Clinica Chimica Acta 446 (2015) 82–85
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Survivin over-expression is correlated with a poor prognosis in esophageal cancer patients Haifeng Xia 1, Shaomu Chen 1, Haitao Huang, Haitao Ma ⁎ Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, People's Republic of China
a r t i c l e
i n f o
Article history: Received 3 December 2014 Received in revised form 3 April 2015 Accepted 6 April 2015 Available online 17 April 2015 Keywords: Survivin Prognosis Esophageal cancer Meta-analysis
a b s t r a c t Background: The prognostic role of survivin in esophageal cancer (EC) remains controversial. This meta-analysis aimed to clarify the association of survivin with survival in EC patients. Methods: Relevant studies published up to November 2014 were identified using PubMed and Embase. Only studies in which survivin was detected through immunohistochemical staining were included. STATA 12.0 was used in this meta-analysis. Results: A total of 9 studies, which comprised 610 patients, were included in the meta-analysis. The combined hazard ratio (HR) of 1.76 (95% CI, 1.40–2.21; P b 0.001) suggests that survivin overexpression in EC patients was significantly associated with poor overall survival. Moreover, the results showed a significant relationship between overall survival and survivin expression was also displayed in studies with a non-Asian country (HR, 1.75; 95% CI, 1.30–2.35), patient number ≥50 (HR, 1.86; 95% CI, 1.57–2.20), the cut-off level ≥5% (HR, 1.43; 95% CI, 0.94–2.17) and the esophageal squamous cell carcinoma (HR, 1.82; 95% CI, 1.43–2.30). However, combined odds ratio of survivin indicated that survivin overexpression has no correlation with stage, grade of differentiation, lymph node status, depth of invasion and distant metastasis of EC (P N 0.05). Conclusion: Survivin overexpression is associated with poor prognosis in EC patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Esophageal cancer (EC) is one of the malignant cancers worldwide and the common cause of cancer death [1]. Despite the rapid advancement in diagnosis and therapy for EC, the average 5-year overall survival has remained at 10–20% [2]. Therefore, to assess prognosis and establish reasonable treatment of EC patients, it is important for us to search an ideal tumor molecular marker. However, no specific biological marker can be used in EC routinely. Survivin, an inhibitor of apoptosis protein with a molecular weight of ~16.3 kDa, is considered to play an important role in cell proliferation, angiogenesis and inhibition of apoptosis [3–6]. Survivin seems to exist in either the nucleus or the cytoplasm of tumor cells, or both of these 2 subcellular pools [7]. Functionally, survivin has been implicated in inhibition of apoptosis, which directly inhibits caspase-3 and caspase-7 activity, thus preventing apoptosis [8]. Survivin is predominantly upregulated during the G2/M phase with a cell cycle dependent manner by the activation of cell cycle homology region within the promoter, suggesting that survivin can help cancer cells to overcome G2/M checkpoint to promote cell infinite proliferation [9]. Moreover, survivin has ⁎ Corresponding author. Tel.: +86 13606202960. E-mail address: [email protected] (H. Ma). 1 These authors contributed to the study equally.
http://dx.doi.org/10.1016/j.cca.2015.04.009 0009-8981/© 2015 Elsevier B.V. All rights reserved.
been showed to be over-expressed in almost all types of human tumors, but not detectable in most of normal adult tissues [10]. Accordingly, survivin may become a potential tumor marker. The expression of survivin has been reported to be a promising prognostic indicator, associated with a worse overall survival [11]. However, evidence regarding the value of survivin to predict prognosis of EC remains controversial. Therefore, we performed this meta-analysis to clarify this question. 2. Methods 2.1. Publication search PubMed and Embase electronic databases were searched for studies relating to survivin and EC up to November 2014. The following search terms were “survivin”, “esophageal cancer” and “esophageal carcinoma”. The references of retrieved articles were also manually searched for additional studies. No language of published articles was restricted. The published studies included in this meta-analysis should meet the following criteria: (1) measured survivin expression in primary EC tissues; (2) survivin evaluation using immunohistochemistry (IHC) and (3) relationship identified between survivin expression and EC prognosis. If the studies did not meet all inclusion criteria, they were excluded from our meta-analysis.
