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Abstract

BACKGROUND:

Oxidative stress plays an important role in promoting proliferation and metastases of cancer, which can be represented by ischemia-modified albumin (IMA). The purpose of this study was to evaluate serum IMA level in patients with operable advanced gastric cancer and analyze its prognostic significance.

MATERIALS AND METHODS:

A total of 274 patients with primary stage III gastric cancer underwent curative operation were enrolled in this study. Serum IMA level was measured within 24 hours before surgery, comparing with 112 healthy donors. The correlation between serum IMA level and survival outcome was analyzed by the Kaplan-Meier with Log-Rank test and Cox’s regression methods, respectively.

RESULTS:

Serum IMA level from gastric cancer was higher than healthy control (0.41 $\pm$ 0.12 VS 0.23 $\pm$ 0.08; $P<$ 0.001). Finally, 173 and 181 patients out of all 274 patients studied had died and recurrent, respectively. All patients were stratified into two groups using the optimal cutoff value (0.45) of IMA level using a sensitivity of 92.5% and a specificity of 65.2% as optimal conditions from receiver operating curve analysis. Patients with a IMA $\geqslant$ 0.45 had poorer mean overall survival (44.68 months VS 30.94 months, $P=$ 0.010) and mean recurrence free survival (42.36 months VS 28.82 months, $p=$ 0.01) than patients with a IMA $<$ 0.45 in univariate analysis and IMA also been confirmed as independent predictor for survival for GC patients in multivariate analysis (OR, 0.731; 95% CI: 0.329–1.282; $p=$ 0.023).

CONCLUSIONS:

Serum IMA level can be considered as an independent prognostic factor for operable and advanced gastric cancer.

Keywords

Ischemia-modified albumin survival gastric cancer

1. Introduction

Gastric cancer accounted for the third most prevalent malignancy in the world, which also represents the second most frequent cancer and the third leading cause of cancer-related deaths in China [1, 2]. Although significant advances in gastric cancer treatment have been achieved through endoscopic surgery, new therapeutic approaches and multidisciplinary teamwork, prognosis of gastric cancer is far from satisfying, with a 5-year survival rate of 29.6% [3, 4, 5]. Surgery remains the only curative treatment approach for localized gastric cancer [6]. However, 50%–90% patients with advanced gastric cancer die of local recurrent or distant metastasis after a curative resection [7, 8, 9]. For localized advanced cancer, the important of preoperative risk stratification of the patients though prognostic factors which can be obtained easily and inexpensively has been increasingly recognized [7, 10, 11]. It has been revealed that oxidative stress plays an important role in promoting proliferation, tumor invasion and development of metastases [12, 13]. However, there was no sufficient data of the association between gastric cancer risk and parameters of oxidative stress.

Oxidative stress involves macromolecular oxidative damage, induces tissue protein denaturation, DNA damage, and lipid peroxidation, and interferes with the body’s normal metabolic activity, leading to the occurrence and/or development of cancer [14, 15]. Reactive oxygen species (ROS) as main active oxides mediating oxidative stress, are involved in the occurrence and development of cancer through the induction of DNA damage and genetic mutations, inhibition of apoptosis, and promotion of the proliferation, invasion, and metastasis of tumor cells [16, 17]. Overproduction of ROS results in ischemia-modified albumin (IMA) formation in vivo by oxidative modification of serum albumin [18, 19]. IMA has been confirmed as a useful biomarker for oxidative stress [20]. Otherwise, increased IMA levels were detected in in gastric cancer [21]. However, there was no study concerning the clinical value of serum IMA level in gastric cancer, especially for localized advanced diseases.

In this study, we try to furtherly evaluate the serum IMA level in patients with advanced gastric cancer and analyzed its prognostic significance.

2. Materials and methods

2.1 Patients

This prospective study enrolled 274 consecutive patients undergone curative resection for histologically confirmed stage III gastric cancer at the Digestive System Department in Shanxi Cancer Hospital between June 1, 2010 and June 1, 2016. According to the inclusion criteria, the study only involved histologically and clinically confirmed stage III gastric cancer cases, patients with age greater than 18 years old and life expectancy more than 6 months. Patients with preoperative severe comorbidity, such as other ischemic diseases, severe cardiac or neurological disorders, malignant disease, chronic inflammatory disease, acute and chronic infective disease, preexisting organ failure, chronic obstructive airways disease and immunosuppressive disorders, were excluded from the study. In addition, patients had extremely low or high serum albumin levels ( $<$ 20 or $>$ 55 g/L) were also excluded [22]. Likewise, patients that received preoperative adjuvant treatments and chemotherapy were excluded. A control group consisted of 112 healthy age- and sex-matched volunteers. Written informed consent was obtained from individual patients and subjects. This study was approved by the Ethics Committee of the Shanxi Cancer Hospital.

