RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations.The p.R4810K and other rare variants of ring finger protein 213 gene  with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0.RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy . It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country . The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China . Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population . Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet.Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.This meta-analysis shows the critical roles of The online version of this article (10.1186/s12199-017-0680-1) contains supplementary material, which is available to authorized users. Moyamoya disease (MMD) is an idiopathic steno-occlusive disease of intracranial arteries characterized by progressive bilateral and occasionally unilateral stenosis and occlusion of the distal internal carotid artery, with frequent involvement of the middle cerebral artery and anterior cerebral artery, and by the abnormal development of a hazy network of basal collateral vessels , 2. MMD RNF213) on 17q25.3 as a novel susceptibility gene for MMD in Japan and East Asian population, respectively  significantly increases MMD risk in Japan, Korea, and China (odds ratios (ORs) were 338.94, 135.63, and 14.70 in a dominant model, respectively)  or RNF 213*[tw] or ring finger protein 213*[tw]. Articles in all languages were searched and translated as necessary. After relevant articles were retrieved, references were also checked for other potentially relevant articles not found in the initial search.Electronic databases PubMed, EMBASE, Web of Science, WANFANG DATA, and China National Knowledge Infrastructure (CNKI) were used to retrieve potentially relevant articles on human genetic studies of MMD and ICASO that had been published up to 5 September 2017. Search terms used were RNF213 rare variants with proven MMD or ICASO  in all ethnicities. The detailed inclusion criteria were (1) well-designed case control studies to investigate the relationship between at least one genetic variant of RNF213 and MMD or ICASO, or case-only studies which investigated the carrier rate of RNF213 variants in MMD or ICASO and the carrier rates of the target variants were available in the general population; (2) clear diagnostic criteria of MMD and ICASO; (3) original papers contained independent and sufficient genotype data to calculate ORs and 95% confidence intervals (CIs); (4) all variants included in the meta-analysis should be evaluated in at least two published studies. Where duplicate or overlapped datasets existed, only the largest study was included. The studies without essential information or with overlapped data, review articles, case reports, and animal models were excluded. For the variants identified just in one study or the sample number that was limited to perform association analysis, a qualitative systematic review was performed.We included related studies evaluating associations of http://www.oege.org/software/hwe-mr-calc.shtml). Quality assessment of primary studies was performed using Newcastle–Ottawa quality assessment scale (NOS) [Data were extracted by two of the authors (XL and JD), and differences were resolved by consensus (JY). For each included study, the following information was extracted: first author, year of publication, study population (country), mean age, familial history of MMD, numbers of patients and controls, frequency of genotypes, and Hardy–Weinberg equilibrium (HWE) status. Where genotype frequencies for each variant were unavailable, we estimated the number of cases per genotype category by using published information on risk allele frequencies and ORs for MMD or ICASO. The HWE of controls was obtained either directly from the article or indirectly by calculating from genotype distributions using a web-based program (le (NOS) . Each stZ test, and p < 0.05 was considered statistically significant.Statistical analyses were conducted using STATA12.0 software . Frequency of the genotypes and alleles between MMD/ICASO group and control group were compared using Chi-square or Fisher exact test. For each genetic variant with more than one publication, meta-analysis was performed to determine a pooled OR and 95% CI according to dominant, recessive and allelic models by using a fixed- or random-effect model. The significance of the pooled OR was determined using Q test and quantified by using Higgins I2 statistic. CIs for I2 were also calculated. For Q test, p < 0.05 was considered as having significant heterogeneity. For variant association showing significant inter-study heterogeneity , the random-effect model was used as the pooling method; otherwise, the fixed-effect model was used. To evaluate ethnic-specific effects, subgroup analysis was performed according to the nationality of the study population. Publication bias was assessed by using the Egger regression asymmetry test and visualization of funnel plots if more than seven studies were included, and the significance was set at the p < 0.05 level. Sensitivity analysis was performed by sequentially excluding individual study to calculate the pooled OR of the remaining studies and assess the stability of the results.Heterogeneity among studies was assessed using Cochran Five hundred sixty-four articles were identified through the database check, and no article was identified through the related references check. After screening for duplication and eligibility, data from 24 studies met the inclusion criteria and was included. A detailed workflow chart showing the study selection is presented in Fig. RNF213 rare variants  and MMD [RNF213 p.R4810K and ICASO [In total, twenty articles investigated the association between seven  and MMD , 35–40; nd ICASO , 40–43. RNF213 p.R4810K. Nineteen articles representing 23 studies evaluated their associations, of which 8 were conducted in Japanese; 7, in Korean; and 8, in Chinese with a total of 2331 MMD cases and 5476 controls.The most robust variant associated with MMD was p < 0.0001)  Table . Country1) Table , Fig. 2aRNF213 p.R4810K significantly increased familial MMD risk in Japanese, Korean, and Chinese population, with 5 ~ 36 times larger effect sizes than that in sporadic cases   in each ethnic population revealed that RNF213 p.R4810K, the associations between the other six rare variants  and MMD were evaluated in at least two published studies. The detailed information was presented in Tables Except There were two rare variants—p.E4950D and p.A5021V—significantly associated with MMD in Chinese population in the pooled analysis  Fig. . No signp < 0.0001 , followed by that in Japan  and China   and the Egger regression asymmetry test  did not find significant asymmetry , with 5 ~ 36 times larger effect sizes than that for sporadic cases   may contribute to sporadic MMD. In this study, we found another two rare variants—p.E4950D and p.A5021V—in RNF213 significantly increased MMD risk in Chinese population in the pooled analysis . In addition, more than 40 other rare missense variants of RNF213 were identified in Chinese MMD cases but absent in controls  [RNF213 p.D4013N-transfected human umbilical vein endothelial cells displayed significant lowered migration activity which was similar with the experiment result of p.R4810K transfection and strongly indicated the disease-causing effect [RNF213 [RNF213 p.R4810K remain unaffected with MMD [MMD is a rare idiopathic intracranial vascular disorder with strong genetic components. Genetic study of familial MMD clearly indicated autosomal dominant inheritance pattern . RNF213 .E5176G) . Of them.E5176G) , 19. Recg effect . Howeverwith MMD . Unknownwith MMD . Both geRNF213 rare variants were identified in MMD cases worldwide [RNF213 p.R4810K was not identified in European, Hispanic, or Black descent MMD patients, other rare variants in RNF213 were identified in these populations, such as p.A529del, p.R3922Q, p.N3962Q, p.C3997Y, p.D4013N, and p.R4019C  and to a less degree in Chinese population . About the association results, there are two possible explanations: (1) MMD has been misclassified as ICASO due to the atypical manifestation with the absence of one or two diagnostic criteria and lead to the spurious association between RNF213 p.R4810K and ICASO or (2) RNF213 p.R4810K is indeed associated with ICASO. Currently, MMD was diagnosis based on the findings of magnetic resonance angiography or digital subtraction angiography: (1) steno-occlusive lesions around the terminal portions of the internal carotid arteries , (2) moyamoya vessels at the base of the brain appearing as abnormal vascular networks, (3) findings 1 and 2 are present bilaterally [RNF213 p.R4810K increased with the number of observed angiographic criteria. They demonstrated that the current criteria is limited in distinguishing MMD and ICASO, and a substantial proportion of patients with adult-onset MMD may be misclassified as having ICASO [RNF213 p.R4810K variant in a subsequent research, which demonstrated that the RNF213 p.R4810K is also a high-risk variant for ICASO [RNF213 p.R4810K variant, which can be differentiated from ICASO caused by atherosclerosis by using genetic analysis [RNF213 p.R4810K variant contributed less extent of ICASO risk compared to that in Korea and Japan . Similar with