June Wang

Risk of tuberculosis in patients treated with TNF-α antagonists: a systematic review and meta-analysis of randomised controlled trials

Objectives An increased risk of tuberculosis (TB) has been reported in patients treated with TNF-α antagonists, an issue that has been highlighted in a WHO black box warning. This review aimed to assess the risk of TB in patients undergoing TNF-α antagonists treatment. Methods A systematic literature search for randomised controlled trials (RCTs) was performed in MEDLINE, Embase and Cochrane library and studies selected for inclusion according to predefined criteria. ORs with 95% CIs were calculated using the random-effect model. Subgroup analyses considered the effects of drug type, disease and TB endemicity. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Results 29 RCTs involving 11 879 patients were included (14 for infliximab, 9 for adalimumab, 2 for golimumab, 1 for etanercept and 3 for certolizumab pegol). Of 7912 patients allocated to TNF-α antagonists, 45 (0.57%) developed TB, while only 3 cases occurred in 3967 patients allocated to control groups, resulting in an OR of 1.94 (95% CI 1.10 to 3.44, p=0.02). Subgroup analyses indicated that patients of rheumatoid arthritis (RA) had a higher increased risk of TB when treated with TNF-α antagonists (OR 2.29 (1.09 to 4.78), p=0.03). The level of the evidence was recommended as ‘low’ by the GRADE system. Conclusions Findings from our meta-analysis indicate that the risk of TB may be significantly increased in patients treated with TNF-α antagonists. However, further studies are needed to reveal the biological mechanism of the increased TB risk caused by TNF-α antagonists treatment.

The prognostic value of abnormally expressed lncRNAs in colorectal cancer: A meta-analysis

Background Colorectal cancer (CRC) is the third most prevalent cancer type and the third leading cause of cancer-related deaths worldwide, it is urgently needed to discover a new marker for the progress of CRC. Many long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in CRC, and may be feasible as effective biomarkers and prognostic factors. The aim of this study was to identify the prognostic value of various lncRNAs in CRC. Methods Pubmed, Web of Science, Embase and Cochrane Library were searched for potentially related studies. A total of 34 eligible studies including 30 on overall survival (OS), 7 on disease-free survival (DFS), 1 on relapse-free survival (RFS), 2 on disease-specific survival (DSS) and 29 on clinicopathological features were qualified from the databases. Results The results showed that the expression levels of lncRNAs were significantly associated with poor OS (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.68–2.57, P<0.001, I2 = 70%), DFS (HR = 1.79, 95% CI = 1.54–2.08, P<0.001, I2 = 6%) and DSS (HR = 0.11, 95% CI = 0.02–0.54, P = 0.007, I2 = 14%). Subgroup analysis further showed that lncRNA transcription level was significantly associated with tumor differentiation (odds ratio (OR) = 0.51, 95% CI = 0.34–0.77, P = 0.001), lymph node metastasis (OR = 1.63, 95% CI = 1.23–2.17, P = 0.0007), distant metastasis (OR = 2.06, 95% CI = 1.29–3.30, P = 0.002), TNM stage (OR = 0.44, 95% CI = 0.32–0.62, P<0.001), tumor invasion depth (OR = 0.48, 95% CI = 0.39–0.60, P<0.001). Conclusions The meta-analysis demonstrated that abnormal lncRNA transcription level may serve as a promising indicator for prognostic of patients with CRC.

The prognostic and diagnostic value of circulating tumor cells in bladder cancer and upper tract urothelial carcinoma: a meta-analysis of 30 published studies