2.2 Clinical assessment

Clinical and histopathological data of all the patients were collected from the clinical records by one surgeon. This data, which included information such as gender, age, tumor site and size, T stage, lymph node status, TNM and pathological differentiation, was further checked by another surgeon. The histopathological and clinical staging of the tumors were evaluated though postoperative histopathological examination and clinical assessment, respectively, according to the according to the 7th American Joint Committee on Cancer (AJCC) TNM classification. Routine blood test and biochemical tests were performed on the day before the surgery to obtain serum C reactive protein level and serum albumin levels. Outcome was assessed as overall survival (OS) and recurrence-free survival (RFS). OS was accurately defined as the duration from date of surgery to death while RFS was calculated by the time of surgery to tumor recurrence.

2.3 Measurement of IMA

Five milliliter peripheral venous blood samples of all patients and control were obtained to evaluate serum IMA level on the day before the surgery. Serum IMA level was measured by using the method of Bar-Or et al. [23]. Briefly, 200 $\mu$ L of patient plasma was placed into glass tubes and 50 $\mu$ L of 0.1% cobalt chloride (Sigma-Aldrich, Germany) was added. After gentle shaking, the mixing solution was incubated for 10 minutes to ensure sufficient cobalt albumin binding. Then, 50 $\mu$ L of 1.5 mg/ml dithiothreitol (DTT) (Sigma-Aldrich, Germany) was added as a colorizing agent and the binding reaction was halted 2 minutes later by adding 1.0 mL of 0.9% NaCl. A colorimetric control was prepared for each samples. For control samples, 50 $\mu$ L of distilled water was used to instead of 50 $\mu$ L of 1.5 mg/mL DTT. Specimen absorbencies were analyzed at 470 nm by a spectrophotometer (Shimadzu UV1601, Australia). The color of the DTT containing specimens was compared with that of the colorimetric control tubes. The results were reported as absorbance units (ABSUs).

2.4 Follow-up

All Patients were followed up in regular intervals through outpatient visit including physical examination, laboratory examinations and imaging studies including blood routine test, biochemistry and tumor markers every 3 months for the first 2 years, every 6 months for the next 3 years, and once annually thereafter. Gastroscopy, and enhanced abdominal CT or MRI scans were performed generally every 12 months. Clinical follow-up lasted from the date of surgery to either the time of death or February 2017.

2.5 Statistical analysis

Analyses were performed with SPSS 20.0 (IBM, USA). $P<$ 0.05 (two sided) was considered as statistically significant level. Data for categorical variables are expressed as a percentage and continuous variables as mean $\pm$ SD. The optimal cutoff value of the serum IMA level predicting survival was determined though receiver operating characteristic (ROC) curve analysis. The $\chi$ 2 test or Fisher’s exact test was used to analyze categorical variables while continuous variables in normal distribution were analyzed by independent student’s t test, or by Mann-Whitney U-test in abnormal distribution. The OS and RFS and survival curve was studied in Kaplan-Meier analyses by using the log-rank test. The Cox regression model with Enter method was used to assess the OR and multivariate analysis.

3. Results

3.1 Patient

The baseline demographic and clinicpathologic characteristics of 274 patients, who undergone curative resection for histologically confirmed stage III gastric cancer, are shown in Table 1. There were 191 males and 83 females, an average age of 59.7 $\pm$ 5.6 years. The most frequently detected site of tumor formation was the stomach body, which accounted for 126 of 274 patients (46.1%). There were 91 patients identified with T2 tumor stage, and 183 patients with T3 or T4 tumor stage, according to the TNM staging protocol. In pathology, histopathological examination revealed that 160 patients presented with well/moderately differentiated adenocarcinomas, while 114 patients had poorly differentiated tumors. Moreover, there was no statistical significant association between the serum IMA level and clinicpathologic characteristics including age and gender of patients, tumor size, histological differentiation type, T stage and Lymph node involvement, except serum albumin (Table 1).