MMD, ethnicity-specific genetic and environmental factors may contribute to this discrepancy. Further well-designed genetic epidemiology studies focusing on ethnicity-specific risk factors such as choosing the relative genetically homogenous population and comprehensively collecting the detailed environmental factors of ICASO are needed.In this study, we also found that ng ICASO . Howeveror ICASO . We prefanalysis . HoweverRNF213 p.R4810K and other rare variants lead to intracranial vascular lesions are still unknown [RNF213 p.R4810K affected neither the transcription level nor the ubiquitin ligase activity of the protein [RNF213 in zebrafish leads to abnormal sprouting and irregular diameter of intracranial vessels, suggesting some role of RNF213 in the vascular formation [RNF213 p.R4810K carrier to develop vascular lesions [RNF213 p.R4810K showed a reduced angiogenesis of transgenic mouse response to hypoxia in vivo [Scholz et al. found that Rnf213 was a co-regulated gene for the WNT signaling enhancer R-spondin3 (RSPO3) and identified that endothelial RSPO3-driven non-canonical WNT/Ca(2+)/NFAT signaling as a critical maintenance pathway of the remodeling vasculature [PTP1B) controlled non-mitochondrial oxygen consumption by regulating RNF213 to promote tumor survival during hypoxia and concluded that PTP1B/RNF213/α-KGDD pathway was critical for survival of tumors in the hypoxic microenvironment [RNF213 R4810K and other rare variants under different environmental condition such as hypoxia and chronic inflammation is expected to provide answers to the pending questions.To date, the mechanisms of how  unknown . An in v protein . Knockdoormation . Hitomi ormation , 47. Howormation , 48. Unk lesions . Recentl in vivo . Scholz culature . Banh etironment  The inveThe limitations of this study should be considered. First, due to the fact that we analyzed the association between rare variants and diseases, the number of cases and controls involved in the meta-analysis for moderate effect rare variants may be less powered, studies with larger sample size and high quality are needed to explore the associations in the future; second, MMD and ICASO appears to have complex determiners, with both genetic predisposition and environmental triggers. Unknown modifier factor(s) may also be contributory to MMD and ICASO. Multivariate analysis to adjust for the confounding factors such as behavior or clinical or biochemical factors in our meta-analysis was not available. Further comprehensive studies focusing on multiple ethnicity-specific factors are needed; third, ICASO may represent a broad spectrum of diseases and there are various phenotypes , which may belong to different clinical entities. Due to no more clinical information available in the original papers, subgroup analysis could not be performed according to these factors, which may lead to bias. Further studies with detailed clinical features are needed; fourth, this analysis was constrained to studies which were published and deposited in English and Chinese databases, the other databases were not available, and selection bias could not be excluded  may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.This comprehensive systematic review and meta-analysis reveals that the critical roles of Additional file 1: Figure S1.RNF213 p.R4810K with MMD and ICASO under a dominant model (TIFF 1024 kb)Sensitivity analysis of the association of Additional file 2: Table S1.RNF213 identified in different populations (XLSX 14 kb)Other rare variants of Additional file 3:Literature list (XLSX 67 kb)


P = 0.002), heterozygous , and dominant  models. The association was more prominent in Asians. No significant association was found using any genetic model for the rs11801299, rs1380576, rs10900598, and rs1563828 SNPs. These results indicate that the rs4245739 polymorphism may contribute to a decreased cancer susceptibility and support the hypothesis that genetic variants in the MDM4 genes act as important modifiers of cancer risk.Molecular epidemiological research suggests that mouse double minute 4 (MDM4) polymorphisms may be associated with cancer susceptibility, but results remain controversial. To derive a more precise evaluation, we performed a PRISMA compliant meta-analysis focused on five single nucleotide polymorphisms  of MDM4. Overall, 23 studies involving 22,218 cases and 55,033 controls were analyzed. The results showed that rs4245739 was significantly associated with a decreased cancer risk in the allelic (C vs. A: odds ratio [OR] = 0.848, 95% confidence interval [CI] = 0.765–0.941,  Mouse double minute 4  is a member of the MDM family that also includes MDM2 and its derivatives. MDM4 can bind directly to p53 and inhibit its transcriptional activation, as well as mediate various cellular pathways based on p53 . Tumor sMolecular epidemiological research suggests that genetic variations in MDM4 gene may be associated with the cancer risk. Recently, a single nucleotide polymorphism (SNP) in the 3′ untranslated region of the MDM4 gene, rs4245739 A > C has been found to affect MDM4 mRNA stability and protein levels , breast Figure P = 0.002), heterozygous , and dominant  models , 3433, 3Q test and I2 statistics, for which P < 0.1 and/or I2 > 50% indicated the presence of significant heterogeneity. The DerSimonian and Laird random-effects methods were used to calculate the OR if significant heterogeneity was present; otherwise the Mantel-Haenszel fixed-effects model was applied. Meta-regression analysis was undertaken to explore potential sources of heterogeneity across studies when statistical heterogeneity was detected. The covariates included publication year, ethnicity, cancer type, genotyping methods, and source of controls. In order to avoid false-positive results, the Bonferroni method was used to adjust the significance level of each covariate. Subgroup analyses were performed based on ethnicity cancer type, and source of controls.The associations between MDM4 polymorphisms and the risk of cancer were measured by ORs with 95% CIs based on five genetic models: allelic model, homozygous model, heterozygous model, dominant model, and recessive model. Statistical heterogeneity across studies was assessed using Cochran's P > 0.05) was also calculated [Leave-one-out sensitivity analysis was conducted by sequentially excluding individual studies one at a time and recalculating ORs to evaluate the stability of the results. We also performed a sensitivity analysis by excluding the low-quality studies and computing the ORs for high-quality studies only. Publication bias was assessed using the funnel plot, Begg's and Egger's linear regression test, and the trim-and-fill method . The failculated .P value of < 0.05 (two-sided) was considered statistically significant. All statistical analyses were performed using Stata software .A


Resistin levels have been reported to be abnormal in obesity-related cancer patients with epidemiological studies yielding inconsistent results. Therefore, a meta-analysis was performed to assess the association between blood resistin levels and obesity-related cancer risk. A total of 13 studies were included for pooling ORs analysis. High resistin levels were found in cancer patients . After excluding one study primarily contributing to between-study heterogeneity, the association between resistin levels and cancer risk was still significant . Stratification analysis found resistin levels were not associated with cancer risk in prospective studies. Meta-regression analysis identified factors such as geographic area, detection assay, or study design as confounders to between-study variance. The result of 18 studies of pooling measures on SMD analysis was that high resistin levels were associated with increased cancer risk , but not in the pooling SMD analysis of prospective studies. Except for the studies identified as major contributors to heterogeneity by Galbraith plot, resistin levels were still higher in cancer patients  in retrospective studies. Meta-regression analysis found factors, such as geographic area, BMI-match, size, and quality score, could account for 66.7% between-study variance in pooling SMD analysis of retrospective studies. Publication bias was not found in pooling ORs analysis. Our findings indicated high resistin levels were associated with increased obesity-related cancer risk. However, it may not be a predictor. Obesity and diabetes are considered as important risk factors of cancers. According to a population-based study in 2012, a quarter of the cancer cases possess high body-mass index (BMI) . HoweverResistin was first identified by a screening of adipocyte products that were decreased by rosiglitazone in mice. It was considered as the potential link between obesity and diabetes . ResistiTo the best of our knowledge, no systematic review evaluated the association of blood resistin levels with obesity-related cancer risk. More convincing evidence is needed to reveal the role of resistin in obesity-related cancers. The present study aimed to evaluate the association of circulating resistin levels with the risk of obesity-related cancers by conducting a meta-analysis.The procedure of literature selection is presented in Figure 13 studies for meta-analysis performed on ORs were published from 2007 to 2016, involving 2756 cases and 3350 controls. 