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脊柱去松质骨化截骨术治疗强直性脊柱炎并脊柱后凸畸形的疗效分析

Aim: This meta-analysis comprehensively analyzes the findings of relevant studies to investigate the prognostic effect of osteopontin (OPN) expression in patients with non-small-cell lung cancer (NSCLC).
Materials and Methods: The Web of Science (1945~2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966~2013), EMBASE (1980~2013), CINAHL (1982~2013), and the Chinese Biomedical Database (CBM) (1982~2013) were searched without language restrictions. This meta-analysis was conducted with the use of STATA software (Version 12.0, Stata Corporation, and College Station, Texas USA). Hazard ratios (HR) with their corresponding 95% confidence interval (95%CI) were calculated.
Results: Ten clinical cohort studies, which recruited a total of 1,133 NSCLC patients, were selected for statistical analysis. The main findings of our meta-analysis showed that patients with OPN-positive expression had significantly shorter overall survival spans than OPN-negative expression patients (HR = 1.47, 95%CI = 1.15~1.79, P < 0.001). Ethnicity-stratified analysis revealed a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians (Asians: HR = 1.53, 95%CI = 0.95~2.11, P < 0.001; Caucasians: HR = 1.56, 95%CI = 1.08~2.03, P < 0.001; respectively).
Conclusions: The present meta-analysis is consistent with the hypothesis that increased expression of OPN protein may be significantly associated with poor prognosis in patients with NSCLC. Thus, increased OPN expression may serve as a potential prognostic factor for NSCLC.
KEY WORDS: Osteopontin, Prognosis, Non-small cell lung cancer, Meta-analysis
INTRODUCTION
NON-SMALL-CELL lung cancer (NSCLC) refers to any type of epithelial lung cancer aside from small cell lung cancer; lung cancer is the most common cause of cancer deaths in both men and women worldwide.[1] An estimated 226,200 new cases (116,500 in men and 109,700 in women) of lung and bronchial cancer were diagnosed in 2012, and 160,300 deaths (87,700 in men and 72,600 in women) were estimated to occur from these diseases.[2] Nowadays, lung cancer has become predominant among former rather than current smokers, not only in the United States, but also around the world.[3] Countries such as China, which has experienced a dramatic increase in cigarette smoking rates over the past 2 decades, has yet to see the peak in lung cancer incidence that is still expected.[4] Generally, different combinations of various genetic and non-genetic risk factors may contribute to the risk of NSCLC.[5,6] The primary non-genetic risk factors for NSCLC include smoking tobacco, drinking alcohol, insufficient exercise, air pollution, and occupational exposure.[7,8] Recently, some documents have indicated that transfection of osteopontin (OPN) expression increase malignant phenotype and OPN knock-out, in contrast, decreases malignant potential, thereby an increased expression of OPN may be closely related to the pathogenesis of NSCLC.[9,10]
OPN, also known as bone sialoprotein I (BSP-1 or BNSP), is a major member of the secreted acidic proteins family; it acts as a multifunctional glycophosphoprotein, which was originally identified as a protein secreted from malignant epithelial cells.[9] Along with its function in biomineralization, wound healing, and tissue remodeling, OPN also serves an important adhesive bone matrix protein, playing a critical role in immune cell recruitment, cell activation, and apoptosis. [11-13] In fact, OPN may interact with multiple cell surface receptors that are ubiquitously expressed and may contribute to its activation in many physiological and pathological processes, including bone turnover, tumorogenesis, inflammation, ischemia, and immune responses.[14,15] For these reasons, it is hypothesized that manipulation of plasma levels of OPN may be useful in treating autoimmune diseases, cancer metastasis, bone mineralization diseases, and some forms of stress.[16-18] Indeed, previous evidence has shown that increased levels of OPN were detected in various diseases, including development of allergic airway disease, breast cancer, ovarian cancer, Duchenne muscular dystrophy.[19-22] More importantly, overexpression of OPN was also documented to be frequently observed in many human NSCLC cases, and associated with shortened survival in patients with early-stage or late-stage disease.[23] A possible explanation for OPN being generally responsible for the invasion and metastasis of lung cancer cells is by interacting with integrins and participating in the promotion of cell proliferation, metastasis, extracellular matrix remodeling, and cell adhesion reduction, all of which eventually contribute to tumor deterioration.[4,24] In this regard, elevated expression levels of OPN may be significantly correlated with the overall survival of NSCLC patients.[4] Therefore, we hypothesize that increased expression of OPN may be a critical in predicting the clinical outcome of NSCLC. In recent decades, several studies have confirmed that elevated OPN levels may be an indicator of biologically aggressive NSCLC, based on its critical role in mediating angiogenesis and stimulating growth, metastasis, and survival of malignant cells [25,26], though other studies have illustrated inconsistent and sometimes contradictory results.[27,28] Given the conflicting evidence on this topic, we conducted a meta-analysis of all available cohort studies to explore the correlation between OPN expression and NSCLC prognosis.