H. Xia et al. / Clinica Chimica Acta 446 (2015) 82–85
83
Table 1 Main characteristics of the studies included in the meta-analysis. First author
Year
Patient ethnicity
Patient number
Histology type
Stage
Clinicopathological features
Cut-off level
Grabowski Dabroski Rosato (1) Rosato (2) Mega Hsu Takeno (1) Takeno (2) Zhu Li Malhotra
2003 2004 2006 2006 2006 2009 2010 2010 2011 2012 2013
Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian East Asian East Asian Caucasian
84 42 56 56 122 46 71 71 102 50 37
ESCC ESCC EAC ESCC ESCC ESCC ESCC ESCC ESCC ESCC EAC
I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–III I–III
D, LN, T, M, S D, LN, T, M, S D, LN, T, S D, LN, T, S D, LN, T, M, S D, LN, T, M, S D, LN, T, M, S D, LN, T, M, S LN, T, M, S D, LN, T T, S
5% 5% 20% 20% Score 1 Score 175 10% 50% Score 0 NR NR
ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma; NR, not reported; D, histological differentiation; LN, lymph node metastasis; T, depth of tumor invasion; M, metastasis; S, stage.
2.2. Data extraction Data extraction was carried out independently by 2 authors (XHF and CSM) from eligible studies. The main characteristics of each study, such as first author's name, publication year of article, ethnic group of the study population, cut-off value level of survivin and clinicopathological parameters, were noted.
cut-off value level and histology type were conducted. In order to estimate the correlation between survivin overexpression and clinicopathological features (stage, grade of differentiation, lymph node status, the depth of invasion and distant metastasis), Odds ratios (ORs) and 95% CIs were combined. An observed OR N 1 suggested a worse prognosis for the group with survivin overexpression. The potential publication bias was assessed by Begg's funnel plot and Egger's test [15]. All analyses were performed using STATA ver 12.0 software [16]. The statistically significant test was decided by a P b 0.05.
2.3. Statistical analysis Survivin outcome data were synthesized using the time-to-event HR (a benefit of survival would be represented by an HR b1) [12]. When HR values were not given explicitly in an article, they were calculated from available numerical data or Kaplan–Meier survival curve [13]. The χ2-based Q statistic and I2 statistic were used to measure heterogeneity among studies. When P N 0.10 for the Q-test or I b 50% indicates a lack of heterogeneity among studies, a fixed effect model was selected to combine the data. Otherwise, a random effect model was used [14]. Subgroup analyses by stratifying on patient ethnicity, number of patients,
3. Results 3.1. Study characteristics On the basis of the inclusion criteria, there were nine eligible studies including 610 EC patients [17–25]. They were published between 2003 and 2013. Languages of those nine studies were written in English. The identified studies and main characteristics were listed in Table 1. The sample sizes ranged from 37 to 122 patients. Survivin expression was
Fig. 1. Forest plot of meta-analysis of the effect of survivin expression on survival in EC patients (group 1: nuclear survivin).
84
H. Xia et al. / Clinica Chimica Acta 446 (2015) 82–85
Table 2 Subgroup analysis of pooled HR of EC patients with survivin overexpression. Stratified analysis
I2 (%)
P value Q test
1.75 (1.30–2.35) 1.65 (1.49–1.82)
87.1 0
b0.001 NS
1.86 (1.57–2.20) 1.71 (0.32–9.03) 1.43 (0.94–2.17)
71.3 88.9
0.001 b0.001 b0.001
1.82 (1.43–2.30) 1.93 (0.43–8.58)
87.7 69.8
b0.001 NS
Pooled HR (95% CI) Random effects
Patient ethnicity Non-Asian Asian No. of patients ≥50 b 50 Cut-off level ≥ 5% Histology type ESCC EAC
HR, hazard ratio; 95% CI, 95% confidence interval.