8 and 4 articles focused on breast and colorectal cancer, respectively –20. 6 arFor pooling SMD analysis, 17 articles constituted 2421 cases and 2731 controls. Because 1 article consisted of 2 studies , 27, 29,I2 = 31.2%, P = 0.133). So a fixed-effects model was adopted , a random-effects model was used. Higher resistin levels were present in cancer patients   Figure . However2I = 5.0%, P  = 0.396)  = 0.087) , detection assay , and study design  were found to be significant factors  a. For th= 0.396) . After e= 0.087) . FurtherP = 0.180)  (P = 0.150)  Figure . For poo) Figure . Egger's= 0.001) . For poo= 0.001) . However) Figure .Currently, increased attention has been paid to the role of resistin in obesity-related cancers. Whether circulating resistin levels are higher in cancer patients is inconsistent. A meta-analysis was conducted by pooling both ORs and SMD. Higher resistin levels were found to be associated with increased obesity-related cancer risk. Serum resistin levels may be an independent risk of obesity-related cancers, but not a predictor. It may be the first attempt to synthesize the existing studies to evaluate the association of circulating resistin levels with obesity-related cancer risk.It is widely accepted that increased BMI and insulin resistance are associated with increased obesity-related cancer risk. Resistin was considered as an adipocytokine secreted by adipocytes, monocytes and macrophages, especially in the visceral adipose tissue. Increasing evidence has shown human resistin could stimulate the production of pro-inflammatory cytokines and was an inflammatory biomarker , 32. ChrThe heterogeneity of between-study is common in meta-analysis. Meta-analysis showed significant between-study heterogeneity, especially in pooling SMD analysis. Sensitivity analysis, subgroup analysis, Galbraith plots, and meta-regression analysis were used to explore the potential causes of between-study heterogeneity and to reduce the heterogeneity. Sensitivity analysis didn't find any single study affected the estimated significance of pooled ORs or SMD. Galbraith plots indicated that 1 outlier study contributed to heterogeneity in pooling ORs analysis, while 4 outlier studies contributed to heterogeneity in pooling SMD analysis of retrospective studies. The results of the outlier studies greatly deviated from the pooling results. After omitting these studies, heterogeneity was insignificant. The pooling results didn't change significantly because of excluding the outlier studies. Meta-regression analysis found factors such as geographic area, detection assay, or study design almost completely accounted for some between-study variance in pooling ORs analysis, while geographic area, BMI-match, size, and quality score contributed significantly to heterogeneity of between-study in pooling SMD analysis of retrospective studies.However, some limitations in the meta-analysis should be demonstrated, and the results should be prudently explained. First, our meta-analysis was limited to articles published in English. Slight publication bias may exist, especially for pooling SMD analysis. Some eligible articles may have been missed. Second, most studies included in our meta-analysis were case-control studies. It's widely known that case-control studies have inherent limits, such as selection bias, admission rate bias, detection signal bias. Third, the confounding factors in the studies for ORs analysis were inadequately considered due to various adjustments made in studies and some potential confounders were not considered in the majority of studies, such as diseases other than cancer, inflammatory conditions, drugs, and hormonal factors. Additionally, it should be noted that remarkable heterogeneity existed in pooling SMD analysis, and may have reduced the reliability of the meta-analysis.In conclusion, this meta-analysis suggests circulating resistin levels may be higher in obesity-related cancer patients than in normal controls, and an independent biomarker of obesity-related cancer risk. But it may not be a predictor of obesity-related cancer risk. Given the limited number of studies included as well as the significant heterogeneity, more randomized and large-scale clinical trials, carefully controlled for potential confounding factors, are needed to confirm this association between resistin levels and obesity-related cancer risk in the future.A comprehensive literature screening was conducted for publications up to February 20th, 2016 from the following databases: (1) Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/); (2) Embase (https://www.embase.com/); (3) Cochrane (http://www.cochranelibrary.com/). Search terms: “resistin, RETN”, “cancer, tumor, neoplasm, carcinoma” and “serum, plasma, circulating, blood” were used in combination to retrieve the relevant literatures. Only papers written in English language were considered in this study. In addition, reference lists of articles were scrutinized to identify additional articles. This study was planned and conducted in accordance with standards of quality for reporting meta-analysis .Only studies meeting the following criteria were included: (1) the study must be an original epidemiological study; (2) the exposure of interest must be the serum or plasma resistin detected in blood samples; (3) the outcome of interest must be concerned with obesity-related cancers, including prostate, breast, colorectal, thyroid, renal, endometrial, pancreatic and esophageal cancers; (4) the study must report odds ratio (OR) or relative risk (RR), corresponding 95% confidence intervals (CI), mean and standard deviation (SD), or data to calculate these. Studies that did not refer to cancer, serum or plasma resistin, healthy controls, and that were conducted on animals, cells, or tissues were excluded. Two investigators (Wei Zheng and Wei-Jing Gong) reviewed all studies independently to identify and determine whether an individual study was eligible for inclusion in this meta-analysis. Any disagreement between the studies was resolved by consensus with a third reviewer (Zhao-Qian Liu).Data was extracted and assessed by two independent researchers (Li-Ming Tan and Wei-Jing Gong) using the Newcastle-Ottawa Scale (NOS). Disagreements were resolved by consensus. Data extracted from eligible studies included first author's last name, year of publication, country of origin, study design, BMI, age, cancer type, sample size, resistin detection assay, confounders adjusted in multivariate analysis, RR or OR with corresponding 95%CI for the risk of cancer incidence, mean and SD, or data to calculate them , 35.Q-statistic test and 2I test. If P < 0.05 and 2I> 50%, a random effect model was used, otherwise, a fixed effect model was used [P < 0.05.Heterogeneity of effect size among studies was assessed by the Cochrane's was used , 37. Senwas used , 39. Funwas used , 41. Sta


The clinical validity of circulating tumor cells (CTCs) is still controversial in patients with triple-negative breast cancer (TNBC).A comprehensive literature search was performed to identify relevant articles in the PubMed, Web of Science, MEDLINE, and Embase databases through September 2015. The outcomes of interest were disease progression and overall survival. The hazard ratio (HR) and 95% confidence interval (95% CI) were considered the effect indicators and were pooled in meta-analyses under a fixed- or random-effect model according to heterogeneity.heterogeneityP = 0.010, 2I = 52.2%) and reduced overall survival . Further subgroup analyses demonstrated that CTC-positive patients also had poor disease progression and overall survival in different subsets, including cancer stage.Ten of the eligible studies were included for a total of 642 enrolled TNBC patients. Overall analyses revealed that the presence of CTCs predicted aggressive disease progression (HR = 2.18, 95% CI = 1.59-2.99, Our meta-analysis provides strong evidence that detection of CTC in the peripheral blood is an independent prognosticator of poor survival outcomes for TNBC patients. Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in women worldwide . As a diCirculating tumor cells (CTCs) are cells released from the primary tumor into the peripheral blood and are considered to be a main cause of tumor metastasis . In receAlthough a previous pooled analysis explored the prognostic relevance of CTC status in metastatic breast cancer, including TNBC , the effFigure Early stage (M0) and metastatic stage M1) TNBC patients were enrolled in 3 , 16, 17  TNBC patheterogeneityP = 0.010, 2I = 52.2%)   were available in 8 studies , 14–18 aheterogeneityP = 0.010, 2I = 52.2%), so we carried out a univariate meta-regression analysis to explore the potential sources. Several covariates, including publication year, sample size, and cancer stage, were considered, and the results indicated that sample size was the main factor responsible for the heterogeneity  and OS . We then explored the effects of CTC status on outcomes for various sampling times. CTCs detected at baseline indicated an increased risk for both disease progression  and poor OS . However, CTCs detected at mid-therapy exhibited prognostic significance for disease progression  but not for OS . We also assessed the effects of CTC status on outcomes for various detection methods. CTCs detected by CellSearch assay or RT-PCR indicated a worse prognosis for both disease progression  and OS . However, we did not find any significant prognostic effect of CTCs detected using IE/FC . In addition, the effects of CTC status on outcomes were evaluated separately for different sample sizes, detection rates, and cut-off criteria. The stratified results showed that compared to CTC-negative patients, CTC-positive patients had a higher risk for both disease progression and OS in these subgroups , the trim-and-fill analysis revealed that after incorporating 5 additional studies, the funnel plot was symmetrical, and the adjusted pooled HR was still similar to that in the main meta-analysis , the adjusted pooled HR continued to show a significant association between CTC status and OS  and large sample groups (≥30). To explore the clinical utility of CTC status in TNBC, we also carried out subgroup analyses using different stratified factors. Although M0 and M1 patients had very different prognoses, the presence of CTCs indicated worse survival outcomes for TNBC. CTCs detected at baseline or mid-therapy indicated a poor disease progression outcome. However, CTCs detected at mid-therapy failed to significantly predict poor OS, which may have been due to the insufficient statistical power. RT-PCR and CellSearch assay are two widely used methods for CTC detection. Our meta-analysis showed that CTCs detected by these two methods had a significant prognostic effect. However, for IE/FC, a new method developed by Magbanua et al. [When pooling the disease progression data, we observed significant heterogeneity among studies. The meta-regression analysis identified sample size as the primary source of this heterogeneity. However, the heterogeneity decreased or even disappeared after dividing subjects into small . The search items included various combinations of “breast”, “cancer”, “neoplasm”, “carcinoma”, “malign*”, “triple negative” and “circulating”. The reference lists of the retrieved articles and reviews were also checked manually for potentially relevant studies. Only articles written in English published in peer-reviewed journals were included.via a flow chart as recommended by the PRISMA statement [Studies were considered eligible if they fulfilled all the following criteria: (1) retrospective or prospective cohort studies; (2) investigated the progression or survival of TNBC patients stratified by CTC status; (3) reported HRs and 95% CIs or provided sufficient information to extrapolate them. For studies with overlapping data, we only kept the study with the larger sample size. The process was performed independently by two authors, and any discrepancy was resolved by discussion or consultation with a third party if required. We documented the process tatement  , regardless of whether they were tested by multivariate analysis. For one study , the rep2I index, which is considered significant if P < 0.10 or 2I > 50 % by convention [The HR and 95% CI were directly recorded from each included study or extrapolated as suggested by methods of Parmar  and Tiernvention . We thennvention –40. To e


A large amount of researches have demonstrated that vitamin D receptor (VDR) gene polymorphisms are associated with diabetic nephropathy (DN) risk in diabetes mellitus (DM) patients. Nevertheless, the results are inconclusive and inconsistent.We screened PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Wanfang databases for those relevant studies updated in May 2016.P values > 0.05). In the stratified analysis, TT genotype was related to DN susceptibility in Asians . The sensitivity analysis showed that the results in overall populations, Caucasians and Asians were dependable.7 studies involving 2564 subjects were recruited. We evaluated the genotypic and allelic differences between DN patients and DM controls. Overall analysis showed that no significant association was found among the ApaI, BsmI, FokI,TaqI gene polymorphisms and DN susceptibility in diabetic patients (all No significant association was found among the ApaI, BsmI, FokI, TaqI polymorphisms and DN risk in overall populations, the TaqI variants might related to DN susceptibility in Asians. Further researches are required to testify our meta-analysis. The vascular complications of diabetes mellitus (DM) can lead to high disability rates and mortality rates. Poorly controlled blood glucose leads to the occurrence and development of complications in patients with DM . As one Previous studies showed that vitamin D endocrine system played an important role in the development of DM –11. HighTo provide an accurate estimation, we operated a systematic review to investigate the relation of DN and the four VDR gene polymorphisms.The related articles were searched from PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Wanfang databases. The The retrieval strategy were as follows: “VDR, vitamin D receptor, diabetic nephropathy (DN), ApaI, BsmI, FokI, TaqI, polymorphism, genotype”. In addition, we retrieved references of selected articles. Here are the inclusion criteria: 1) case-control study; 2)DN as ending; 3) carried out in human population; 4) Clearly define genetic variants of case and control can offer sufficient calculational data. Here are the exclusion criteria: (1) case reports or review articles; (2) articles that did not offer the detailed genotype information; (3) studies on the correlation between DN and other genes; (4) studies investigate the role of VDR genotype in other diseases. The largest or most recent study was selected when continuous or multiple publications that occur under the same search condition .For each study the following information was evaluated independently by two investigators according to the standard protocol:1) name of first author; (2) year of publication; (3) original country; (4) ethnicity of the subjects; (5) genotype distribution or allele frequencies; and (6) number of cases and controls , otherwise a fixed-effect model using the Mantel–Haenszel (M–H) method was carried out. The asymmetry funnel plots were used to estimate the publication bias. The exact test was carried out to assess whether the genotype distribution in control population were accord with Hardy-Weinberg equilibrium (HWE) expectations. A sensitivity analysis of the overall population was used by omitting one study in each turn. Cochrane Review Manager Version 5.1  was used to performed the statistical analyses. All the P values were double tailed test and the significance was set at P < 0.05.The odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association among the four VDR gene polymorphisms and DN risk. Statistical analysis were divided into Caucasian and Asian populations in subgroup analysis. The Chi-square based Q-statistic test was used to assess the heterogeneity between the studies. The search yielded 67 articles, 7 studies , 22–27 cP values >0.05) , however, p value equals to 0.04 seems not enough to support relationship between genetic variant and diabetic nephropathy. Besides, there was no significant correlation between other three polymorphisms and DN risk in Asians and Caucasians(Table It has been shown in Table 5) Figs. , 4 and 5ansTable . AltogetBegg’s funnel plots and Egger’s test were carried out to analyse the publication bias. Results showed that there was no evidence of publication bias in the 7 studies (data not shown). However, due to the small number of studies, publication bias cannot be ruled-out in this paper.DN is the most common microvascular complication in diabetes patients, and the most common reason of ESRD in the United States . 40% DM The vitamin D has important biological functions, such as modulating immunity system, influencing insulin secretion and improving insulin resistance , 33, whiThe VDR gene is located on chromosome 12 at q12-q14, it has14eons, 8 protein-coding exons and 6 untranslated region. ApaI and BsmI VDR gene variants locate in intron 8 and TaqI variants locate in exon 9. The FokI variants locate in the codon initiating translation, which has been reported to cause severe protein dificiency . A largeP values >0.05). Since genetic factors can affect the results of meta analysis, subgroup analysis were also preformed by race for the four polymorphisms. Our results indicate that there was a relationship between TT genotype and DN risk in Asians , however, p value equals to 0.04 seems not enough to support relationship between genetic variants and DN. Since only one published study in Asian populations was included in the BsmI and FokI groups, the stratified analysis for Asians might not be reliable in these two groups. Besides, there was no significant associations among the other three gene variants and DN in Caucasians and Asians as potential genetic markers for DN. Nevertheless, the results of our research showed that none of these polymorphisms was significantly associated with DN risk in diabetic patients in overall population results we reported have to be considered as exploratory. Martin et al.’s  is by faIn conclusion, our meta-analysis showed that no significant association was observed among the ApaI, BsmI, FokI and TaqI variants and DN susceptibility in overall populations, the TaqI variants may be associated with DN risk in Asian populations. Future larger scale epidemiological investigation of this topic should be conducted to confirm or refute our findings.


Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma.−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms.We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold , MSRA , LINC00208 and BLK , KHDRBS2 , TPPP and CEP72 , TMOD1 , SATB2 , and HTR3C and ABCC5 . The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA  after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation.Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies.Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council. Oesophageal adenocarcinoma is a fatal cancer that ranks eleventh in mortality among all malignant disorders.FOXF1, GDF7, and TBX5 associated with the development of Barrett's oesophagus,CRTC1, BARX1, FOXP1, and ALDH1A2 associated with development of both Barrett's oesophagus and oesophageal adenocarcinoma.Barrett's oesophagus and oesophageal adenocarcinoma have heritable components with substantial overlap in the set of genes contributing to risk of each condition.Therefore, our international consortium aimed to do a meta-analysis of all available datasets from genome-wide association studies for Barrett's oesophagus and oesophageal adenocarcinoma to identify additional genetic variants associated with risk for both disorders. Furthermore, we aimed to identify genetic variants that contribute specifically to risk for oesophageal adenocarcinoma and, thereby, might serve as markers for individualised surveillance and intervention strategies for Barrett's oesophagus. To our knowledge, our study is the first in which datasets from genome-wide association studies have been analysed using bioinformatics approaches to gain further information about the underlying genes and cellular pathways associated with Barrett's oesophagus and oesophageal adenocarcinoma.Evidence before this studyWe searched PubMed on Feb 29, 2016, to identify genetic risk markers for Barrett's oesophagus and oesophageal adenocarcinoma identified through genome-wide association studies. We did not apply any publication date restrictions. The search was restricted to papers published in the English language. Search terms were:  AND (“Barrett's” OR “adenocarcinoma”) AND (“genome wide association study” OR “GWAS”). Three genome-wide association studies have been published to date and have led to the identification of eight genetic risk loci contributing to both Barrett's oesophagus and oesophageal adenocarcinoma. These encouraging findings, however, account for only a part of the genetic risk for Barrett's oesophagus and oesophageal adenocarcinoma. In particular, no variants have been identified so far that contribute solely to development of oesophageal adenocarcinoma and, thereby, might serve as markers for more effective surveillance and intervention strategies for Barrett's oesophagus.Added value of this studyCFTR, mutations of which lead to cystic fibrosis. Patients with cystic fibrosis show highly increased incidence of gastro-oesophageal reflux, and this reflux represents the main risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. Therefore, our data suggest that cystic fibrosis, Barrett's oesophagus, and oesophageal adenocarcinoma might have a common pathophysiological feature of gastro-oesophageal reflux, with CFTR playing an important part in this process. We also identified a risk variant near HTR3C/ABCC5 that was associated solely with development of oesophageal adenocarcinoma. This variant might constitute a novel marker for the prediction of transition from Barrett's oesophagus to oesophageal adenocarcinoma.Within an international consortium, we did a meta-analysis of four datasets available to date from genome-wide association studies, totalling more than 27 000 individuals. We identified nine new risk loci for Barrett's oesophagus or oesophageal adenocarcinoma, or both, which represents a doubling of the number of known risk loci. The most strongly associated new risk variant is located within Implications of all the available evidenceIdentification of novel risk loci and cellular pathways provides further insights into the causes of Barrett's oesophagus and oesophageal adenocarcinoma and impetus for further functional studies. The marker specific to oesophageal adenocarcinoma should help to identify patients at higher risk for the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Together, this information should lead to better molecular treatments and individualised prevention and intervention strategies for clinical management of Barrett's oesophagus and oesophageal adenocarcinoma.We obtained genome-wide genotype data for patients with Barrett's oesophagus, individuals with oesophageal adenocarcinoma, and representative controls from four genome-wide association studies in Europe, North America, and Australia:Patients with Barrett's oesophagus were identified by histopathological diagnosis of intestinal metaplasia, and individuals with oesophageal adenocarcinoma had a histopathological diagnosis of adenocarcinoma. We excluded all other patients. Informed consent was obtained in the four studies from all participants and ethics approval was obtained from the ethics boards of every participating institution.−10 in patients for Hardy-Weinberg equilibrium; and SNPs with a significant (p<0·001) difference in missingness between cases and controls. Based on identity by descent calculated from autosomal markers, we removed one of each pair of individuals with high levels of relatedness (p-hat>0·2) and a higher proportion of missing genotypes. We also removed participants who lay beyond six SDs from the mean of the first two genotypic principal components of the 1000 Genomes European descent population.We did a quality control assessment of genotyped markers, genotyped individuals, and the imputation, using the same protocol at all participating sites. We used PLINK version 1.90For the imputation, we used SHAPEIT version 2.1214We did association testing for Barrett's oesophagus and oesophageal adenocarcinoma as separate disorders. We then repeated the analysis after combining the two groups of patients into a single group. We assessed associations in SNPTEST version 2.5.2,−8.We analysed SNPs that passed the post-imputation quality control assessment in every study  and were present in at least three studies of Barrett's oesophagus and two studies of oesophageal adenocarcinoma. An imputation quality score greater than 0·4 ensures that SNPs that were not well imputed were excluded, and a minor allele frequency greater than 0·001 ensures that SNPs that were not common in our study population were excluded from the analysis . We did I2 statistic, and we calculated p values for heterogeneity with Cochran's Q test, as implemented in METAL version 2011-03-25.We investigated the presence of genetic heterogeneity between studies with the We created Q-Q and Manhattan plots for the meta-analysis in R. We used LocusZoom version 1.1To investigate whether independent associations exist in regions of genome-wide significance, we did association analyses conditioned on the strongest associated SNP in every region (1 Mb either side of the top SNPs) with meta-analysis summary statistics and the approach implemented in GCTA version 1.25.2.−8) based on the analysisBecause some SNPs could be associated with Barrett's oesophagus and oesophageal adenocarcinoma but not meet the genome-wide significance threshold because of insufficient statistical power , we used a new approach−6 .We did gene-based association tests with the approach implemented in VEGAS version 2,−8, p<10−6, and p<10−4) for pathways analysis. We set the Bonferroni-corrected threshold for pathways analysis at a p value of less than 1·15 × 10−6  and a false discovery rate of less than 0·05. Similarly, we set the Bonferroni-corrected threshold for tissue-enrichment analysis to a p value of less than 8 × 10−6  and a false discovery rate less than 0·05.We analysed pathways and tissue enrichment with methods implemented in DEPICT version 1.1.We did bioinformatics analyses as described in the The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study, except personal identifying information, and had final responsibility for the decision to submit for publication.6167 people with Barrett's oesophagus, 4112 individuals with oesophageal adenocarcinoma, and 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia were included in the meta-analysis. In total, 11 942 825 SNPs for Barrett's oesophagus, 13 074 274 for oesophageal adenocarcinoma, and 11 951 684 for both Barrett's oesophagus and oesophageal adenocarcinoma were used for the meta-analysis of genome-wide association studies. Q-Q and Manhattan plots from the separate Barrett's oesophagus and oesophageal adenocarcinoma meta-analyses, and from the combined Barrett's oesophagus and oesophageal adenocarcinoma meta-analysis, are shown in the −8) were identified for Barrett's oesophagus alone, of which three were not previously reported (−8) for oesophageal adenocarcinoma alone were identified, of which four were previously unreported (−8), of which seven were previously unreported (HTR3C and ABCC5 (rs9823696) that was only recorded in the oesophageal adenocarcinoma meta-analysis and, therefore, was specific for this disorder . By contrast, all risk loci identified for Barrett's oesophagus were also associated with oesophageal adenocarcinoma , the posterior probability for the region containing LPA was 0·925 in the empirical Bayesian approach  in oesophageal adenocarcinoma