Prognostic Significance of Circulating Tumor Cells in Non-Small-Cell Lung Cancer Patients: A Meta-Analysis

Background

The prognostic significance of circulating tumor cells (CTCs) detected in patients with non-small-cell lung cancer (NSCLC) is still inconsistent. We aimed to assess the prognostic relevance of CTCs using a meta-analysis.

Methods

We searched PubMed, Web of Science and EMBASE for relevant studies that assessed the prognostic relevance of CTCs in NSCLC. Statistical analyses were conducted to calculate the summary incidence, odds ratio, relative risks (RRs) and 95% confidence intervals (CIs) using fixed or random-effects models according to the heterogeneity of included studies.

Results

A total of 20 studies, comprising 1576 patients, met the inclusion criteria. In identified studies, CTCs were not correlated with histology (adenocarcinoma vs squamous cell carcinoma) (odds ratio [OR]  =  0.88; 95% confidence interval [CI]: 0.59–1.33; Z = –0.61; P = 0.545). However, pooled analyses showed that CTCs were associated with lymph node metastasis (OR = 2.06; 95% CI: 1.18–3.62; Z = 2.20; P = 0.027) and tumor stage (OR  = 1.95; 95% CI: 1.08–3.54; Z = 2.53; P = 0.011). Moreover, CTCs were significantly associated with shorter overall survival (relative risk [RR]  = 2.19; 95% CI: 1.53–3.12; Z = 4.32; P<0.0001) and progression-free/disease-free survival (RR  = 2.14; 95% CI: 1.36–3.38; Z = 3.28; P<0.0001).

Conclusion

The presence of CTCs indicates a poor prognosis in patients with NSCLC. Further well-designed prospective studies are required to explore the clinical applications of CTCs in lung cancer.     

Prognostic Value of Cancer Stem Cell Marker Aldehyde Dehydrogenase in Ovarian Cancer: A Meta-Analysis

Objective

Aldehyde dehydrogenase (ALDH) has recently been reported as a marker of cancer stem-like cells in ovarian cancer. However, the prognostic role of ALDH in ovarian cancer still remains controversial. In this study, we aimed to evaluate the association between the expression of ALDH and the outcome of ovarian cancer patients by performing a meta-analysis.

Methods

We systematically searched for studies investigating the relationships between ALDH expression and outcome of ovarian cancer patients. Only articles in which ALDH expression was detected by immunohistochemical staining were included. A meta-analysis was performed to generate combined hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS).

Results

A total of 1,258 patients from 7 studies (6 articles) were included in the analysis. Our results showed that high ALDH expression in patients with ovarian cancer was associated with poor prognosis in terms of Os (HR, 1.25; 95% CI, 1.07-1.47; P = 0.005) and DFS (HR, 1.58; 95% CI, 1.00-2.49; P = 0.052), though the difference for DFS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg’s and Egger’s tests (Begg’s test, P = 0.707; Egger’s test, P = 0.355).

Conclusion

The present meta-analysis indicated that elevated ALDH expression was associated with poor prognosis in patients with ovarian cancer.     

Single Gene Prognostic Biomarkers in Ovarian Cancer: A Meta-Analysis

Purpose

To discover novel prognostic biomarkers in ovarian serous carcinomas.

Methods

A meta-analysis of all single genes probes in the TCGA and HAS ovarian cohorts was performed to identify possible biomarkers using Cox regression as a continuous variable for overall survival. Genes were ranked by p-value using Stouffer’s method and selected for statistical significance with a false discovery rate (FDR) <.05 using the Benjamini-Hochberg method.

Results

Twelve genes with high mRNA expression were prognostic of poor outcome with an FDR <.05 (AXL, APC, RAB11FIP5, C19orf2, CYBRD1, PINK1, LRRN3, AQP1, DES, XRCC4, BCHE, and ASAP3). Twenty genes with low mRNA expression were prognostic of poor outcome with an FDR <.05 (LRIG1, SLC33A1, NUCB2, POLD3, ESR2, GOLPH3, XBP1, PAXIP1, CYB561, POLA2, CDH1, GMNN, SLC37A4, FAM174B, AGR2, SDR39U1, MAGT1, GJB1, SDF2L1, and C9orf82).