Table 1
Correlation between the serum IMA level and clinicpathologic characteristics in patients with stage III gastric cancer

Characteristic	IMA level (ABSU)		p
	$\geqslant$ 0.45	$<$ 0.45
	( $n=$ 188)	( $n=$ 86)
Age(years)			0.783
$\geqslant$ 60	93	41
$<$ 60	95	45
Gender			0.561
Male	129	62
Female	59	24
BMI (kg/m ${}^{2}$ )	22.3 $\pm$ 3.1	21.6 $\pm$ 2.8	0.075
Laboratory data
Albumin (g/L)	32.6 $\pm$ 6.2	26.8 $\pm$ 5.2	$<$ 0.001
CRP (mg/L)	112.4 $\pm$ 84.5	128.5 $\pm$ 78.4	0.136
Tumor site			0.700
Gastric cardia	41	23
Gastric body	88	38
Gastric antrum	49	25
Tumor size (cm)			0.998
$\geqslant$ 5	59	27
$<$ 5	129	59
Tumor invasion depth			0.500
T2	60	31
T3 $+$ T4	128	55
Lymph node involvement			0.613
N0	98	42
N1	90	44
Pathological differentiation			0.747
Well/Moderate	111	49
Poor	77	37

BMI, body mass index; IMA, ischemia-modified albumin; CRP, C-reactive protein.

3.2 Serum IMA level in patients with gastric cancer

The mean serum IMA level from 274 patients with stage III gastric cancer was 0.41 $\pm$ 0.12, which was significantly statistically higher than that of healthy control ( $n=$ 112; 0.23 $\pm$ 0.08; $P<$ 0.001), see in Fig. 1A. According to the ROC curve analysis, the optimal cutoff levels for the IMA predicting survival of gastric cancer patients was 0.45 using a sensitivity of 92.5% and a specificity of 65.2% as optimal conditions, respectively. The area under the curve was 0.794 with a 95% confidence interval (95% CI) for the area between 0.672 and 0.916, $P<$ 0.001 (Fig. 1B).

Figure 1.

Evaluation of serum IMA level in patients with advanced gastric cancer. Panel A showed the results of the analyzing difference of IMA level between patients with gastric cancer ( $n=$ 274) and healthy control ( $n=$ 112) (mean percentage of IMA in gastric cancer, 0.41 $\pm$ 0.12; in healthy subjects, 0.23 $\pm$ 0.08, $P<$ 0.001). Panel B showed the receiver-operator characteristic curve for IMA predicting survival of gastric cancer. the areas under the curve were 0.7394 with a 95% confidence interval (95% CI) for the area between 0.672 and 0.916, $P<$ 0.001.

Figure 2.

Prognostic significance of serum IMA level for stage III gastric cancer. Left panel showed the association between IMA and OS (mean OS in IMA $<$ 0.45, 44.68 months; in IMA $\geqslant$ 0.45, 30.94 months, $P=$ 0.010). Right panel showed the association between IMA and RFS (mean RFS in IMA $<$ 0.45, 42.36 months; in IMA $\geqslant$ 0.45, 28.82 months, $P=$ 0.010).

Table 2

Univariate and multivariate analyses of the prognostic factors of OS for stage III gastric cancer

	Univariate			Multivariate
	n	MS (months)	p	OR	95%CI	p
Age (years)			0.322
$\geqslant$ 60	134	31.81
$<$ 60	140	30.27
Gender			0.948
Male	191	26.72
Female	83	31.46
Tumor site			0.832
Gastric cardia	64	28.22
Gastric body	126	27.16
Gastric antrum	74	29.31
Tumor size (cm)			0.062
$\geqslant$ 5	86	26.48
$<$ 5	188	35.22
Tumor invasion depth			0.451
T2	91	32.43
T3 $+$ T4	183	22.72
Lymph node involvement			0.021	2.232	1.013–2.516	0.026
N0	140	38.26
N1	134	24.13
Pathological differentiation			0.042	1.437	1.031–2.725	0.041
Well/Moderate	160	31.25
Poor	114	24.12
IMA level			0.010	0.181–0.977	0.012	0.181–0.977
$<$ 0.45	86	44.68
$\geqslant$ 0.45	188	30.94

OS, overall survival; MS, median survival; CI, confidence interval; OR, odds ratio; IMA, ischemia-modified albumin.