and in Barrett's oesophagus. Although we did not identify any secondary peaks  at genome-wide significance in the conditional association analysis of the combined meta-analysis, two loci  showed some evidence of secondary peaks  heterogeneity for the magnitudes of association of SNPs between studies in the fixed-effects meta-analysis  than with the fixed effects meta-analysis (p=3·2 × 10−9). Consistent with p values for heterogeneity for the other risk loci . Apart from the risk loci identified in the single variant analysis, we did not identify other loci reaching gene-based genome-wide significance (p<2·8 × 10−6) after correction for genomic inflation in the gene-based association analysis , which is strongly associated with Barrett's oesophagus and oesophageal adenocarcinoma (p=1·2 × 10−8), showed some evidence of association with BMI in the GIANT studyNone of the published genome-wide significant risk loci for BMI and obesity were associated with Barrett's oesophagus and oesophageal adenocarcinoma in the combined meta-analysis at the genome-wide significance level (data not shown). However, rs2898290 (within r2>0·80)—represent expression quantitative trait loci that regulate the expression of genes within the regions. Moreover, several of the implicated risk variants change sequence motifs for protein binding sites and are located within DNAase hypersensitivity regions and within regions with enhancer or promoter motifs.The nine newly identified Barrett's oesophagus and oesophageal adenocarcinoma risk loci were characterised by analysis of multiple functional annotation databases . Many loOur meta-analysis identified 16 independent risk loci for development of Barrett's oesophagus, oesophageal adenocarcinoma, or both, at the level of genome-wide significance. Nine loci had not been identified before; all previously reported risk loci were associated with both Barrett's oesophagus and oesophageal adenocarcinoma in our meta-analysis. Thus, our study has more than doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma, which further exemplifies the scientific value of meta-analysis of genome-wide association studies through international collaborations. Moreover, we identified an oesophageal adenocarcinoma-specific risk locus that was independent of development of Barrett's oesophagus. The sample size of our meta-analysis was large enough to do a pathway analysis to investigate genetic pathways associated with development of Barrett's oesophagus and oesophageal adenocarcinoma. Our findings indicated that cellular pathways involved in muscle-cell differentiation and mesenchyme development and differentiation were implicated in causing Barrett's oesophagus and oesophageal adenocarcinoma.−10) was rs17451754 on chromosome 7q31. This SNP is located within intron 21 of the CFTR gene and affects a region marked by enhancer histone modifications in the gastrointestinal tract mucosa and by DNAse hypersensitivity.CFTR encodes an ATP-binding cassette membrane protein that functions as a chloride channel and is mutated in cystic fibrosis,CFTR lead to secretions that are abnormally viscous and altered in their chemical composition, leading to severe dysfunction of the respiratory system and gastrointestinal tract. Up to 81% of patients with cystic fibrosis have gastro-oesophageal reflux, a major risk factor for Barrett's oesophagus and oesophageal adenocarcinoma, and more than 50% of these individuals are treated with proton-pump inhibitors in high-income countries.CFTR risk variants in patients with Barrett's oesophagus and oesophageal adenocarcinoma, it seems plausible that a common pathophysiological mechanism for gastro-oesophageal reflux is triggered by CFTR. This idea underlines the importance of CFTR as a true disease gene within this region. Fine mapping of all genetic variation at this locus, and extensive functional studies, are needed to test this hypothesis because other pathomechanisms and risk genes cannot be excluded entirely. Moreover, detailed genotype–phenotype studies of Barrett's oesophagus and oesophageal adenocarcinoma, and of isolated patients with gastro-oesophageal reflux stratified for the CFTR risk variant, are needed that take the implicated mechanisms of gastro-oesophageal reflux in cystic fibrosis into account. This work might yield new insights in the area of Barrett's oesophagus and oesophageal adenocarcinoma research.Findings of the functional annotation database analysis of the newly identified Barrett's oesophagus and oesophageal adenocarcinoma risk loci exemplify how data from genome-wide association studies can uncover new causal and clinical aspects of Barrett's oesophagus and oesophageal adenocarcinoma . The newHTR3C gene. Highly correlated variants of this marker (r2>0·80) have been identified as regulatory active expression quantitative trait loci that affect expression of the ABCC5 gene at this locus.ABCC5 represents an interesting oesophageal adenocarcinoma candidate gene. The corresponding gene product belongs to the group of ATP-binding cassette membrane proteins that play a part in energy-dependent transport of various endogenous and exogenous substrates and has been implicated in cancer development and progression.FOXF1 and FOXP1),ABCC5 has a role during embryonal development of the intestine.HTR3C and ABCC5 alone accounts for only a fraction of the phenotypic variance; the OR is 1·17 between patients with oesophageal adenocarcinoma and controls, and 1·02 between individuals with Barrett's oesophagus and controls. However, identification of further oesophageal adenocarcinoma-specific markers with larger samples of patients with Barrett's oesophagus and oesophageal adenocarcinoma, together with incorporation of relevant environmental and clinical data , and application of modern polygenic score approaches will help to identify patients with Barrett's oesophagus at higher risk for oesophageal adenocarcinoma. Development of such risk-prediction methods would be an important advance in clinical management, because this information could be used for more effective and individualised surveillance and intervention strategies. Since genetic data can be used for risk prediction at very early stages , risk profiling approaches should also focus on markers that contribute solely to development of Barrett's oesophagus and are independent of the cause of gastro-oesophageal reflux.To our knowledge, the first risk locus to be identified that is specific to oesophageal adenocarcinoma is rs9823696 on chromosome 3q27. This SNP lies 4·9 kb downstream of the Pathways analyses showed that cellular processes related to muscle-cell differentiation and mesenchyme development and cell differentiation are associated with development of Barrett's oesophagus and oesophageal adenocarcinoma. Involvement of the muscle-cell differentiation pathway is especially interesting because this pathway might represent a link to cellular mechanisms in the development of hiatal hernias, which have been associated with gastro-oesophageal reflux and Barrett's oesophagus.TPPP and CEP72. Here, the magnitude of association was larger in the Bonn study than in the other studies included in our meta-analysis. This finding points to a so-called winner's curse effect  in the Bonn study rather than to systematic differences between studies, because heterogeneity was only noted at this locus.The only locus that showed significant heterogeneity between studies was related to SNPs within or near Our study has several limitations. Although we have provided bioinformatics evidence for the functional relevance of our findings, we do not provide in-vitro or in-vivo evidence for the biological function of these findings. Further studies are needed to investigate how the identified risk loci contribute to development of Barrett's oesophagus and oesophageal adenocarcinoma at the molecular and cellular level. Moreover, our study included control individuals who were not screened for the presence of Barrett's oesophagus. Although most controls were probably not affected by Barrett's oesophagus, inclusion of individuals screened for the absence of Barrett's oesophagus would have increased our power to detect further risk loci for Barrett's oesophagus and oesophageal adenocarcinoma. Furthermore, we did not include genome-wide data from a sufficiently high number of patients with isolated gastro-oesophageal reflux. Such data would have enabled us to identify risk variants that are predictive for the transition from gastro-oesophageal reflux to Barrett's oesophagus. Finally, the sample size of our study has only power for identification of risk loci with moderate effects. Although we have used the largest available sample of genome-wide association study data analysed so far from individuals with Barrett's oesophagus and oesophageal adenocarcinoma, further data from additional patients would have led to identification of more risk loci.HTR3C and ABCC5 genes that is not observed in Barrett's oesophagus. Although the strength of genome-wide association study meta-analyses is identification of disease loci, fine-mapping and functional studies of new risk loci are now needed to reveal the disease pathophysiology. This next step—together with identification of additional risk loci using larger sample sizes through international collaborative efforts—should lead to identification of key molecules that have an important role in development of Barrett's oesophagus and oesophageal adenocarcinoma, which should finally pave the way for new molecular targets for development of advanced prevention and intervention strategies.In conclusion, our meta-analysis identified nine new risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and highlighted genes and cellular pathways likely to be implicated in disease development. To our knowledge, we have identified for the first time an oesophageal adenocarcinoma association near the