There are inconsistent conclusions in the association between circulating tumor cells (CTCs) and urothelial cancer (UC). We performed a meta-analysis to assess the prognostic and diagnostic value of CTCs in UC. We search Medline, Embase and Web of science for relevant studies. The study was set up according to the inclusion/exclusion criteria. 30 published studies with a total of 2161 urothelial cancer patients were included. Meta-analysis showed that CTC-positive was significantly associated with tumor stage (≤ II vs III, IV) (OR = 4.60, 95% CI: 2.34-9.03), histological grade (I, II vs III) (OR = 2.91, 95% CI: 1.92-4.40), metastasis (OR = 5.12, 95% CI: 3.47-7.55) and regional lymph node metastasis (OR = 2.47, 95% CI: 1.75-3.49). It was also significantly associated with poor overall survival (OS) (HR = 3.98, 95% CI: 2.20-7.21), progression/disease-free survival (PFS/DFS) (HR = 2.22, 95% CI: 1.80-2.73) and cancer-specific survival (CSS) (HR = 5.18, 95% CI: 2.21-12.13). Overall sensitivity and specificity of CTC detection assays were 0.35 (95% CI: 0.28-0.43) and 0.97 (95% CI: 0.92-0.99) respectively. In summary, our meta-analysis suggests that the presence of CTCs in the peripheral blood is an independent predictive indicator of poor outcomes for urothelial cancer patients. It can also be used as a noninvasive method for the confirmation of cancer diagnosis. More studies are required to further explore the role of this marker in clinical practice.There are inconsistent conclusions in the association between circulating tumor cells (CTCs) and urothelial cancer (UC). We performed a meta-analysis to assess the prognostic and diagnostic value of CTCs in UC. We search Medline, Embase and Web of science for relevant studies. The study was set up according to the inclusion/exclusion criteria. 30 published studies with a total of 2161 urothelial cancer patients were included. Meta-analysis showed that CTC-positive was significantly associated with tumor stage (≤ II vs III, IV) (OR = 4.60, 95% CI: 2.34–9.03), histological grade (I, II vs III) (OR = 2.91, 95% CI: 1.92–4.40), metastasis (OR = 5.12, 95% CI: 3.47–7.55) and regional lymph node metastasis (OR = 2.47, 95% CI: 1.75–3.49). It was also significantly associated with poor overall survival (OS) (HR = 3.98, 95% CI: 2.20–7.21), progression/disease-free survival (PFS/DFS) (HR = 2.22, 95% CI: 1.80–2.73) and cancer-specific survival (CSS) (HR = 5.18, 95% CI: 2.21–12.13). Overall sensitivity and specificity of CTC detection assays were 0.35 (95% CI: 0.28–0.43) and 0.97 (95% CI: 0.92–0.99) respectively. In summary, our meta-analysis suggests that the presence of CTCs in the peripheral blood is an independent predictive indicator of poor outcomes for urothelial cancer patients. It can also be used as a noninvasive method for the confirmation of cancer diagnosis. More studies are required to further explore the role of this marker in clinical practice.

Tumor Necrosis Factor-α T-857C (rs1799724) Polymorphism and Risk of Cancers: A Meta-Analysis

Objectives. To investigate the potential association of tumor necrosis factor-α T-857C polymorphism with susceptibility to the five common malignant tumors. Materials and Methods. A comprehensive search of PubMed/Medline, Embase, and Web of Science databases was performed up to November 2015. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analysis, heterogeneity analyses, and publication bias were also texted in the meta-analysis. Results. A total of twenty-two publications involving 5215 cases and 6755 controls were recruited. Overall, the meta-analysis revealed an increased risk between the TNF-α T-857C polymorphism and gastric cancer susceptibility in T versus C model, heterozygote genetic model, and dominant genetic model. An increased risk between the TNF-α T-857C polymorphism and hepatocellular cancer susceptibility in homozygote genetic model and recessive genetic model was also found. No significant association was found between the TNF-α T-857C polymorphism and colorectal cancer, cervical cancer, and prostate cancer. Conclusions. Our meta-analyses suggest that TNF-α T-857C polymorphism may be associated with increased risk of gastric cancer and hepatocellular cancer development. Therefore, the TNF-α T-857C polymorphism could be considered as one possible risk factor of gastric cancer and hepatocellular cancer according to our study.

Prognostic Value of HMGA2 in Human Cancers: A Meta-Analysis Based on Literatures and TCGA Datasets

Background: Emerging evidences have shown that the high-mobility group protein A2 (HMGA2) can aberrantly express in human cancers, and it could be an unfavorable prognostic factor in cancer patients. However, the prognostic value of HMGA2 was still unclear. Therefore, in this study, we explored the potential prognostic value of HMGA2 in human cancers by using meta-analysis based on published literatures and The Cancer Genome Atlas (TCGA) datasets. Methods: Through searching PubMed, Embase, Web of Science and Cochrane Library databases, we were able to identify the studies evaluating the prognostic value of HMGA2 in cancers. Then, UALCAN and TCGA datasets were used to validate the results of our meta-analysis. Results: In all, 15 types of cancers were included in this meta-analysis. Pooled results showed that high level of HMGA2 was significantly correlated with poor OS (HR = 1.88, 95% confidence interval (CI) = 1.68-2.11, P < 0.001) and poor DFS (HR = 2.49, 95% CI = 1.44-4.28, P = 0.001) in cancer patients. However, subgroup analyses revealed that the high expressed HMGA2 was associated with poor OS in head and neck cancer, gastric cancer and colorectal cancer, but not esophageal cancer and ovarian cancer. Based on TCGA datasets, we analyzed 9944 patients with 33 types of cancers. Significant association between HMGA2 overexpression and poor OS was found in 14 types of cancers. Taken together, consistent results were observed in clear cell renal cell carcinoma, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Conclusion: Our meta-analysis showed the significance of HMGA2 and its prognostic value in various cancers. High level of HMGA2 could be associated with poor OS in patients with clear cell renal cell carcinoma, head and neck cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma, but not esophageal adenocarcinoma and ovarian carcinoma.