evaluated by immunohistochemistry (IHC) in all of the included studies. Different cut-off values for the survivin expression level were used. 3.2. Meta-analysis results Fig. 1 shows the main results of this meta-analysis. The overall HR was 1.76 (95% CI, 1.40–2.21; test for heterogeneity P b 0.001). Three studies including 227 EC patients surveyed the association between overall survival (OS) and nuclear survivin. We found a statistical significance (HR, 1.89, 95% CI, 1.45–2.46, P b 0.001). We also performed subgroup analysis by patient ethnicity, number of patients, cut-off value level and histology type. The results revealed that a significant relationship between overall survival and survivin overexpression was also displayed in studies with a non-Asian country (HR, 1.75; 95% CI, 1.30– 2.35), patient number ≥ 50 (HR, 1.86; 95% CI, 1.57–2.20), the cut-off level ≥5% (HR, 1.43; 95% CI, 0.94–2.17) and the esophageal squamous cell carcinoma (HR, 1.82; 95% CI, 1.43–2.30) (Table 2). As shown in Table 3, survivin expression was correlated with stages (I/II vs. III/IV: OR, 0.43; 95% CI, 0.20–0.91), grade of differentiation (moderate/well vs. poor: OR, 1.54; 95% CI, 0.63–3.75), lymph node status (negative vs. positive: OR, 0.52; 95% CI, 0.25–1.11), the depth of invasion (T3/T4 vs. T1/T2: OR, 1.05; 95% CI, 0.24–4.65) and distant metastasis (positive vs. negative: OR, 1.02; 95% CI, 0.52–1.89), but without significance (P ≥ 0.05). 3.3. Publication bias The Begg's funnel plot and Egger's test were used in detecting publication bias in the meta-analysis. No evidence of publication bias was detected in the analysis of OS (Begg's test, P = 0.815; Egger's test, P = 0.844). 4. Discussion Meta-analysis is an effective method to combine the results of randomized controlled trails. Recently, this approach has been applied successfully for evaluation of prognostic indicators in patients with malignant diseases [26–28]. This meta-analysis aimed to explore the
Table 3 Meta-analysis of survivin overexpression and clinicopathological features of EC. Stratification
Pooled OR (95% CI)
P value
Fixed effects Stage Grade of differentiation Lymph node status The depth of invasion Distant metastasis OR, odds ratio.
0.43 (0.20–0.91) 1.54 (0.63–3.75) 0.52 (0.25–1.11) 1.05 (0.24–4.65) 1.02 (0.52–1.89)
0.05 0.34 0.09 0.95 0.98
Heterogeneity I2 (%)
P value
0 20.8 0 60.1 0
NS NS NS 0.009 NS
association between survivin upregulation and survival and clinicopathological features of EC. We combined the outcomes of 610 EC patients from 9 studies, showing that survivin overexpression significantly predicted poor OS. In addition, there seems to be survivin overexpression that was correlated with higher stages, higher grade of differentiation, lymph node metastasis, the higher depth of invasion and distant metastasis, but without significance (P N 0.05). These results are very important for treatment and prognosis of EC and improving the understanding of EC biology. Heterogeneity is a potential problem to affect meta-analysis results. We had dealt with a number of heterogeneity problems in this systematic review [29]. Firstly, we selected studies in which survivin was detected by immunohistochemical staining to reduce heterogeneity as far as possible. Furthermore, in the included studies we found that different cut-off values for survivin upregulation in tissues (scores 0–175, 5–50%) were applied. It is impossible to use subgroup analysis to solve this problem. Finally, the potential source of heterogeneity might be linked with the approach of deducing the HRs. We calculated the HRs from the survival curves when they were not obtained directly in the studies. However, this approach did not completely eliminate inaccuracy, showing that the extrapolated HR might be less reliable than the HR reported directly in the studies [30]. In this meta-analysis, we analyzed survivin overexpression and OS and the clinicopathological features in EC which made our analysis more valid. Further, Begg's and Egger's tests indicate no publication bias, showing that the present meta-analysis results were not biased and more convincible. However, this meta-analysis also has some limitations, and the results should be interpreted with caution [31]. First, there was significant heterogeneity in the included studies, we have already adopted various measures to reduce heterogeneity as far as possible. Second, due to lack of relevant original studies' information, such as the patients' age, comorbidity and sex, we could not perform these factors to subgroup analysis. Third, this meta-analysis depended on the published studies rather than the individual patient data (IPD). Because negative results were not more possibly published than the positive ones, the meta-analysis relied on the published data more likely to overestimate the effects of survivin compared with IPD analyses. Therefore, we tried to extract all relevant information; some missing data were still inevitable. Finally, in our research most of the patients were from western countries, which induce a problem about the results' external validity and applicability to the patients from Asia. So we performed subgroup analysis by patient ethnicity. In conclusion, for the first time, this meta-analysis indicated that survivin overexpression was significantly linked with poor OS in EC patients.