Delay performance of adjuvant chemotherapy (AC) after surgery has been presented to affect survival of breast cancer patients adversely, but the risk factors for delay in initiation remain controversial. Therefore, we conducted this systematic review of the literature and meta-analysis aiming at identifying the risk factors for delay of adjuvant chemotherapy (DAC) in non-metastatic breast cancer patients.The search was performed on PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Database from inception up to July 2016. DAC was defined as receiving AC beyond 8-week after surgery. Data were combined and analyzed using random-effects model or fixed-effects model for risk factors considered by at least 3 studies. Heterogeneity was analyzed with meta-regression analysis of year of publication and sample size. Publication bias was studied with Egger’s test.A total of 12 observational studies including 186982 non-metastatic breast cancer patients were eligible and 12 risk factors were analyzed. Combined results demonstrated that black race , rural residents  and receiving mastectomy  were significantly associated with DAC, while married patients  was less likely to have a delay in initiation. No significant impact from year of publication or sample size on the heterogeneity across studies was found, and no potential publication bias existed among the included studies.Risk factors associated with DAC included black race, rural residents, receiving mastectomy and single status. Identifying of these risk factors could further help decisions making in clinical practice. Breast cancer is the most common type of malignant tumor and second leading cause of death in women worldwide. It is estimated that there will be 249,260 new cases and 40,890 deaths in United States in 2016 . AlthougWhile worse survival outcome from delay of adjuvant chemotherapy (DAC) has been well established, the risk factors for DAC remain unknown. Since the risk factors could not be evaluated by randomized controlled trails, evidence from numerous observational studies demonstrated that the risk factors associated with DAC included demographics, clinical characteristics, pathologic characteristics and surgical approaches–7, 10–18Due to a lack of understanding of the risk factors, we therefore conducted this systematic review and meta-analysis to identify the impact of risk factors on DAC.A systematic review was conducted to identify all studies concerning the risk factors for DAC in non-metastatic breast cancer patients by searching PubMed, Embase, Chinese National Knowledge, and Wanfang Database from inception up to July 2016. Two investigators (XFH and BCZ) independently carried out the search using the following keywords simultaneously: (1) breast cancer or breast carcinoma or breast neoplasm or breast tumor; (2) adjuvant treatment or adjuvant chemotherapy; (3) delay chemotherapy or delayed chemotherapy. The reference lists of the selected articles were also reviewed for additional relevant studies.The inclusion criteria were as follow: the time interval between surgery and administration of AC was defined; at least one risk factor concerning DAC was investigated; odds ratio (OR) or risk ratio (RR), and associated 95% confidence intervals (CI) were available or could be calculated from the original articles. Only full-report in English was included. For duplicated cases, the most comprehensive one was eligible for inclusion. Articles were excluded if they did not meet the above criteria, or the information provided was insufficient for the outcome data extraction or quality assessment.All the searched articles were independently reviewed by two investigators (XFH and BCZ). After reading the titles and abstracts, the full texts were retrieved for those potentially included articles to achieve further assessment for inclusion. Discordance in selection was solved through discussion. For the included studies, following data were extracted: author details, year of publication, data source if available, study location, sample size, age of participants, TNM stage, AC regimens if available, cut-off categorical value of time interval, any information about quality assessment under the guideline of the Newcastle-Ottawa Scale, any risk factor investigated, OR, RR and associated 95% CIs. The accuracy of extracted data was ultimately confirmed by a third investigator (FY).2 statistic. Substantial heterogeneity was defined if an I2 value exceeded 50%. Forest plots were carried out to estimate the pooled ORs using the random-effects model when I2 value exceeded 50%, or the fixed-effects model when I2 value not exceeding 50%. Meta-regression analysis was performed to assess the impact of year of publication and sample size on the effect on the inter-study heterogeneity. The publication bias was assessed by Egger’s test. A two-tailed p-value < 0.05 was considered statistically significant. All the statistical analyses were conducted by Stata software (Stata SE 12.0). This systematic review and meta-analysis was performed under the guidelines of MOOSE  and progesterone receptor [PR] negative vs ER and/or PR positive), histological grade (well and/or moderately differentiated vs poorly differentiated), surgical approach (breast conserving surgery [BCS]vs mastectomy), number of involved nodes (0–9 vs ≥ 10), tumor size (0-5cm vs > 5cm), and lymphatic vascular invasion status (absent vs present).2 = 66.7%), a 60% higher risk for rural residents than urban residents , and a 35% higher risk for patients receiving mastectomy than patients receiving BCS . While married patients were less likely to have a delay in initiation compared with single patients , worse comorbidity status , poorer histological differentiation , presence of lymphatic vascular invasion , higher TNM stage , involved nodes ≥10 , tumor size > 5cm  and ER / PR positive status Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.


Obstructive sleep apnea (OSA) is a sleep disorder characterized as complete or partial upper airflow cessation during sleep. Although it has been widely accepted that OSA is a risk factor for the development of hypertension, the studies focusing on this topic revealed inconsistent results. We aimed to clarify the association between OSA and hypertension, including essential and medication-resistant hypertension.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. PubMed and Embase databases were used for searching the relevant studies published up to December 31, 2016. A quantitative approach of meta-analysis was performed to estimate the pooled odds ratio (OR) and 95% confidence interval (CI).P < 0.05). Meanwhile, the combination of 20 original studies on the association of OSA with essential hypertension also presented significant results with the pooled ORs of 1.184  for mild OSA, 1.316  for moderate OSA and 1.561  for severe OSA.Twenty-six studies with 51 623 participants  met inclusion criteria and were included in this study. Among them, six studies showed a significant association between OSA and resistant hypertension (pooled OR = 2.842, 95% CI = 1.703-3.980, Our findings indicated that OSA is related to an increased risk of resistant hypertension. Mild, moderate and severe OSA are associated essential hypertension, as well a dose-response manner relationship is manifested. The associations are relatively stronger among Caucasians and male OSA patients. Obstructive sleep apnea (OSA) is a sleep disorder characterized as complete or partial upper airflow cessation during sleep, which mainly results from narrowed oropharyngeal or velopharyngeal anatomy ,2. OSA i Online Supplementary Document(Online Supplementary Document). The protocol of this study has been registered in PROSPERO (No. CRD42017064336), available at https://www.crd.york.ac.uk/PROSPERO/.We followed the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The reported PRISMA Checklist is provided in Table S1 inThe databases of PubMed and Embase were searched for literature published up to December 31, 2016. The search strategy was designed as a combination of the following key words: “obstructive sleep apnea” or “obstructive sleep apnea syndrome” or “sleep apnea” or “sleep disordered breathing” or “OSA” or “OSAS” or “SDB” and “hypertension” or “HTN”. In addition, studies cited in the references at the retrieved articles were further screened.Online Supplementary Document(Online Supplementary Document)).Two authors independently reviewed the title, abstract and full text of the publications to determine the suitability for inclusion. Eligible studies were included based on the following criteria: 1) studies conducted on human populations; 2) studies conducted to investigate the relationships between OSA and essential and/or resistant hypertension; 3) case-control studies, case-control comparison of baseline data in cohort populations or clinical populations, and cohort studies; 4) odds ratios (OR) and 95% confidence interval (CI) available or can be calculated; 5) OSA patients diagnosed