Conclusion

A meta-analysis of all single genes identified thirty-two candidate biomarkers for their possible role in ovarian serous carcinoma. These genes can provide insight into the drivers or regulators of ovarian cancer and should be evaluated in future studies. Genes with high expression indicating poor outcome are possible therapeutic targets with known antagonists or inhibitors. Additionally, the genes could be combined into a prognostic multi-gene signature and tested in future ovarian cohorts.     

Prognostic Value and Implication for Chemotherapy Treatment of ABCB1 in Epithelial Ovarian Cancer: A Meta-Analysis

BackgroundChemotherapy resistance is reported to correlate with up-regulation of anti-tumor agent transporter ABCB1 (p-gp) in epithelial ovarian cancer (EOC), but the results remain controversial. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the association between high ABCB1 status or ABCB1 gene variants and overall survival (OS), progression free survival (PFS), and total response rate (TR) in patients with EOC.ResultsThirty-eight retrospective studies of 8607 cases qualified for meta-analysis were identified. Our results suggested that ABCB1 over-expression was significantly associated with unfavorable OS (HR = 1.54; 95% CI, 1.25–1.90), PFS (HR = 1.49; 95% CI, 1.22–1.82) and TR (RR = 0.63; 95% CI, 0.54–0.75). After adjustment for age, clinical stage, residual disease, histological type and tumor grade, high ABCB1 status remained to be a significant risk factor for adverse OS and PFS. Patients with recurrent ABCB1 positivity suffered from poorer OS than those with primary ABCB1 positivity. However, stratified by chemotherapy regimen, inverse correlation between high ABCB1 status and poor OS, PFS and TR were only found in patients underwent platinum-based chemotherapy but not in patients received standard platinum/paclitaxel-based chemotherapy. No evidence was found for any association between ABCB1 gene polymorphisms and OS, PFS or TR.ConclusionHigh ABCB1 status is significantly associated with chemo-resistance and poor prognosis in patients with EOC. Large-scale, prospective studies are needed to assess the clinical value of ABCB1 expression in EOC more accurately.     

Prognostic Value of LGR5 in Colorectal Cancer: A Meta-Analysis

Objective

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has recently been reported to be a marker of cancer stem cells (CSCs) in colorectal cancer (CRC), and the prognostic value of LGR5 in CRC has been evaluated in several studies. However, the conclusions remain controversial. In this study, we aimed to evaluate the association between the expression of LGR5 and the outcome of CRC patients by performing a meta-analysis.

Methods

We systematically searched for relevant studies published up to February 2014 using the PubMed, Web of Science, EMBASE and Wangfang databases. Only articles in which LGR5 expression was detected by immunohistochemistry were included. A meta-analysis was performed using STATA 12.0, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between LGR5 expression and the prognosis of CRC patients.

Results

A total of 7 studies comprising 1833 CRC patients met the inclusion criteria, including 6 studies comprising 1781 patients for overall survival (OS) and 3 studies comprising 528 patients for disease-free survival (DFS). Our results showed that high LGR5 expression was significantly associated with poor prognosis in terms of OS (HR: 1.87, 95% CI: 1.23–2.84; P = 0.003) and DFS (HR: 2.44, 95% CI: 1.49–3.98; P<0.001). Further subgroup analysis revealed that many factors, including the study region, number of patients, follow-up duration and cutoff value, affected the significance of the association between LGR5 expression and a worse prognosis in patients with CRC. In addition, there was no evidence of publication bias, as suggested by Begg’s and Egger’s tests.

Conclusions

The present meta-analysis indicated that high LGR5 expression was associated with poor prognosis in patients with CRC and that LGR5 is an efficient prognostic factor in CRC.     

Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis

PURPOSE: The prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the association between SMAD4 expression and the outcome of pancreatic cancer patients by performing a meta-analysis. METHODS: We systematically searched for relevant studies evaluating the relationship between SMAD4 expression and the outcome of pancreatic cancer patients until May 2015. A meta-analysis was performed using STATA 12.0, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 expression and the prognosis of pancreatic cancer patients. RESULTS: The analysis included 1762 patients from 14 studies, with 1401 patients from 11 studies and 927 patients from 8 studies included in the univariate and multivariate analyses, respectively. Loss of SMAD4 expression was found to be significantly correlated with poor overall survival, with the combined HR (95% CI) of 1.20 (1.03-1.40). After adjusting for potential confounders using the Cox regression model, the pooled HR (95% CI) was 1.88 (1.31-2.70). In subgroup analysis, study region, number of patients, follow-up duration, and cutoff value were found to affect the significance of the association between loss of SMAD4 expression and poor prognosis. In addition, there was no evidence of publication bias, as suggested by Begg’s and Egger’s test. CONCLUSIONS: Loss of SMAD4 was associated with poor survival and was a negative prognostic indicator in patients with pancreatic cancer.     

The Prognostic Value of p16 Hypermethylation in Cancer: A Meta-Analysis

Background

The prognostic value of p16 promoter hypermethylation in cancers has been evaluated for several years while the results remain controversial. We thus performed a systematic review and meta-analysis of studies assessing the impact of p16 methylation on overall survival (OS) and disease-free survival (DFS) to clarify this issue.

Methods

We searched Pubmed, Embase and ISI web of knowledge to identify studies on the prognostic impact of p16 hypermethylation in cancers. A total of 6589 patients from 45 eligible studies were included in the analysis. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to estimate the effect using random-effects model.

Results

The analysis indicated that p16 hypermethylation had significant association with poor OS of non-small cell lung cancer (NSCLC) (HR 1.74, 95% CI: 1.36–2.22) and colorectal cancer (CRC) (HR 1.80; 95% CI 1.27–2.55). Moreover, the significant correlation was present between p16 hypermethylation and DFS of NSCLC (HR 2.04, 95% CI: 1.19–3.50) and head and neck cancer (HR 2.24, 95% CI: 1.35–3.73). Additionally, in the analysis of the studies following REMARK guidelines more rigorously, p16 hypermethylation had unfavorable impact on OS of NSCLC (HR 1.79, 95% CI: 1.35–2.39) and CRC (HR 1.96, 1.16–3.34), and on DFS of NSCLC (HR 2.12, 95% CI: 1.21–3.72) and head and neck cancer (HR 2.24, 95% CI: 1.35–3.73).

Conclusions

p16 hypermethylation might be a predictive factor of poor prognosis in some surgically treated cancers, particularly in NSCLC.     

The Prognostic Value of Global DNA Hypomethylation in Cancer: A Meta-Analysis

Background

Aberrant methylation of the global genome has been investigated as a prognostic indicator in various cancers, but the results are controversial and ambiguous.

Methods and Findings

This meta-analysis presents pooled estimates of the evidence to elucidate this issue. We searched the electronic databases: PubMed, Embase, ISI Web of Science and the Cochrane library (up to August 2013) to identify all of the relevant studies. The association between the level of surrogates'' indexes of genome-wide hypomethylation (LINE-1, Alu and Sat–α) and the overall survival (OS) of cancer patients was examined. In addition, the pooled hazard ratios (HRs) with their 95% confidence interval (95%CI) were calculated to estimate the influences through fixed-effects and random-effects model. Finally, twenty studies with total population of 5447 met the inclusion criteria. The results indicate that the summary HRs for the studies employing LINE-1, Alu, and Sat-α repetitive elements also show that the global DNA hypomethylation have significant desirable effects on the tumour prognostic value. The pooled HRs (and CIs) of LINE-1, Alu and Sat-α were 1.83 (1.38–2.44), 2.00 (1.16–3.45), and 2.92 (1.04–8.25), with a heterogeneity measure index of I² (and p-value) shows of 66.6% (p = 0.001), 57.1% (p = 0.053) and 68.2% (p = 0.076) respectively. The meta-regression and subgroup analysis indicated that the percentage of hypomethylated sample of cancer patients is one source of heterogeneity.

Conclusion

Our meta-analysis findings support the hypothesis that the global DNA hypomethylation is associated with a detrimental prognosis in tumour patients.     