References [1] Wang Z, Qiao Q, Chen M, Li X, Wang Z, Liu C, et al. miR-625 down-regulation promotes proliferation and invasion in esophageal cancer by targeting Sox2. FEBS Lett 2014;588:915–21. [2] Koshy M, Esiashvilli N, Landry JC, Thomas Jr CR, Matthews RH. Multiple management modalities in esophageal cancer: combined modality management approaches. Oncologist 2004;9:147–59. [3] Reed JC, Bischoff JR. BIRinging chromosomes through cell division—and survivin' the experience. Cell 2000;102:545–8. [4] Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett 2006;244:164–71. [5] Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917–21. [6] Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci U S A 2002;99:4349–54. [7] Huang LN, Wang DS, Chen YQ, Zhao CL, Gong BL, Jiang AB, et al. Expression of survivin and patients survival in non-small cell lung cancer: a meta-analysis of the published studies. Mol Biol Rep 2013;40:917–24. [8] Machtay M, Jeremic B. Complex and controversial issues in locally advanced nonsmall cell lung carcinoma. Semin Surg Oncol 2003;21:128–37. [9] Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 1998;58:5315–20.
H. Xia et al. / Clinica Chimica Acta 446 (2015) 82–85 [10] Ulukus EC, Kargi HA, Sis B, Lebe B, Oztop I, Akkoclu A, et al. Survivin expression in non-small-cell lung carcinomas: correlation with apoptosis and other apoptosisrelated proteins, clinicopathologic prognostic factors and prognosis. Appl Immunohistochem Mol Morphol 2007;15:31–7. [11] Li C, Li Z, Zhu M, Zhao T, Chen L, Ji W, et al. Clinicopathological and prognostic significance of survivin over-expression in patients with esophageal squamous cell carcinoma: a meta-analysis. PLoS One 2012;7 [e44764]. [12] Xie YL, An L, Jiang H, Wang J. Nuclear survivin expression is associated with a poor prognosis in Caucasian non-small cell lung cancer patients. Clin Chim Acta 2012; 414:41–3. [13] Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. [14] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–60. [15] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. [16] Zhang LQ, Wang J, Jiang F, Xu L, Liu FY, Yin R. Prognostic value of survivin in patients with non-small cell lung carcinoma: a systematic review with meta-analysis. PLoS One 2012;7:e34100. [17] Grabowski P, Kühnel T, Mühr-Wilkenshoff F, Heine B, Stein H, Höpfner M, et al. Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma. Br J Cancer 2003;88:115–9. [18] Dabrowski A, Filip A, Zgodziński W, Dabrowska M, Polańska D, Wójcik M, et al. Assessment of prognostic significance of cytoplasmic survivin expression in advanced oesophageal cancer. Folia Histochem Cytobiol 2004;42:169–72. [19] Mega S, Miyamoto M, Li L, Kadoya M, Takahashi R, Hase R, et al. Immunohistochemical analysis of nuclear survivin expression in esophageal squamous cell carcinoma. Dis Esophagus 2006;19:355–9. [20] Rosato A, Pivetta M, Parenti A, Iaderosa GA, Zoso A, Milan G, et al. Survivin in esophageal cancer: an accurate prognostic marker for squamous cell carcinoma but not adenocarcinoma. Int J Cancer 2006;119:1717–22.