 
MATERIALS AND METHODS
Literature search and selection criteria
The Web of Science (1945~2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966~2013), EMBASE (1980~2013), CINAHL (1982~2013), and the Chinese Biomedical Database (CBM) (1982~2013) were searched without language restrictions. We used the following keywords and MeSH terms in conjunction with a highly sensitive search strategy: (“osteopontin” , “sialoprotein 1” , “secreted phosphoprotein 1” , “bone sialoprotein 1” , “uropontin” , “OPG” , “Eta-1” , “2ar”) and (“non-small cell lung carcinomas” or “non-small-cell lung cancer” or “non-small cell lung cancer” or “NSCLC” or “NSCLC carcinogenesis” or “non-small cell lung carcinogenesis”). A manual search on the basis of references identified in the included articles was also carried out to acquire additional potential articles.
Eligible studies were those that conformed to the following criteria: (1) must concern the correlation between increased OPN expression and prognosis in NSCLC; (2) all patients diagnosed with NSCLC must be confirmed via pathological examination, including bronchoscopic biopsy, percutaneous lung biopsy, pleural biopsy, pleural fluid cytology, and metastatic lymph node biopsy; (3) the survival curves for the OPN-positive and -negative groups must be provided in those included studies; (4) Sufficient information and integrity data with regard to expression levels of OPN should be provided in the included studies. Articles that did not meet all of the inclusion criteria were excluded. If the authors published several similar studies of the same subjects, either the most recent publication or the publication with the largest sample size was included. Articles that did not meet all of the inclusion criteria were excluded. Exclusion criteria were: (1) animal studies or NSCLC cell lines studies; (2) diagnostic uncertainty; (3) duplicate published results; (4) lack of data integrity.
Data extraction and methodological assessment
Two independent authors used a standardized form to extract the following data from included studies: publication language, year of article publication, the first author’s surname, geographical location, study design, total number of cases, sample size, control source, survival curves for the OPN-positive and -negative groups methylation detection method, methylation frequency, etc. In case of disagreement on any respect of data and analyses, more discussion should be continued by the third expert.
Two observers independently assessed the methodological quality with the use of the Newcastle-Ottawa Scale (NOS) criteria [29]. The standard for NOS criteria were: (1) selection of the cohort: representativeness of the exposed cohort (NOS1); selection of the non-exposed cohort (NOS2); ascertainment of exposure (NOS3); demonstration that outcome of interest was not present at start of study (NOS4); (2) comparability of the cohorts: whether the study was selected and analyzed according to the most important factor (NOS5); whether the study controlled other confounding factors (NOS6); (3) assessment of outcome: was follow-up long enough for outcomes to occur (NOR8); adequacy of follow-up of cohorts (NOR9). The NOS criterion comprises three aspects: (1) subject selection: 0~4; (2) comparability of subject: 0~2; (3) clinical outcome: 0~3. NOS scores range from 0 to 9, but a score with good quality should be ≥ 7.
Statistical analysis
In order to achieve rigorous statistical analysis, STATA statistical software (Version 12.0, Stata Corporation, College Station, TX, USA) was to handle statistical data. Hazard ratios (HR) and their corresponding 95% confidence intervals (95%CI) were calculated. The statistical significance of pooled HRs was evaluated with the Z test. Between-study heterogeneity was assessed with Cochran’s Q-statistic and I2 tests [30]. If I2 > 50%, which indicates that these studies were heterogeneous, or P value < 0.05, then the random-effect model was employed; otherwise, the fixed-effects model was implemented. We also made use of subgroup analyses to explore sources of heterogeneity. A sensitivity analysis was implemented for the purpose of evaluating the influence of a single study on the overall estimate. Potential publication bias was examined with Funnel plots and Egger’s linear regression test [31].
 
RESULTS
Characteristics of included studies
Initially, our highly sensitive search strategy identified 184 articles. After screening the titles and abstracts of all retrieved articles, 95 articles were excluded; then, the full texts were also reviewed and another 76 articles were further excluded. An additional 3 studies were also excluded due to a lack of data integrity [Figure 1]. Eventually, 10 clinical cohort studies, which recruited a total of 1,133 NSCLC patients were selected for statistical analysis [4,9,25-28,32-35]. As shown in Figure 2, the range of publication years of the eligible studies was from 2005 to 2013. Overall, 5 studies were conducted among Asian populations, and the other 5 studies among Caucasian populations. Enzyme-linked immunosorbent assay (ELISA), and Max Vision methods were utilized in the studies of this meta-analysis. NOS scores of all included studies were ≥ 5. The main characteristics and methodological quality of eligible studies are recorded in Table 1.
Quantitative data analysis
Since no heterogeneity was detected among studies (I2 = 0.00%, P = 0.527), the fixed effects model was employed. Our findings suggest that NSCLC patients with positive expression of OPN had worse overall survival than those with negative OPN expression (HR = 1.47, 95%CI = 1.15~1.79, P < 0.001) [Figure 3]. Ethnicity-stratified analysis indicated that there was a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians (Asians: HR = 1.40, 95%CI = 0.97~1.83, P < 0.001HR = 1.53, 95%CI = 0.95~2.11, P < 0.001; Caucasians: HR = 1.56, 95%CI = 1.08~2.03, P < 0.001; respectively) [Figure 4]. We also performed subgroup analyses based on sample size and sample source; the results indicated a significant association between OPN-positive expression and poor prognosis of NSCLC patients in all such subgroups (all P < 0.05). Sensitivity analysis indicated that the removal of any single study could not affect the overall pooled ORs [Figure 5]. There was no significant evidence for asymmetry in the funnel plots [Figure 6]. No evidence of publication bias was presented by Egger’s test (t = 0.49, P = 0.636).