Detection of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer

PURPOSE: Gastric cancer studies indicated a potential correlation between circulating tumor cells (CTCs) in peripheral blood and tumor relapse/metastasis. The prevalence and significance of circulating tumor microemboli (CTM) in gastric cancer remain unknown. We investigated the prevalence and prognostic value of CTCs and CTM for progression-free survival (PFS) and overall survival (OS) in gastric cancer patients. METHODS:Eighty-one gastric cancer patients consented to provide 5 ml of peripheral blood before systematic therapy. CTCs and CTM were isolated using isolation by size of epithelial tumor cells and characterized by cytopathologists. For 41 stage IV gastric cancer patients, CTM was investigated as a potential biomarker to predict prognosis. RESULTS:CTCs were detected in 51 patients; the average count was 1.81. In clinical stage I, II, III, and IV patients, the average CTC counts were 1.40, 0.67, 1.24, and 2.71, respectively. CTM were detected in 3 of 33 clinical stage I to IIIb patients, at an average of 0.12 (0-2). CTM were detected in 13 of 53 clinical stage IIIc to IV patients, at an average of 1.26 (0-22). In stage IV patients, CTM positivity correlated with the CA125 level. PFS and OS in CTM-positive patients were significantly lower than in CTM-negative patients (P < .001). CTM positivity was an independent factor for determining the PFS (P = .016) and OS (P = .003) of stage IV patients in multivariate analysis. Using markers of the epithelial-mesenchymal transition, single CTCs were divided into three phenotypes including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. For CTM, CK?/Vimentin+/CD45? and CK+/Vimentin+/CD45? phenotypes were observed, but the CK+/Vimentin?/CD45? CTM phenotype was not. CA125 was detected in gastric cancer cell lines BGC823 and MGC803. CONCLUSIONS: In stage IV patients, CTM positivity was correlated with serum CA125 level. CTM were an independent predictor of shorter PFS and OS in stage IV patients. Thus, CTM detection may be a useful tool to predict prognosis in stage IV patients.     

Diagnostic Value of Osteopontin in Ovarian Cancer: A Meta-Analysis and Systematic Review

AimsOsteopontin (OPN) plays an important role in many physiological and pathological processes (wound healing, inflammation, immune response, and tumorigenesis). This meta-analysis assessed the diagnostic value of osteopontin in ovarian cancer.ConclusionsOsteopontin could be a useful biomarker in diagnosis of ovarian cancer. Due to the design deficits of the eligible studies, a future study with a larger sample size and better design is needed to rigorously confirm the diagnostic potential of osteopontin in ovarian cancer.     

The Prognostic Value of Phosphorylated AKT Expression in Non-Small Cell Lung Cancer: A Meta-Analysis

Objectives

Phosphorylated AKT (p-AKT), constitutive activation of AKT, is a potentially interesting prognostic marker and therapeutic target in non-small cell lung cancer (NSCLC). However, the available results of p-AKT expression in NSCLC are heterogeneous. Therefore, a meta-analysis of published researches investigating the prognostic relevance of p-AKT expression in patients with NSCLC was performed.

Materials and Methods

A literature search via PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases was conducted. Data from eligible studies were extracted and included into meta-analysis using a random effects model.

Results

A total of 1049 patients from nine studies were included in the meta-analysis. Nine studies investigated the relationship between p-AKT expression and overall survival using univariate analysis, and five of these undertook multivariate analysis. The pooled hazard ratio (HR) for overall survival was 1.49 (95% confidence interval (CI): 1.01-2.20) by univariate analysis and 1.02 (95% CI: 0.54-1.95) by multivariate analysis.

Conclusion

Our study shows that positive expression of p-AKT is associated with poor prognosis in patients with NSCLC. However, adequately designed prospective studies need to perform.     