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[21] Takeno S, Yamashita S, Takahashi Y, Ono K, Kamei M, Moroga T, et al. Survivin expression in oesophageal squamous cell carcinoma: its prognostic impact and splice variant expression. Eur J Cardiothorac Surg 2010;37:440–5. [22] Hsu KF, Lin CK, Yu CP, Tzao C, Lee SC, Lee YY, et al. Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma. Dis Esophagus 2009;22:402–8. [23] Zhu H, Wang Q, Hu C, Zhang W, Quan L, Liu M, et al. High expression of survivin predicts poor prognosis in esophageal squamous cell carcinoma following radiotherapy. Tumour Biol 32: 1147-53. [24] Li C, Yan Y, Ji W, Bao L, Qian H, Chen L, et al. OCT4 positively regulates survivin expression to promote cancer cell proliferation and leads to poor prognosis in esophageal squamous cell carcinoma. PLoS One 2012;7:e49693. [25] Malhotra U, Zaidi AH, Kosovec JE, Kasi PM, Komatsu Y, Rotoloni CL, et al. Prognostic value and targeted inhibition of survivin expression in esophageal adenocarcinoma and cancer-adjacent squamous epithelium. PLoS One 2013;8:e78343. [26] Wang L, Shao ZM. Cyclin e expression and prognosis in breast cancer patients: a meta-analysis of published studies. Cancer Invest 2006;24:581–7. [27] Meert AP, Martin B, Delmotte P, Berghmans T, Lafitte JJ, Mascaux C, et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with metaanalysis. Eur Respir J 2002;20:975–81. [28] Nakamura H, Kawasaki N, Taguchi M, Kabasawa K. Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: a meta-analysis. Thorax 2006;61:140–5. [29] Huang YJ, Qi WX, He AN, Sun YJ, Shen Z, Yao Y. The prognostic value of survivin expression in patients with colorectal carcinoma: a meta-analysis. Jpn J Clin Oncol 2013;43:988–95. [30] He J, Zhang FM, Wu Y, Zhang W, Zhu X, He X, et al. Prognostic role of microRNA-155 in various carcinomas: results from a meta-analysis. Dis Markers 2013;34:379–86. [31] Fan J, Wang L, Jiang GN, He WX, Ding JA. The role of survivin on overall survival of non-small cell lung cancer, a meta-analysis of published literatures. Lung Cancer 2008;61:91–6.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Survivin over-expression is correlated with a poor prognosis in esophageal cancer patients Haifeng Xia 1, Shaomu Chen 1, Haitao Huang, Haitao Ma ⁎ Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, People's Republic of China
a r t i c l e
i n f o
Article history: Received 3 December 2014 Received in revised form 3 April 2015 Accepted 6 April 2015 Available online 17 April 2015 Keywords: Survivin Prognosis Esophageal cancer Meta-analysis
a b s t r a c t Background: The prognostic role of survivin in esophageal cancer (EC) remains controversial. This meta-analysis aimed to clarify the association of survivin with survival in EC patients. Methods: Relevant studies published up to November 2014 were identified using PubMed and Embase. Only studies in which survivin was detected through immunohistochemical staining were included. STATA 12.0 was used in this meta-analysis. Results: A total of 9 studies, which comprised 610 patients, were included in the meta-analysis. The combined hazard ratio (HR) of 1.76 (95% CI, 1.40–2.21; P b 0.001) suggests that survivin overexpression in EC patients was significantly associated with poor overall survival. Moreover, the results showed a significant relationship between overall survival and survivin expression was also displayed in studies with a non-Asian country (HR, 1.75; 95% CI, 1.30–2.35), patient number ≥50 (HR, 1.86; 95% CI, 1.57–2.20), the cut-off level ≥5% (HR, 1.43; 95% CI, 0.94–2.17) and the esophageal squamous cell carcinoma (HR, 1.82; 95% CI, 1.43–2.30). However, combined odds ratio of survivin indicated that survivin overexpression has no correlation with stage, grade of differentiation, lymph node status, depth of invasion and distant metastasis of