Table 3

Univariate and multivariate analyses of the prognostic factors of RFS for stage III gastric cancer

	Univariate			Multivariate
	n	MS (months)	p	OR	95%CI	p
Age (years)			0.771
$\geqslant$ 60	134	27.18
$<$ 60	140	26.33
Gender			0.933
Male	191	25.34
Female	83	28.42
Tumor site			0.332
Gastric cardia	64	25.16
Gastric body	126	26.22
Gastric antrum	74	26.31
Tumor size (cm)			0.132
$\geqslant$ 5	86	25.48
$<$ 5	188	28.92
Tumor invasion depth			0.481
T2	91	28.43
T3 $+$ T4	183	22.62
Lymph node involvement			0.035	1.853	1.162–2.356	0.012
N0	140	36.26
N1	134	22.23
Pathological differentiation			0.022
Well/Moderate	160	30.05
Poor	114	22.18
IMA level			0.010	0.862	0.153–0.973	0.023
$<$ 0.45	86	42.36
$\geqslant$ 0.45	188	28.82

RFS, recurrent-free survival; MS, median survival; CI, confidence interval; OR, odds ratio; IMA, ischemia-modified albumin.

Figure 3.

Pathological differentiation stage wise survivability. Panel A and B showed that preoperative IMA was not significantly correlated with OS and RFS of patients with well or moderate differentiation gastric cancer while panel C and D showed there was significant association between IMA and OS and RFS of patients with poor differentiation gastric cancer.

3.3 Prognostic significance of serum IMA level for gastric cancer

The median follow-up time was 23.2 months (6.4–79.57 months). At the endpoint, 173 (63.14%) out of all 274 patients studied had died, including 44 (51.16%) in 86 patients with a IMA $<$ 0.45 and 129 (68.62%) out of 188 patients with a IMA $\geqslant$ 0.45, respectively. One hundred and thirty-four (71.28%) in group of 188 patients with a IMA $\geqslant$ 0.45 had tumor relapse while 47 (54.65%) in 86 patients with a IMA $<$ 0.45 suffered from recurrence. Kaplan-Meier univariate survival analysis showed lymph node involvement, histological differentiation type and preoperative IMA were related to postoperative survival of stage III gastric cancer patients. Among these prognostic factors, The mean OS of patients with preoperative IMA $<$ 0.45 was 44.68 months, which statistically significantly higher than 30.94 months of those with a IMA $\geqslant$ 0.45 ( $p=$ 0.01) (Table 2, Fig. 2). Furthermore, we obtained similar result in the multivariate analysis for OS (OR, 0.774; 95% CI: 0.181–0.977; $p=$ 0.012) (Table 2). Otherwise, in univariate analysis of RFS, patients with high IMA also had shorter mean RFS than patients with low IMA (42.36 months VS 28.82 months, $p=$ 0.01), and the IMA was also confirmed as a significant independent predictor for RFS in multivariate analysis (OR, 0.862; 95% CI: 0.153–0.973; $p=$ 0.023) (Table 3).

A multivariate analysis enrolled sex and gender of patients, tumor size, lymph node involvement, histological differentiation type and preoperative IMA into the COX regression model to determine independent prognostic factors for operable stage III gastric cancer. The result showed that IMA (OR, 0.774; 95% CI: 0.181–0.977; $p=$ 0. 012) and lymph node involvement (OR, 2.232; 95% CI, 1.013–2.516; $p=$ 0.026) and pathological differentiation (OR, 1.437; 95% CI, 1.031–2.725; $p=$ 0.041) were the independent prognostic factors for OS (Table 2). Furthermore, IMA (OR, 0.862; 95% CI: 0.153–0.973; $p=$ 0.023) and lymph node involvement (OR, 1.853; 95% CI, 1.162–2.356; $p=$ 0.012) were the independent prognostic factors for RFS (Table 3).

3.4 Relationships of the preoperative IMA with pathological differentiation for the prognosis of stage III gastric cancer

Furthermore, we also evaluate the correlation of preoperative IMA with the pathological differentiation for the prognosis of gastric cancer using Kaplan-Meier survival analysis. The mean OS of patients with a IMA $\geqslant$ 0.45 was not significantly poorer than that of patients with a IMA $<$ 0.45 for well or moderate differentiation gastric cancer (41.01 months VS 36.55 months, $p=$ 0.296), and the RFS analysis showed similar results (40.99 months VS 34.44 months, $p=$ 0.193). However, for poor differentiation tumor, patients with a IMA $<$ 0.45 can has better mean OS (42.35 months VS 24.74 months, $p=$ 0.004) and mean RFS (38.29 months VS 21.93 months, $p=$ 0.008), comparing to patients with a IMA $\geqslant$ 0.45 (Fig. 3A–D).