Prognostic Value and Clinicopathology Significance of MicroRNA-200c Expression in Cancer: A Meta-Analysis

MiR-200c has been shown to be related to cancer formation and progression. However, the prognostic and clinicopathologic significance of miR-200c expression in cancer remain inconclusive. We carried out this systematic review and meta-analysis to investigate the prognostic value of miR-200c expression in cancer. Pooled hazard ratios (HRs) of miR-200c for overall survival (OS) and progression-free survival (PFS) were calculated to measure the effective value of miR-200c expression on prognosis. The association between miR-200c expression and clinical significance was measured by odds ratios (ORs). Twenty-three studies were included in our meta-analysis. We found that miR-200c was not significantly correlated with OS (HR = 1.41, 95%Cl: 0.95-2.10; P = 0.09) and PFS (HR = 1.12, 95%Cl: 0.68-1.84; P = 0.67) in cancer. In our subgroup analysis, higher expression of miR-200c was significantly associated with poor OS in blood (HR = 2.10, 95%CI: 1.52-2.90, P<0.00001). Moreover, in clinicopathology analysis, miR-200c expression in blood was significantly associated with TNM stage, lymph node metastasis and distant metastasis. MiR-200c may have the potential to become a new blood biomarker to monitor cancer prognosis and progression.     

Prognostic Value of Overexpressed p16INK4a in Vulvar Cancer: A Meta-Analysis

Objective

This study aimed to examine the prognostic value of overexpressed p16^INK4a in vulvar cancer. Although the tumor suppressor p16^INK4a has been shown to be of prognostic value in a wide variety of cancers and precancerous lesions, its role in the vulvar cancer is still unclear.

Methods

All publications in English language on the association between p16^INK4a and clinicopathological features of vulvar cancer were searched from Pubmed, Embase, and Web of Science, and those in Chinese language were identified manually and online from the China National Knowledge Infrastructure. Strict inclusion and exclusion criteria were followed. Odds ratios(ORs) or risk ratios(RRs) with 95% confidence intervals(CIs) were pooled to assess the strength of association. Publication bias was estimated using funnel plots and the Egger’s regression test.

Results

A total of 17 studies with 2309 patients were included. The p16^INK4a overexpression was found to correlate significantly with the lower International Federation of Gynecology and Obstetrics stage(I+II vs III+IV; OR = 0.60,95%CI:0.41–0.86,P = 0.006),negative lymph node metastasis(negative vs positive; OR = 0.61,95%CI:0.39–0.95,P = 0.029),patient’s age<55(OR = 0.54,95%CI:0.31–0.96,P = 0.034),human papillomavirus–positive status(OR = 0.01,95%CI:0.00–0.11,P<0.001),and higher overall survival(RR = 0.53,95%CI = 0.35–0.80,P = 0.003).

Conclusion

The p16^INK4a might be associated with a higher survival and indicates better prognosis of vulvar cancer.     

The Prognostic Value of SOX2 Expression in Non-Small Cell Lung Cancer: A Meta-Analysis

Objective

To investigate the association of SOX2 expression in tumor with clinicopathological features and survival of non-small-cell lung carcinoma (NSCLC) patients.

Methods

Publications assessing the clinicopathological characteristics and prognostic significance of SOX2 in NSCLC were identified up to May 2013. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between SOX2 expression and these clinical parameters.

Results

A total of eight studies met the inclusion criteria. Analysis of these data showed that SOX2 expression was positively associated with squamous histology, (pooled OR = 5.26, 95% CI: 1.08–25.6, P = 0.040). Simultaneously, we also found that SOX2 expression was positively associated with overall survival (pooled HR = 0.65, 95% CI: 0.47–0.89, P = 0.007, random-effect).

Conclusions

SOX2 expression in tumor is a candidate positive prognostic biomarker for NSCLC patients.     

Prognostic Value of SPARC in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis

Objective

There is a heated debate on whether the prognostic value of SPARC is favorable or unfavorable. Thus, we carried out a meta-analysis evaluating the relationship between SPARC expression and the prognosis of patients with pancreatic cancer.

Methods

We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled hazard ratios (HRs) and corresponding 95%CI of overall survival (OS) were calculated to evaluate the prognostic value of SPARC expression in patients with pancreatic cancer. We also performed subgroup analyses.

Results

With 1623 patients pooled from 10 available studies, the incorporative HR showed an unfavorable prognosis of patients with pancreatic cancer in the multivariate analysis (HR = 1.55, 95%CI: 1.11–2.17, P = 0.01), but not in univariate analysis (HR = 1.41, 95%CI: 0.47–4.21, P = 0.54) and estimate (HR = 1.24, 95%CI: 0.72–2.13, P = 0.44). And this adverse impact could also be found in the subgroup analyses in multivariate analysis, especially in the stroma (HR = 1.53, 95%CI: 1.05–2.24, P = 0.03). However, the combined HR had the highly significant heterogeneity. No obvious publication bias was found.