EC (P N 0.05). Conclusion: Survivin overexpression is associated with poor prognosis in EC patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Esophageal cancer (EC) is one of the malignant cancers worldwide and the common cause of cancer death [1]. Despite the rapid advancement in diagnosis and therapy for EC, the average 5-year overall survival has remained at 10–20% [2]. Therefore, to assess prognosis and establish reasonable treatment of EC patients, it is important for us to search an ideal tumor molecular marker. However, no specific biological marker can be used in EC routinely. Survivin, an inhibitor of apoptosis protein with a molecular weight of ~16.3 kDa, is considered to play an important role in cell proliferation, angiogenesis and inhibition of apoptosis [3–6]. Survivin seems to exist in either the nucleus or the cytoplasm of tumor cells, or both of these 2 subcellular pools [7]. Functionally, survivin has been implicated in inhibition of apoptosis, which directly inhibits caspase-3 and caspase-7 activity, thus preventing apoptosis [8]. Survivin is predominantly upregulated during the G2/M phase with a cell cycle dependent manner by the activation of cell cycle homology region within the promoter, suggesting that survivin can help cancer cells to overcome G2/M checkpoint to promote cell infinite proliferation [9]. Moreover, survivin has ⁎ Corresponding author. Tel.: +86 13606202960. E-mail address: [email protected] (H. Ma). 1 These authors contributed to the study equally.
http://dx.doi.org/10.1016/j.cca.2015.04.009 0009-8981/© 2015 Elsevier B.V. All rights reserved.
been showed to be over-expressed in almost all types of human tumors, but not detectable in most of normal adult tissues [10]. Accordingly, survivin may become a potential tumor marker. The expression of survivin has been reported to be a promising prognostic indicator, associated with a worse overall survival [11]. However, evidence regarding the value of survivin to predict prognosis of EC remains controversial. Therefore, we performed this meta-analysis to clarify this question. 2. Methods 2.1. Publication search PubMed and Embase electronic databases were searched for studies relating to survivin and EC up to November 2014. The following search terms were “survivin”, “esophageal cancer” and “esophageal carcinoma”. The references of retrieved articles were also manually searched for additional studies. No language of published articles was restricted. The published studies included in this meta-analysis should meet the following criteria: (1) measured survivin expression in primary EC tissues; (2) survivin evaluation using immunohistochemistry (IHC) and (3) relationship identified between survivin expression and EC prognosis. If the studies did not meet all inclusion criteria, they were excluded from our meta-analysis.
H. Xia et al. / Clinica Chimica Acta 446 (2015) 82–85
83
Table 1 Main characteristics of the studies included in the meta-analysis. First author
Year
Patient ethnicity
Patient number
Histology type
Stage
Clinicopathological features
Cut-off level
Grabowski Dabroski Rosato (1) Rosato (2) Mega Hsu Takeno (1) Takeno (2) Zhu Li Malhotra
2003 2004 2006 2006 2006 2009 2010 2010 2011 2012 2013
Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian East Asian East Asian Caucasian
84 42 56 56 122 46 71 71 102 50 37
ESCC ESCC EAC ESCC ESCC ESCC ESCC ESCC ESCC ESCC EAC
I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–IV I–III I–III
D, LN, T, M, S D, LN, T, M, S D, LN, T, S D, LN, T, S D, LN, T, M, S D, LN, T, M, S D, LN, T, M, S D, LN, T, M, S LN, T, M, S D, LN, T T, S
5% 5% 20% 20% Score 1 Score 175 10% 50% Score 0 NR NR
ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma; NR, not reported; D, histological differentiation; LN, lymph node metastasis; T, depth of tumor invasion; M, metastasis; S, stage.