4. Discussion

In this study, we prospectively analyzed the preoperative serum IMA level of patients with stage III gastric cancer, and found that gastric cancer patients had a significant higher IMA level than healthy subjects, and that IMA level was a useful and independent predictor of survival in patients with advanced gastric cancer from univariate and multivariate analysis. Therefore, we confirmed that the serum IMA level can be examined for optimal risk stratification of individual patients with gastric cancer, and serum IMA level can serve as a biomarker for predicting postoperative prognosis of patients with advanced gastric cancer.

Oxidative stress plays an important role in the development of cancer [24, 25, 26]. oxidative stress induces production of ROS, and then cause tissue injury or DNA damage, and as mutagen that promotes tumor initiation. In detail, ROS can oxidize guanine in DNA and RNA to form 8-hydroxyguanine (8-OHG) [27], which potentially introducing missense mutations [28]. Moreover, a large body of study has found a strong correlation between the formation of 8-OHG and carcinogenesis [29, 30]. Release of oxygen free radicals resulting from ROS overproduction induces IMA formation in vivo by oxidative modification of serum albumin [18, 31]. Otherwise, IMA, as an easily and inexpensively measurable biomarker closely relating to oxidative stress, has been proved that increased in several cancer concerning oxidative stress, such as gastric cancer, colorectal cancer and bladder cancer [19, 32]. In this study, we furtherly confirmed serum IMA level in gastric cancer patients was higher than healthy subjects.

Oxidative stress can promote several pathways that enable tumor progression and aggressiveness through regulation of proliferation, apoptosis and invasion of tumor cells [33, 34]. Furthermore, the severity of tissue inflammation and oxidative stress is directly associated with prognosis of cancer [35]. Thus, IMA level, as a factor directly reflecting oxidative stress, has been confirmed as a potential prognostic biomarker in other diseases involved with oxidative stress, such as severe sepsis and myocardial infraction [32, 36]. In current study, we first explore prognostic significance of preoperative serum IMA level in patients with stage III gastric cancer, and found that serum IMA level was significantly associated with OS and RFS of patients with gastric cancer.

Furthermore, in this study, we firstly confirmed that serum IMA level was an independent marker of prognosis in gastric cancer patients comparing with other classical predictors including lymph node involvement and pathological differentiation. At the end of study, mortality rate was higher for patients with high IMA level than with lower levels, so physicians should be aware of the risk of patient with a high IMA level and provide more proactive intervention to decrease IMA level. However, IMA level is not a direct contributor to poor outcomes, but a marker of severe oxidative stress. Targeting the original abnormal process might be a reasonable strategy to decrease IMA levels, such as correcting tissue ischemia and mitochondrial target therapy [37].

4.1 Strengths and limitations of this study

Several limitations may influence the interpretation of the results of this study. One limitation is the single center study. A large-scale, multicenter, prospective study should be conducted to confirm long-term results and obtain more definite evidence. Furthermore, we analyzed the cutoff levels of the IMA level though ROC curve in a small cohort, may imply some overestimation [38]. Thus, the results of this study may not be comparable with those of other studies. A meta-analysis including various IMA validation studies may be required to confirm more definite cutoff values for the IMA.

In conclusion, our study confirmed that patients with advanced gastric cancer have higher serum IMA level, which was correlate with serum albumin level. More important, we found that preoperative serum IMA level was an independent prognostic factor for operable and advanced gastric cancer.

Footnotes

Conflict of interest

All authors declare that there exist no conflicts of interest in this study.

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Significance of preoperative ischemia- modified albumin in operable and advanced gastric cancer

Abstract

BACKGROUND:

MATERIALS AND METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Patients

2.2 Clinical assessment

2.3 Measurement of IMA

2.4 Follow-up

2.5 Statistical analysis

3. Results

3.1 Patient

Table 1 Correlation between the serum IMA level and clinicpathologic characteristics in patients with stage III gastric cancer

3.4 Relationships of the preoperative IMA with pathological differentiation for the prognosis of stage III gastric cancer

4. Discussion

4.1 Strengths and limitations of this study

Footnotes

Conflict of interest

References

Table 1
Correlation between the serum IMA level and clinicpathologic characteristics in patients with stage III gastric cancer