Predictive value of long noncoding RNA ZFAS1 in patients with ischemic stroke

ABSTRACT Background: LncRNAs play an essential role in a variety of diseases. Zinc finger antisense 1 (ZFAS1), a newly identified lncRNA, is a transcript antisense to the 5ʹ end of the gene Znfx1. The purpose of this study was to aim to compare the levels of ZFAS1 between ischemic stroke (IS) and healthy control subjects and explore its potential role as a noninvasive biomarker in the diagnosis of IS. Methods: A total of 176 patients and 111 healthy controls were included in the study. RT-qPCR was performed to detect the expression of ZFAS1. Results: The results showed that level of ZFAS1 in IS patients was significantly lower than controls (P = 0.0002). Furthermore, we found that the ZFAS1 levels in large-artery atherosclerosis (LAA) strokes were significantly downregulated than those in non-LAA strokes and controls. Meanwhile, ZFAS1 levels in the small vessel occlusion (SVO) group were lower than those in cardioembolism (CE) (P = 0.0197) and controls (P = 0.0041). Multinomial logistic regression analyses showed that the expression of ZFAS1 was not associated with the CE (P = 0.185) and SVO (P = 0.268) stroke groups, while lower ZFAS1 levels (P < 0.003, adjusted OR = 0.218, 95% CI: 0.079–0.597) showed significant associations with increased probability of having LAA strokes, compared to control subjects. The receiver operating characteristic curve analyses indicated that the sensitive of ZFAS1 was 89.39% in differentiating LAA strokes from controls. Conclusion: These results suggest that ZFAS1 might be used as a potential noninvasive biomarker for the diagnosis of LAA stroke.

TACC3 as an independent prognostic marker for solid tumors: a systematic review and meta-analysis

Recent studies have showed that the transforming acidic coiled coil 3 (TACC3), was aberrantly up-regulated in various solid tumors and was reported to be correlated with unfavorable prognosis in cancer patients. This study aimed to examine the relationship between TACC3 and relevant clinical outcomes. Pubmed, Web of Science, Embase and Cochrane Library were systematically searched to obtain all eligible articles. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the influence of TACC3 expression on overall survival (OS) and disease-free survival (DFS) in solid tumors patients. A total of 1943 patients from 11 articles were included. The result indicated that a significantly shorter OS was observed in patients with high expression level of TACC3 (HR=1.90, 95% CI=1.63–2.23). In the subgroup analysis, the association was also observed in patients with cancers of digestive system (HR=1.85, 95% CI=1.53–2.24). Statistical significance was also observed in subgroup meta-analysis stratified by the cancer type, analysis type and sample size. Furthermore, poorer DFS was observed in patients with high expression level of TACC3 (HR=2.67, 95% CI=2.10–3.40). Additionally, the pooled odds ratios (ORs) showed that increased TACC3 expression was also related to positive lymph node metastasis (OR=1.68, 95% CI=1.26–2.25), tumor differentiation (OR=1.90, 95% CI=1.25–2.88) and TNM stage (OR=1.66, 95% CI=1.25-2.20). In conclusion, the increased expression level of TACC3 was associated with unfavorable prognosis, suggesting that it was a valuable prognosis biomarker or a promising therapeutic target of solid tumors. Further studies should be conducted to confirm the clinical utility of TACC3 in human solid tumors.

The roles of ncRNAs in the diagnosis, prognosis and clinicopathological features of breast cancer: a systematic review and meta-analysis

Background A number of studies have shown that noncoding RNAs (ncRNAs) are abnormally expressed in breast cancers. However, the roles of ncRNAs remain unclear in breast cancer. Here, we aim to investigate the potential diagnostic and prognostic roles of ncRNAs in breast cancer. Methods Comprehensive literature search in Medline and Web of Science and a meta-analysis were performed to identify the association between ncRNAs and diagnosis, prognosis, and clinicopathological features of breast cancer. Results A total of 103 eligible studies, involving16, 828 independent participants, were included in the meta-analysis. In total, there were 98 individual and 11 grouped ncRNAs. 51 studies were eligible for survival analysis, 27 studies were eligible for diagnostic analysis, and 46 studies were eligible for clinicopathological features analysis. The abnormal expression of ncRNAs is associated with OS, RFS and PFS in breast cancer patients. For the diagnosis value of ncRNAs, the pooled OR and 95% CI for sensitivity, specificity, DOR and AUC on all ncRNAs were 0.83 [95% CI: 0.82- 0.84], 0.80 [95% CI: 0.79- 0.82], 24.77 [95% CI: 17.44- 35.16] and 0.9037, respectively. The analysis showed that downregulation of ncRNAs in breast cancer was associated with decreased risk of LNM, increased tumor size and PR expression, whereas, upregulation of ncRNAs was associated with increased HER2 expression. Conclusions High expression of ncRNAs was associated with poor OS, RFS, and PFS, while low expression of ncRNAs was related to favorable OS and RFS. Meanwhile, ncRNAs have potential diagnostic value for breast cancer.

The Clinicopathological and Prognostic Implications of FoxP3+ Regulatory T Cells in Patients with Colorectal Cancer: A Meta-Analysis

Background and Objective: Forkhead box P3 (FoxP3) is known as the specific marker for regulatory T lymphocytes (Tregs), which are responsible for self-tolerance and disturb the antitumor immunity. However, the prognostic implication of tumor-infiltrating FoxP3+ Tregs in patients with colorectal cancer (CRC) still remains controversial. The aim of this present study was to investigate the prognostic role of FoxP3+ Tregs in CRC through meta-analysis. Methods: PubMed, Embase and Web of Science were searched for relevant articles up to December 12, 2016. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the prognostic value of FoxP3+ Tregs in CRC. Odds ratio (OR) was calculated to investigate the correlation between FoxP3+ Tregs and pathological parameters. Results: A total of 18 studies comprising 3,627 patients with CRC were enrolled in our meta-analysis. The combined HR for FoxP3+ Tregs on cancer-specific survival was 0.70 (95% CI = 0.62–0.80, P < 0.001). High FoxP3+ Tregs level was also associated with favorable prognosis on overall survival (HR = 0.76, 95% CI = 0.58–1.01, P = 0.058), with P-value very close to the statistical threshold. Yet, there was no correlation between FoxP3+ Tregs infiltration and disease-free survival (HR = 0.83, 95% CI = 0.63–1.09, P = 0.182). Moreover, FoxP3+ Tregs infiltration was significantly correlated with pT stage (OR = 0.50, 95% CI = 0.39–0.65, P < 0.001), tumor grade (OR = 0.77, 95% CI = 0.61–0.98, P = 0.032), lymphatic invasion (OR = 0.25, 95% CI = 0.07–0.89, P = 0.033) and vascular invasion (OR = 0.67, 95% CI = 0.52–0.86, P = 0.001). Conclusion: The present meta-analysis suggests that high FoxP3+ Tregs infiltration is inclined to indicate favorable prognosis and is associated with the pathogenesis of CRC. Immunotherapy targeting Tregs in patients with CRC should be further investigated.

Risk of infection in patients with spondyloarthritis and ankylosing spondylitis receiving antitumor necrosis factor therapy: A meta‑analysis of randomized controlled trials

Antitumor necrosis factor (TNF) agents have been widely used for the treatment of spondyloarthritis (SpA) and ankylosing spondylitis (AS). However, these agents may increase the risk of infection due to suppressing the immune response. The present meta-analysis was performed to systematically investigate the risk of overall infection, serious infection and tuberculosis in patients with SpA and AS treated with anti-TNF agents. Medline, Embase and the Cochrane library were searched for randomized controlled trials (RCTs) published between January 1998 and December 2015 about infection in patients with SpA receiving anti-TNF therapy. Data were pooled to obtain relative risks (RRs) along with their 95% confidence intervals (CIs). A total of 25 RCTs investigating SpA, including 12 investigating AS specifically, were eligible for the meta-analysis. Similar risks of overall infection were reported in patients with SpA (RR, 1.03; 95% CI, 0.92–1.15) and AS (RR, 1.06; 95% CI, 0.91–1.24) treated with anti-TNF agents. The RR of serious infection for patients with SpA or AS receiving anti-TNF therapy compared with a placebo was 1.27 (95% CI, 0.67–2.38) and 1.57 (95% CI, 0.63–3.91), respectively. In addition, 4 RCTs with outcomes of tuberculosis in patients with SpA receiving anti-TNF agents were identified, all in infliximab-treated patients (RR, 2.52; 95% CI, 0.53–12.09). However, due to the limited number of RCTs, this finding should be interpreted with caution. The present meta-analysis did not find any significantly increased risk of infection associated with anti-TNF therapy in patients with SpA or AS. However, due to short duration of follow-up in the RCTs and the rarity of serious infections and tuberculosis, patients treated with anti-TNF agents still should be closely monitored in clinical practice.