2.2. Data extraction Data extraction was carried out independently by 2 authors (XHF and CSM) from eligible studies. The main characteristics of each study, such as first author's name, publication year of article, ethnic group of the study population, cut-off value level of survivin and clinicopathological parameters, were noted.
cut-off value level and histology type were conducted. In order to estimate the correlation between survivin overexpression and clinicopathological features (stage, grade of differentiation, lymph node status, the depth of invasion and distant metastasis), Odds ratios (ORs) and 95% CIs were combined. An observed OR N 1 suggested a worse prognosis for the group with survivin overexpression. The potential publication bias was assessed by Begg's funnel plot and Egger's test [15]. All analyses were performed using STATA ver 12.0 software [16]. The statistically significant test was decided by a P b 0.05.
2.3. Statistical analysis Survivin outcome data were synthesized using the time-to-event HR (a benefit of survival would be represented by an HR b1) [12]. When HR values were not given explicitly in an article, they were calculated from available numerical data or Kaplan–Meier survival curve [13]. The χ2-based Q statistic and I2 statistic were used to measure heterogeneity among studies. When P N 0.10 for the Q-test or I b 50% indicates a lack of heterogeneity among studies, a fixed effect model was selected to combine the data. Otherwise, a random effect model was used [14]. Subgroup analyses by stratifying on patient ethnicity, number of patients,
3. Results 3.1. Study characteristics On the basis of the inclusion criteria, there were nine eligible studies including 610 EC patients [17–25]. They were published between 2003 and 2013. Languages of those nine studies were written in English. The identified studies and main characteristics were listed in Table 1. The sample sizes ranged from 37 to 122 patients. Survivin expression was
Fig. 1. Forest plot of meta-analysis of the effect of survivin expression on survival in EC patients (group 1: nuclear survivin).
84
H. Xia et al. / Clinica Chimica Acta 446 (2015) 82–85
Table 2 Subgroup analysis of pooled HR of EC patients with survivin overexpression. Stratified analysis
I2 (%)
P value Q test
1.75 (1.30–2.35) 1.65 (1.49–1.82)
87.1 0
b0.001 NS
1.86 (1.57–2.20) 1.71 (0.32–9.03) 1.43 (0.94–2.17)
71.3 88.9
0.001 b0.001 b0.001
1.82 (1.43–2.30) 1.93 (0.43–8.58)
87.7 69.8
b0.001 NS
Pooled HR (95% CI) Random effects
Patient ethnicity Non-Asian Asian No. of patients ≥50 b 50 Cut-off level ≥ 5% Histology type ESCC EAC
HR, hazard ratio; 95% CI, 95% confidence interval.