Conclusions

SPARC might be an unfavorable indicator in patients with pancreatic cancer, especially in the stroma. More and further researches should be conducted to reveal the prognostic value of SPARC.     

Prognostic Value of Survivin in Patients with Gastric Cancer: A Systematic Review with Meta-Analysis

Objective

The prognostic significance of survivin for the survival of patients with gastric cancer remains controversial. Thus, the objective of this study was to conduct a systematic review of the literature evaluating survivin expression in gastric cancer as a prognostic indicator.

Methods

Relevant literature was searched using PubMed, EMBASE, and Chinese biomedicine databases. A meta-analysis of the association between survivin expression and overall survival in patients with gastric cancer was performed. Studies were pooled and summary hazard ratios (HRs) were calculated. Subgroup analyses were also conducted.

Results

Final analysis of 1365 patients from 16 eligible studies was performed. Combined HR suggested that survivin expression had an unfavorable impact on survival of gastric cancer patients (HR=1.39, 95% CI: 1.16-1.68). The unfavorable impact also appeared significant when stratified according to the studies categorized by patients’ ethnicity, detection methods, type of sample, and HR estimate. The combined HR in the English literature showed an inverse effect on survival (HR=1.40, 95% CI: 1.13-1.75), while HR in the non-English literature did not (HR=1.38, 95% CI: 0.93-2.05). When stratified according to the location of survivin expression, combined HR showed that expression in cytoplasm was significantly associated with poor prognosis of gastric cancer patients (HR=1.46, 95% CI: 1.12-1.90). While expression in nucleus was not significantly associated with poor prognosis (HR=1.29, 95% CI: 0.72-2.31), the heterogeneity was highly significant (chi-squared=11.5, I²=74%, p=0.009).

Conclusions

This study showed that survivin expression was associated with a poor prognosis in patients with gastric cancer. Cytoplasmic expression of survivin may be regarded as a prognostic factor for gastric cancer patients. In contrast, survivin expression in nucleus did not have a significant impact on patients’ overall survival.     

EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer

Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far–including the gold standard CellSearch—rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT). Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture an EpCAM^low/neg cell line and EpCAM^neg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAM^pos (e.g. MCF7, SKBR3) and EpCAM^low/neg (MDA-MB-231) breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) for capturing EpCAM^neg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAM^pos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAM^low/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAM^low/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAM^neg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK)-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69%) from 25 metastatic breast cancer patients additional EpCAM^neg CTCs could be identified [range of 1–24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. EpCAM^neg dual-positive (CK^pos/CD45^pos) cells could be traced in 28 out of 29 samples [range 1–480]. By single-cell array-based comparative genomic hybridization we were able to demonstrate the malignant nature of one EpCAM^neg subpopulation. In conclusion, we established a novel enhanced CTC enrichment strategy to capture EpCAM^neg CTCs from clinical blood samples by targeting various cell surface antigens with antibody mixtures and ECM components.     

肿瘤标志物在卵巢恶性肿瘤早期误诊预防中的价值

目的:探讨糖类抗原CA125、CEA与CA199联合检测对卵巢癌有一定的鉴别诊断价值。方法:应用化学发光免疫法对126例经病理查证实的卵巢癌患者(试验组)、104例良性肿瘤患者(对照组)进行血清CA125、CEA与CA199检测。结果:试验组血清检测结果和阳性率均明显高于对照组(P<0.01),联合检测阳性率高于单项检测(P<0.01)。结论:应用检验医学进行CA125、CEA与CA199联合检测对卵巢癌有一定的鉴别诊断价值。可降低误诊率。     

Prognostic Value of Human Equilibrative NucleosideTransporter1 in Pancreatic Cancer Receiving Gemcitabin-Based Chemotherapy: A Meta-Analysis

Background

The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported.

Objective

The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect.

Methods

Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels.

Results

A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37–3.64) and 2.67 (95% CI, 1.87–3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76–4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies.

Conclusion

These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy.