Yong Song

Prognostic Value of Vascular Endothelial Growth Factor Expression in Patients with Lung Cancer A Systematic Review with Meta-Analysis

Background: Vascular endothelial growth factor (VEGF) has been implicated in tumorigenesis and metastasis, and it presumably mediates the proliferation of endothelial cells and promotes vascular permeability. However, the prognostic value of VEGF overexpression in patients with lung cancer remains controversial. Methods: Survival data from published studies were aggregated following a methodological assessment. A systematic review of eligible studies with meta-analysis was performed to quantitatively review the correlation of VEGF overexpression with survival in patients with lung cancer. Results: We conducted a final analysis of 5386 patients from 51 studies. The studies were categorized by histology, disease stage, patient race, VEGF isoform, and laboratory techniques used. Combined hazard ratios suggested that VEGF overexpression had an unfavorable impact on survival of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). However, VEGFC and vascular endothelial growth factor receptor 3 (VEGFR3)/flt-1 overexpression did not significantly correlate with survival in patients with NSCLC. In stage I–III NSCLC with VEGF, the hazard ratio (95% confidence interval) was 1.46 (1.38–1.54) overall, 1.35 (1.24–1.46) in Asian patients, 1.61 (1.49–1.73) in non-Asian patients, 1.41 (1.17–1.65) in SCLC, 1.27 (1.06–1.47) in adenocarcinoma, 1.57 (1.43–1.70) in stage I NSCLC, 1.46 (1.38–1.55) in NSCLC by immunohistochemistry, 1.52 (1.23–1.81) in NSCLC by reverse transcription-polymerase chain reaction, 1.22 (0.96–1.47) in NSCLC with VEGFC, and 1.58 (0.96–2.20) in NSCLC with VEGFR3/flt-1. The data collected were not sufficient to determine the prognostic value of VEGF in patients with squamous cell lung carcinomas. Conclusion: VEGF overexpression indicates a poor prognosis for patients with NSCLC and SCLC; VEGFC and VEGFR3/flt-1 overexpression was not significantly correlated with survival for patients with NSCLC.

Predictive value of ERCC1 and XPD polymorphism in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a systematic review and meta-analysis

The published data on the predictive value of polymorphism of ERCC1 and XPD in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Relevant studies were identified by searching the Medline, Embase, CNKI and American Society of Clinical Oncology abstract databases. Inclusion criteria were patients with advanced NSCLC, received platinum-based chemotherapy, evaluation of polymorphism of ERCC1 and XPD and overall response rate (ORR). A total of 12 studies were included in this meta-analysis. For studies evaluating ERCC1 polymorphism at codon 118, the ORR for the wild-type C/C genotype versus the heterozygous C/T and T/T genotype was 2.17 (95% confidence interval (CI), 1.43–3.33; Pxa0=xa00.000). For studies evaluating XPD Asp312Asn and XPD Lys751Gln, the pooled OR was 1.33 (95% CI, 0.92–1.91; Pxa0=xa00.13) and 1.02 (95% CI, 0.72–1.45; Pxa0=xa00.915), respectively. The results indicated that platinum-based chemotherapy sensitivity was significantly associated with polymorphism of ERCC1 C118T. However, XPD Asp312Asn and XPD Lys751Gln were not predictive makers for platinum-based chemotherapy in patients with advanced NSCLC.

Diagnostic Performance of Integrated Positron Emission Tomography/Computed Tomography for Mediastinal Lymph Node Staging in Non-small Cell Lung Cancer: A Bivariate Systematic Review and Meta-Analysis