evaluated by immunohistochemistry (IHC) in all of the included studies. Different cut-off values for the survivin expression level were used. 3.2. Meta-analysis results Fig. 1 shows the main results of this meta-analysis. The overall HR was 1.76 (95% CI, 1.40–2.21; test for heterogeneity P b 0.001). Three studies including 227 EC patients surveyed the association between overall survival (OS) and nuclear survivin. We found a statistical significance (HR, 1.89, 95% CI, 1.45–2.46, P b 0.001). We also performed subgroup analysis by patient ethnicity, number of patients, cut-off value level and histology type. The results revealed that a significant relationship between overall survival and survivin overexpression was also displayed in studies with a non-Asian country (HR, 1.75; 95% CI, 1.30– 2.35), patient number ≥ 50 (HR, 1.86; 95% CI, 1.57–2.20), the cut-off level ≥5% (HR, 1.43; 95% CI, 0.94–2.17) and the esophageal squamous cell carcinoma (HR, 1.82; 95% CI, 1.43–2.30) (Table 2). As shown in Table 3, survivin expression was correlated with stages (I/II vs. III/IV: OR, 0.43; 95% CI, 0.20–0.91), grade of differentiation (moderate/well vs. poor: OR, 1.54; 95% CI, 0.63–3.75), lymph node status (negative vs. positive: OR, 0.52; 95% CI, 0.25–1.11), the depth of invasion (T3/T4 vs. T1/T2: OR, 1.05; 95% CI, 0.24–4.65) and distant metastasis (positive vs. negative: OR, 1.02; 95% CI, 0.52–1.89), but without significance (P ≥ 0.05). 3.3. Publication bias The Begg's funnel plot and Egger's test were used in detecting publication bias in the meta-analysis. No evidence of publication bias was detected in the analysis of OS (Begg's test, P = 0.815; Egger's test, P = 0.844). 4. Discussion Meta-analysis is an effective method to combine the results of randomized controlled trails. Recently, this approach has been applied successfully for evaluation of prognostic indicators in patients with malignant diseases [26–28]. This meta-analysis aimed to explore the
Table 3 Meta-analysis of survivin overexpression and clinicopathological features of EC. Stratification
Pooled OR (95% CI)
P value
Fixed effects Stage Grade of differentiation Lymph node status The depth of invasion Distant metastasis OR, odds ratio.
0.43 (0.20–0.91) 1.54 (0.63–3.75) 0.52 (0.25–1.11) 1.05 (0.24–4.65) 1.02 (0.52–1.89)
0.05 0.34 0.09 0.95 0.98
Heterogeneity I2 (%)
P value
0 20.8 0 60.1 0
NS NS NS 0.009 NS
association between survivin upregulation and survival and clinicopathological features of EC. We combined the outcomes of 610 EC patients from 9 studies, showing that survivin overexpression significantly predicted poor OS. In addition, there seems to be survivin overexpression that was correlated with higher stages, higher grade of differentiation, lymph node metastasis, the higher depth of invasion and distant metastasis, but without significance (P N 0.05). These results are very important for treatment and prognosis of EC and improving the understanding of EC biology. Heterogeneity is a potential problem to affect meta-analysis results. We had dealt with a number of heterogeneity problems in this systematic review [29]. Firstly, we selected studies in which survivin was detected by immunohistochemical staining to reduce heterogeneity as far as possible. Furthermore, in the included studies we found that different cut-off values for survivin upregulation in tissues (scores 0–175, 5–50%) were applied. It is impossible to use subgroup analysis to solve this problem. Finally, the potential source of heterogeneity might be linked with the approach of deducing the HRs. We calculated the HRs from the survival curves when they were not obtained directly in the studies. However, this approach did not completely eliminate inaccuracy, showing that the extrapolated HR might be less reliable than the HR reported directly in the studies [30]. In this meta-analysis, we analyzed survivin overexpression and OS and the clinicopathological features in EC which made our analysis more valid. Further, Begg's and Egger's tests indicate no publication bias, showing that the present meta-analysis results were not biased and more convincible. However, this meta-analysis also has some limitations, and the results should be interpreted with caution [31]. First, there was significant heterogeneity in the included studies, we have already adopted various measures to reduce heterogeneity as far as possible. Second, due to lack of relevant original studies' information, such as the patients' age, comorbidity and sex, we could not perform these factors to subgroup analysis. Third, this meta-analysis depended on the published studies rather than the individual patient data (IPD). Because negative results were not more possibly published than the positive ones, the meta-analysis relied on the published data more likely to overestimate the effects of survivin compared with IPD analyses. Therefore, we tried to extract all relevant information; some missing data were still inevitable. Finally, in our research most of the patients were from western countries, which induce a problem about the results' external validity and applicability to the patients from Asia. So we performed subgroup analysis by patient ethnicity. In conclusion, for the first time, this meta-analysis indicated that survivin overexpression was significantly linked with poor OS in EC patients.
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