 0.001* 1 0.002* 2.032 (1.429-2.889) < 0.001*
    Moderate 3.948 (1.429-10.910) 3.224 (1.290-8.054)
    Poor 6.360 (2.239-18.061) 5.165 (2.003-13.317)
CEA (Negative vs. Positive) 2.099 (1.332-3.307) 0.001* 1.460 (0.798-2.670) 0.219 1.968 (1.264-3.062) 0.003* 1.358 (0.754-2.445) 0.308
CA19-9 (Negative vs. Positive) 1.997 (1.298-3.073) 0.002* 1.139 (0.509-2.549) 0.751 1.902 (1247-2.900) 0.003* 1.088 (0.485-2.441) 0.837
CA242 (Negative vs. Positive) 1.984 (1.303-3.021) 0.001* 1.523 (0.741-3.131) 0.253 1.918 (1.269-2.900) 0.002* 1.539 (0.748-3.165) 0.242
Combined 3 markers (Negative vs. Positive) 2.599 (1.441-4.688) 0.002* 2.532 (1.400-4.579 0.002* 2.446 (1.383-4,326) 0.002* 2.366 (1.334-4.196) 0.003*
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*

P < 0.05.

Univariate analysis of tumor size, T stage, N stage, differentiation, CEA level, CA19-9 level, CA242 level and the combined three markers showed significant association with DFS (P = 0.004, P = 0.037, P = 0.001, P = 0.002, P = 0.003, P = 0.003, P = 0.002 and P = 0.002, respectively) (Table 4). Multivariate analysis revealed only tumor size, N stage, differentiation and the three markers were independent prognostic factors (HR 1.696, 95% CI 1.113-2.584, P = 0.014; HR 1.514, 95% CI 1.518-1.978, P = 0.002; HR 2.302, 95% CI 1.429-2.889, P < 0.001 and HR 2.366, 95% CI 1.334-4.196, P = 0.003 respectively) (Table 4).

Discussion

The American Joint Cancer Commission/tumor-node-metastasis (AJCC/TNM) classification is widely used as a guideline for staging and represents the best prognostic indicator of outcomes in colorectal cancer patients [20,24]. Histopathological types are also reported to predict the outcome of CRC patients [25]. In clinical practice, accurate AJCC TNM staging and histopathological analysis depend on postoperative pathological detection and diagnosis, which is the gold standard for cancer diagnosis. However, serum tumor markers are easily detected presurgically. Serum CEA, CA19-9 and CA242 are now widely used as tumor markers for both prognostic prediction and post-treatment surveillance of patients with colorectal cancer. Recent studies have focused on the prognostic value of serum tumor markers in CRC [26,27]. However, they usually focused on only one or two markers on special stage CRC patients or their sample sizes were small. To the best of our knowledge, limited work has been conducted to simultaneously investigate the prognostic value of multiple preoperative tumor markers in CRC patients.

Our findings indicate that CRC patients with larger tumor size (> 5 cm) tend to have high serum CEA levels. Kirat HT et al reported that a preoperative CEA level greater than 5 ng/ml correlated with bigger tumor size in colon cancer [28]. In gastric cancer, high preoperative CEA and CA19-9 levels correlated with bigger tumor size [29]. The interaction between CEA and tumor bulk may explain our observations. Tumor markers are produced by tumor cells following abnormal oncogene expression. Greater tumor size implied higher number of tumor cells suggesting a potential correlation between CEA levels and tumor mass.

The influence of tumor histological grade on plasma CEA levels has been controversial with some reports showing moderately differentiated tumors associated with higher serum CEA levels compared with poorly differentiated and well-differentiated tumors [30,31]. Studies showed poorly differentiated tumors contained the highest serum CEA level [32]. Other studies reported well-differentiated carcinomas with the highest level of CEA [33,34]. Our results suggested no significant differences between histologically differentiated colorectal tumors, consistent with some studies [35,36]. Multicenter studies with larger sample sizes are needed to resolve this controversy.

Consistent with other studies [19,37-39], our findings confirm that high levels of preoperative CEA and CA19-9 markers were associated with advanced tumors including T and AJCC stages. Tumor staging is the best prognostic indicator of outcome in colorectal cancer. However, a few patients with similar pathologic stages may display considerable variation in clinical outcomes. Therefore, prognostic factors that are independent of tumor stage and capable of identifying patients with different clinical outcomes for further treatment are desirable. We found that the expression of CEA, CA19-9 and CA242 was associated with advanced disease and poorer survival. The prognosis was poorer in patients with CEA more than 5 ng/ml. Similar results were obtained in CRC patients with higher CA19-9 and CA242 levels. Interestingly, although high CEA, CA19-9 and CA242 levels were associated with poorer outcome, none of them was an independent prognostic biomarker according to our study. Multivariate analysis revealed that combined detection of these three serum tumor markers was an independent prognostic indicator.

In our study, the positive rates for CEA, CA19-9 and CA242 were 54.84%, 47.42% and 37.10%, respectively. Studies have reported widely varying rates of these markers, for example, 20.67%-82.22% for CEA [14,28,40-42] probably due to different sample volumes, detection assays and cut-off values used. The CA242 level was highly consistent with CA19-9 in diagnosis and prognosis of CRC [39]. Our study confirms that CA242 not only correlated with CA19-9 but also CEA. Studies have indicated that the combined detection of tumor markers may improve diagnostic value and prognostic significance compared with single tumor marker. Combining the three markers yielded a positive rate of 71.61% suggesting that the combination of these markers maybe preferable to single tumor marker in improving diagnostic accuracy.

In 2007, the European Group on Tumor Markers (EGTM) published evidence-based clinical practice guidelines for the use of tumor markers in CRC [43]. CEA has been recommended for prognostic surveillance following curative resection and monitoring of therapeutic response in advanced disease. However, the EGTM guidelines found insufficient data to recommend the popular tumor markers comprising CEA, CA19-9 and CA242 for screening, diagnosis, staging, surveillance, or therapeutic monitoring of patients with CRC. Our study indicated that a combination of CEA, CA19-9 and CA242 improved diagnostic sensitivity of CRC from 54.84% to 71.61%. Combined analysis of preoperative CEA, CA19-9 and CA242 enables classification of patients into groups with distinct survival probabilities and the best prognostic significance in colorectal cancer after surgery. These data imply that a combined detection of tumor markers might be a more efficient strategy in clinical practice.

Our study is limited by its retrospective nature and single-center design. We also failed to stratify patients on the basis of different postoperative treatments such as chemotherapy, radiotherapy and other adjuvant therapies, which affect patient outcomes. Multi-center, high-quality, stratified and prospective studies including postoperative treatments are needed to confirm the clinical significance of combination serum tumor markers.

In summary, preoperative serum levels of CEA, CA19-9 and CA242 are associated with poor outcome in patients with colorectal cancer. However, none of them appears to be an independent prognostic factor. Tumor size, T stage, N stage, AJCC stage, differentiation and combined detection of CEA, CA19-9 and CA242 were also related to poor outcome. Tumor size, N stage, differentiation and combined detection of CEA, CA19-9 and CA242 were independent prognostic factors for CRC. A combined analysis of preoperative serum CEA, CA19-9 and CA242 provides adequate data for clinical assessment and management of CRC.

Acknowledgements

This study was funded by the following: National High Technology Research and Development Program (SS2014AA020803), National Natural Science Foundation of China (81220108021), Project of Shanghai Science and Technology Commission (14411950502), Joint Research Projects of Shanghai Municipal Hospital (SHDC12012105) and Project of Shanghai JiaoTong University (YG2012ZD01).

Disclosure of conflict of interest

None.

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