Introduction: Accurate clinical staging of mediastinal lymph nodes (MLNs) of patients with non-small cell lung cancer (NSCLC) is important in determining therapeutic options and prognoses. Integrated positron emission tomography and computed tomography (PET/CT) scanning is becoming widely used for MLN staging in patients with NSCLC. We performed a bivariate meta-analysis to determine the pooled sensitivity (SEN) and specificity (SPE) of this imaging modality. Methods: The PubMed/MEDLINE, Embase, and SpringerLink databases were searched for articles related to PET/CT for MLN staging in patients with NSCLC. SEN and SPE were calculated for every study. Hierarchical summary receiver operating characteristic curves were used to summarize overall test performance and assess study quality. Potential between-study heterogeneity was explored by subgroup analyses. Results: Fourteen of 330 initially identified reports were included in the meta-analysis. When we did not consider the unit of analysis, the pooled weighted SEN and SPE were 0.73 (95% confidence interval [CI]: 0.65–0.79) and 0.92 (95% CI: 0.88–0.94), respectively. In the patient-based data analysis, the pooled weighted SEN was 0.76 (95% CI: 0.65–0.84) and the pooled weighted SPE was 0.88 (95% CI: 0.82–0.92). In the MLN-based data analysis, the pooled SEN was 0.68 (95% CI: 0.56–0.78) and the pooled SPE was 0.95 (95% CI: 0.91–0.97). Conclusions: Integrated PET/CT is a relatively accurate noninvasive imaging technique, with excellent specificity for MLN staging in patients with NSCLC. Nevertheless, current evidence suggests that we should not depend on the results of PET/CT completely for MLN staging in patients with NSCLC.

Evaluation of PCR on Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Aspergillosis: A Bivariate Metaanalysis and Systematic Review

Background Nucleic acid detection by polymerase chain reaction (PCR) is emerging as a sensitive and rapid diagnostic tool. PCR assays on serum have the potential to be a practical diagnostic tool. However, PCR on bronchoalveolar lavage fluid (BALF) has not been well established. We performed a systematic review of published studies to evaluate the diagnostic accuracy of PCR assays on BALF for invasive aspergillosis (IA). Methods Relevant published studies were shortlisted to evaluate the quality of their methodologies. A bivariate regression approach was used to calculate pooled values of the method sensitivity, specificity, and positive and negative likelihood ratios. Hierarchical summary receiver operating characteristic curves were used to summarize overall performance. We calculated the post-test probability to evaluate clinical usefulness. Potential heterogeneity among studies was explored by subgroup analyses. Results Seventeen studies comprising 1191 at-risk patients were selected. The summary estimates of the BALF-PCR assay for proven and probable IA were as follows: sensitivity, 0.91 (95% confidence interval (CI), 0.79–0.96); specificity, 0.92 (95% CI, 0.87–0.96); positive likelihood ratio, 11.90 (95% CI, 6.80–20.80); and negative likelihood ratio, 0.10 (95% CI, 0.04–0.24). Subgroup analyses showed that the performance of the PCR assay was influenced by PCR assay methodology, primer design and the methods of cell wall disruption and DNA extraction. Conclusions PCR assay on BALF is highly accurate for diagnosing IA in immunocompromised patients and is likely to be a useful diagnostic tool. However, further efforts towards devising a standard protocol are needed to enable formal validation of BALF-PCR.

ERCC2/XPD Lys751Gln and Asp312Asn Gene Polymorphism and Lung Cancer Risk: A Meta-Analysis Involving 22 Case–Control Studies

Introduction: Published data on the association between XPD Lys751Gln and Asp312Asn gene polymorphism and lung cancer risk are inconclusive. Methods: To derive a more precise estimation of the relationship, a meta-analysis was performed. Results: A total of 22 studies including 15,507 subjects for XPD Lys751Gln genotype and 13,198 subjects for XPD Asp312Asn genotype were examined. For XPD Lys751Gln genotype, significantly increased lung cancer risk was associated with two variant genotypes (CC versus AA: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.12–1.42, p = 0.473 for heterogeneity; C allele carriers versus AA: OR = 1.18, 95% CI = 1.08–1.36, p = 0.732 for heterogeneity). When stratified by ethnicity, significantly increased risks were found among Caucasians but not in Asians. For XPD Asp312Asn genotype, significantly increased lung cancer risk was associated with two variant genotypes (AA versus GG: OR = 1.24, 95% CI = 1.09–1.42, p = 0.104 for heterogeneity; the A allele carriers versus GG: OR = 1.35, 95% CI = 1.13–1.57, p = 0.219 for heterogeneity). When stratified analysis by ethnicity, significantly increased risks were found among Asians but not in Caucasians. In the subgroup analyses by smoking status, there were no significant associations among the nonsmoker subgroup; however, significantly increased lung cancer risks were found in the smoking group. Conclusion: This meta-analysis suggests that the XPD Lys751Gln and Asp312Asn gene polymorphisms are associated with lung cancer risk, the C allele of XPD Lys751Gln genotype is an increased risk factor for developing lung cancer among Caucasians and in smokers, and the A allele of XPD 312 genotype is also an increased risk factor among Asians and in smokers.