 
DISCUSSION
Our results showed that positive OPN expression was closely correlated with shorter overall survival as compared to negative OPN expression, suggesting that expression levels of OPN may be an important prognostic factor for NSCLC. It is widely accepted that OPN is one of the key factors in tumorigenesis, tumor progression, and metastasis in different malignancies.[25] The specific impact of OPN expression on the clinical outcome of NSCLC, however, still remains unclear. OPN facilitates cell migration and protects against programmed cell death in cancers; hence, the expression of OPN in cancer tissue is associated with tumor growth, tumor staging, and lymph node invasion for patients with NSCLC.[36,37] In general, the role of OPN in promoting cancers mainly involves the modulation of vascular endothelial growth factor expression through the activation of various signaling pathways [24]. In addition, secreted OPN interacts with members of the integrin family, and is implicated in the intracellular signal transduction pathway, which promotes a variety of downstream processes related to tumor progression and cellular transformation.[4] Furthermore, OPN stimulates the expression of the urokinase-type plasminogen activator and increases the migration and adhesion of tumor cells, which further induces cellular transformation and metastasis.[26] Therefore, through this process, OPN is associated with angiogenesis, leading to a more aggressive tumor phenotype and exacerbating cancer severity.[38] Most importantly, tumor hypoxia may influence the malignant progression of transformed cells, and the response to therapy diminishes in cells with a decreased apoptotic potential and increased metastatic ability [27]. In this regard, OPN levels increase in the presence of tumor hypoxia, a condition promoting chemotherapy and radiotherapy resistance, thereby causing poor NSCLC prognosis.[26] We hypothesized that OPN expression associated with overall survival in chemotherapy-treated NSCLC patients may be correlated with NSCLC prognosis. Ostheimer et al. conducted a study on 55 patients with advanced NSCLC, and found a statistically significant association between high expression levels of OPN and shorter overall survival of NSCLC patients.[39] Rud et al. also provided further evidence of the importance of OPN in the etiology of NSCLC, and demonstrated that high expression levels of OPN in NSCLC tumors is connected to poor clinical outcome, insisting that OPN may be a promising and independent prognostic determinant of outcome in patients with NSCLC.[40] Ethnicity-stratified analysis indicated that increased expression levels of OPN might be significantly associated with poor prognosis of NSCLC patients among both Caucasians and Asians. The results indicate that ethnicity difference may not be a predominant source of heterogeneity and may not have a crucial impact on the statistical outcomes. Our results are in partial agreement with previous studies showing that increased expression of OPN may play a critical role in the clinical outcome of NSCLC, adding basis to the idea that increased levels of OPN could be used to identify NSCLC patients with an unfavorable prognosis.
There were admittedly several potential limitations in our meta-analysis. Firstly, due to the small number of studies, our results failed include all of the data from all trials to evaluate the relationship of OPN expression with NSCLC prognosis. Nevertheless, our meta-analysis managed to overcome the limitations of study size in individual studies and acquire more reliable and general information on the correlation between expression levels and the prognosis of NSCLC through systematic aggregation of results from each study. A second potential limitation to our meta-analysis is the fact that the results from this meta-analysis might slightly lack reliability to some extent due to its retrospective nature, which may induce publication bias. Another potential limitation is that our meta-analysis was unable to acquire the original data from the included studies. Even though our meta-analysis faced the above limitations, this is the first example of a meta-analysis focusing on the association of OPN expression with NSCLC prognosis. More importantly, our meta-analysis has clear selection criteria in its literature search strategy. In order to achieve strong objectivity, all research methods were carried out on strict inclusion and exclusion criteria.
In summary, this meta-analysis showed consistency with the idea that increased expression of the OPN protein is significantly associated with poor prognosis in patients with NSCLC. Thus, increased OPN expression may serve as a potential prognostic factor for NSCLC. However, given that several limitations existed in our meta-analysis, further studies with more integral data and larger sample-sizes are needed to achieve a more profound statistical analysis with general applicability.
ACKNOWLEDGMENTS
We would like to acknowledge the helpful comments on this paper received from our reviewers.
CONFLICT OF INTEREST
We declare that we have no conflicts of interest.

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Legends
Figure 1: The flow chart shows study selection procedure. Ten cohort studies were included in this meta-analysis.
Figure 2: The distribution of the number of topic-related literatures in the electronic database during the last decade.
Figure 3: Forest plots for the relationships between increased osteopontin protein expression and prognosis of patients with non-small-cell lung cancer.
Figure 4: Subgroup analysis by ethnicity, sample type, and sample size for the relationship between increased osteopontin protein expression and prognosis of patients with non-small-cell lung cancer.
Figure 5: Sensitivity analysis of the summary odds ratio coefficients on the relationships between increased osteopontin protein expression and prognosis of patients with non-small-cell lung cancer.
Figure 6: Funnel plot of publication biases on the relationship between increased osteopontin protein expression and prognosis of patients with non-small-cell lung cancer.
 

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本文选自温州一枝笔写作事务所:专业代写毕业论文-致力于医学论文职称论文代写代发论文(责任编辑:yzbcc)
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