Chlamydia pneumoniae infection and lung cancer risk: A meta-analysis

Chlamydia pneumoniae (C. pneumoniae) is a common cause of acute respiratory infection and has been hypothesised to cause several chronic diseases, including lung cancer. Numbers studies were conducted to analyse the association between C. pneumoniae infection and risk of lung cancer, but no clear consensus had been found. To assess this relationship more precisely, a meta-analysis was performed. The electronic databases PubMed, Embase, Web of Science and CNKI were searched; Data were extracted and analysed independently by two investigators. Ultimately, 12 studies, involving 2595 lung cancer cases and 2585 controls from four prospective studies and eight retrospective studies were included. Overall, people exposed to C. pneumoniae infection had an odds ratio (OR) of 1.48 (95% confidence interval (CI), 1.32-1.67) for lung cancer risk, relative to those not exposed. C. pneumoniae infection was clearly identified as a risk factor for lung cancer in both prospective studies (OR, 1.16; 95% CI, 1.00-1.36) and retrospective studies (OR, 2.17; 95% CI, 1.79-2.63) and in both IgA ≥ 16 cutoff group (OR, 1.22; 95% CI, 1.06-1.41) and the IgA ≥ 64 cutoff group (OR, 2.35; 95% CI, 1.88-2.93). In conclusion, C. pneumoniae infection is associated with an increased risk for lung cancer, higher titre may be a better predictor of lung cancer risk.

TNF-308 gene polymorphism is associated with COPD risk among Asians: meta-analysis of data for 6,118 subjects.

Chronic obstructive pulmonary disease (COPD) is a complex polygenic disease in which gene–environment interactions play a critical role in disease onset and progression. The gene encoding tumor necrosis factor (TNF) is one of several candidate loci for the pathogenesis of COPD and is highly polymorphic. A number of studies have investigated the association between the TNF-308 polymorphisms and COPD risk in different populations, and resulted in inconsistent results. A systematic review and meta-analysis of the published studies were performed to gain a clearer understanding of this association. The PubMed, Embase, Web of Science, and CNKI databases were searched for case–control studies published from 1966 to April 2009. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Twenty-four eligible studies, comprising 2,380 COPD cases and 3,738 controls, were included in the meta-analysis. The pooled result showed that the TNF-308 polymorphisms were significantly associated with an increased risk of COPD (ORxa0=xa01.335, 95% CI: 1.172–1.522, for allele A carriers versus G/G; ORxa0=xa01.330, 95% CIxa0=xa01.174–1.505, for allele A versus allele G). Subgroup analysis supported the results in the Asian populations, but not in the Caucasian populations. When the analysis was limited to only those studies in which the COPD cases and controls were smokers/ex-smokers, the pooled results supported the conclusion. This meta-analysis suggested that the TNF-308 A allele is a more significant risk factor for developing COPD among Asian populations, but not among Caucasians.

CYP2E1 Rsa I/Pst I polymorphism is associated with lung cancer risk among Asians

The genetic polymorphism of CYP2E1 Rsa I/Pst I is thought to have significant effect on lung cancer risk, but the results are inconsistent. In this meta-analysis, we assessed 21 published studies involving 9380 subjects of the association between CYP2E1 Rsa I/Pst I polymorphism and lung cancer risk. For the homozygote c2/c2 and c2 allele carriers (c1/c2+c2/c2), the pooled ORs for all studies were 0.734 (95% CI=0.628-0.847; P=0.035 for heterogeneity) and 0.852 (95% CI=0.777-0.933; P=0.004 for heterogeneity) when compared with the homozygous wild-type genotype (c1/c1). In the stratified analysis by ethnicity, the same significant risks were found among Asians for both the c2 allele carriers and homozygote c2/c2. Among mixed populations, only significant risk was associated with c2 allele carriers. No significant associations were found in all Caucasians genetic models. In the subgroup analyses by pathological types, for lung SC the ORs of the c2 allele carriers and the homozygote c2/c2 were 0.749 (95% CI=0.683-0.813; P=0.247 for heterogeneity) and 0.726 (95% CI=0.662-0.847; P=0.006 for heterogeneity), respectively. In the subgroup analyses by smoking status, there were no significant associations among smokers or non-smokers subgroup. This meta-analysis suggests that CYP2E1 Rsa I/Pst I c2 allele is a decreased risk factor for the developing lung cancer among Asians and lung SC.

A meta-analysis of TP53 codon 72 polymorphism and lung cancer risk: evidence from 15,857 subjects.

The genetic polymorphism of TP53 codon 72 is thought to have significant effect on lung cancer risk, but the results are inconsistent. In this meta-analysis, we assessed 23 published studies involving 15,857 subjects of the association between TP53 codon 72 polymorphism and risk of lung cancer. For the homozygote Pro/Pro and Pro allele carriers (Pro/Pro+Pro/Arg), the ORs for all studies combined (7495 cases and 8362 controls) were 1.221 (95% CI=1.046-1.425; P=0.021 for heterogeneity) and 1.148 (95% CI=1.040-1.266; P=0.008 for heterogeneity). In the stratified analysis by ethnicity, significantly increased risks were found in Asians (3254 cases and 3350 controls) for both the homozygote Pro/Pro (OR=1.395; 95% CI=1.206-1.613; P=0.806 for heterogeneity) and the Pro allele carriers (OR=1.109; 95% CI=1.000-1.228; P=0.458 for heterogeneity). In Caucasians (3359 cases and 3953 controls), significantly elevated risk was associated with Pro allele carriers (OR=1.180; 95% CI=1.029-1.353; P=0.073 for heterogeneity). In the subgroup analyses by pathological type, the ORs for the homozygote Pro/Pro and Pro allele carriers were 1.289 (95% CI=1.027-1.618; P=0.096 for heterogeneity) and 1.168 (95% CI=1.062-1.284; P=0.231 for heterogeneity) for lung adenocarcinoma (2724 cases and 6591 controls). When stratified by smoking status, the pooled OR was 1.440 (95% CI=1.078-1.923; P=0.042 for heterogeneity) for the Pro allele carriers among smokers (1480 cases and 1414 controls). Although some statistical bias could not be eliminated, this meta-analysis suggests that the Pro allele is a low-penetrant risk factor for developing lung cancer. Additionally, we found that this phenomenon was more prominent in subgroups such as in Asians and Caucasians, in lung adenocarcinoma, or in smokers.

Alpha1-antitrypsin deficiency carriers, serum alpha 1-antitrypsin concentration, and non-small cell lung cancer survival.

Introduction: Although the association between alpha 1-antitrypsin deficiency (&agr;1ATD) carriers and lung cancer risk has been found, the effects of &agr;1ATD carriers and serum alpha 1-antitrypsin (&agr;1AT) concentration on non-small cell lung cancer (NSCLC) survival remained unclear. Methods: Patients were selected from the Epidemiology and Genetics of Lung Cancer Study at Mayo Clinic with the criteria of (1) primary NSCLC diagnosis and (2) available &agr;1ATD carrier status tested by isoelectric focusing serum &agr;1AT concentration by immunonephelometry. The effects of carrier status and serum &agr;1AT concentration on survival were evaluated by Cox proportional hazards models with (1) a landmark approach, where overall survival was defined from the time of blood draw to death from any cause and (2) included only patients with blood draw time before initial treatment. Results: One thousand three hundred twenty-one patients were included in this study, with 179 &agr;1ATD carriers and 1142 noncarriers. No differences in overall survival by &agr;1ATD carrier status were found (adjusted hazard ratio [AHR]: 0.98; 95% confidence interval [CI]: 0.82–1.18). Nevertheless, serum &agr;1AT concentration was significantly associated with survival among all patients in the landmark model (AHR per 50 mg/dl increments: 1.15; 95% CI: 1.10–1.20) and among patients whose blood was drawn for serum &agr;1AT level assessment before any treatment (AHR per 50 mg/dl increments: 1.44; 95% CI: 1.21–1.71). Conclusions: Being an &agr;1ATD carrier had no significant effect on NSCLC survival. The increased serum &agr;1AT concentration was a poor prognosis marker for NSCLC, regardless of carrier status.