with polysomnography, and classified with apnea-hypopnea index (AHI); 6) studies published in English. We evaluated the methodological quality of each study according to the quality assessment scale by reference to PRISMA statement and MOOSE guideline . To assess the robustness of the combined results and evaluate the effect of individual studies on this meta-analysis, we carried out sensitivity analysis by removing each study one at a time. Subsequently, the publication bias was assessed by the Funnel Plots analysis, and Egger’s regression asymmetry test was further complemented. The Trim and Fill method was used to adjust the significant publication bias.All statistical analyses were performed with the Stata14.0 software . The pooled ORs and 95% CIs were calculated to assess the strength of the association between OSA and hypertension. Q test and IOnline Supplementary Document(Online Supplementary Document).Our initial screen returned 15 031 publications in English, of which 4314 were from Pubmed and 10 717 were from Embase. YZ and WY independently excluded 13 846 ineligible articles through reviewing the titles, leaving 1185 articles for further abstract review. Among them, 26 publications with 51 623 participants  met all the inclusion criteria and were enrolled in meta-analysis -34. AmonP < 0.05) .The heterogeneity test showed no significant heterogeneity generated across all primary studies (IP < 0.05), moderate OSA , and severe OSA . These results showed the trend of that the more serious OSA is, the higher hypertension risk occurs. Subgroup analyses were conducted based on study design (prospective/non-prospective) and ethnicity. As shown in 2 values were 10.1% (P = 0.348) in mild OSA, 3.2% (P = 0.416) in moderate OSA, and 0% (P = 0.546) in severe OSA meta-analyses, indicating no significant heterogeneity in each group.Twenty studies investigated the relationship between OSA and essential hypertension ,8,17-34.P < 0.05), demonstrating that OSA was associated with essential hypertension ). The subgroup analysis based on ethnicity showed significant results among Asians  and Caucasians . Additionally, no significant heterogeneity was found . Four studies in the three articles reported the relationship between OSA and essential hypertension among male participants [For the seven studies dividing participants only into OSA and non-OSA groups ,29,31,34icipants . The comOnline Supplementary Document(Online Supplementary Document)). The Trim and Fill analysis was performed to eliminate the effect of publication bias on meta-analysis. As shown in Online Supplementary Document(Online Supplementary Document), the pooled ORs (95% CIs) were 1.327 (1.222-1.441) for moderate OSA and 1.593 (1.369-1.853) for severe OSA meta-analyses, and 1.575 (1.117-2.221) for resistant hypertension.The funnel plot analysis, followed by Egger’s test, was applied to detect the potential publication bias. Significant publication bias existed in the meta-analyses of moderate OSA and severe OSA participants, and the meta-analysis of resistant hypertension (Online Supplementary Document(Online Supplementary Document)), confirming that the results of our meta-analyses were stable. This coincided with the results of heterogeneity tests.To evaluate the robustness of the results, sensitivity analyses were undertaken by sequentially removing each study. Consequently, no obvious change was generated on omission of any individual study  on OSA is quite modest and adjustment for BMI might be an over-adjustment ,32, we hPublication bias, a critical issue in systematic review, mainly results from the tendency that studies with positive results are more likely to be published than those with negative findings. Significant publication bias exists in our meta-analyses of moderate OSA, severe OSA and essential hypertension. To reduce potential confounding of publication bias, we carried out the Trim and Fill analysis. According to the results of Trim and Fill analysis, the pooled ORs remained statistically significant for the association between moderate OSA and essential hypertension, the association between severe OSA and essential hypertension, as well as the association between OSA and resistant hypertension.Comparing to low specificity of sleep questionnaires, AHI is an accurate parameter for determining OSA , which iThis study has certain limitations that are common in systematic reviews meta-analyses of descriptive studies: First, most of the original studies were based on cross-sectional designed investigation, which may limit the argumentation intensity of our conclusion. Second, the subgroup analyses based on age were not performed because of no primary data available from the included studies. Only 5 prospective studies ,21,33,34The present study demonstrates that OSA is related to an increased risk of resistant hypertension, with a stronger association among Caucasian populations and male OSA patients. Mild, moderate and severe OSA are associated essential hypertension, as well a dose-response manner is manifested.Our interpretation of synthesized epidemiological evidence strengthens the acceptance of OSA as a risk factor of hypertension, in term of essential hypertension and resistant hypertension. Given the underlying mechanisms have been explained, the key remaining questions are how does OSA mediate hypertension and how can we implement specific interventions to reduce hypertension induced by OSA. More studies should be conducted to examine the mechanisms of hypertension regulation by OSA, especially among medication-resistant hypertension patients.


Conflicting results identifying the relationship between nonsteroidal anti-inflammatory drugs using and head and neck cancer risk. Therefore, we performed this meta-analysis to clarify and quantitative assessed the relationship between nonsteroidal anti-inflammatory drugs using and head and neck cancer risk. Up to March 2017, 11 original publications were included in this meta-analysis. Our results showed statistically significant association between nonsteroidal anti-inflammatory drugs using and head and neck cancer risk reduction. Subgroups analysis indicated that Aspirin, COX 2 inhibitors, Ibuprofen and Other NSAIDs were associated with a significantly risk reduction of head and neck cancer. Furthermore, nonsteroidal anti-inflammatory drugs using was associated with a significantly lower risk of oral and oropharynx cancer, larynx cancer and hypopharynx cancer. In addition, increasing nonsteroidal anti-inflammatory drugs using (per 2 prescriptions/week increment) was associated with a 4% reduction in head and neck cancer risk, 5% reduction of aspirin using and 6% reduction of other nonsteroidal anti-inflammatory drugs using. Considering these promising results, increasing nonsteroidal anti-inflammatory drugs using might provide health benefits. More studies and large sample size are warranted to validate this association. Head and neck cancer (HNC) include tumors derived from any tissue or organ from the eyes, brain, ears, thyroid and esophageal head and neck, and over 90% of HNC are squamous cell carcinoma. The incidence of global head and neck squamous cell carcinoma (SCCHN) has increased significantly over the last 10 years, especially in women. There are about 645,000 new cases of HNC occurring each year. In 2002, the new cases of HNC was about 100800 cases in Europe, and cause more than 40,000 deaths [Non-steroidal antiinflammatory drugs NSAIDs (NSAIDs) have been widely used in clinical. Since the 1980s, NSAIDs have received widespread attention as anti-tumor properties. Such drugs include aspirin, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib and celecoxib. With anti-inflammatory, anti-rheumatic, pain, fever and anticoagulation and other effects, widely used in clinical osteoarthritis, rheumatoid arthritis, a variety of fever and various pain symptoms .Previous studies have examined the relationship between NSAIDs use and risk of colon cancer, stomach cancer, prostate cancer and breast cancer, have found that NSAIDs use is significantly reduce cancer risk –11. HoweOur meta-analysis was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist .We included eligible studies investigating the relationship of NSAIDs using and HNC risk in general adult populations. To develop a flexible, non-linear, r meta-regression model, we required that an eligible study should have categorized NSAIDs duration into 3 or more levels. If multiple publications were available for a study, we included the longest follow-up study.Eligible studies were systematically searched of PubMed and Embase update to March 2017 for case control or cohort studies examining the relationship between NSAIDs using and HNC risk, with keywords including “head and neck cancer” OR”HNC”OR “Oral” OR “Oropharynx” OR “hypopharynx” OR “larynx” AND “aspirin” OR “NSAIDs” OR “ibuprofen” OR “naproxen” OR “indomethacin” OR “meloxicam” OR “valdecoxib” OR “celecoxib” OR “rofecoxib”. We refer to the relevant original essays and commentary articles to determine further relevant research. Eligible study was included through the reference lists of relevant review articles.Two independent researchers investigate information the relationship between NSAIDs use and HNC risk: study design in case-control or cohort study; outcome was head and neck cancer; the relative risks at least three quantitative categories of NSAIDs use and head and neck cancer risk with 95% confidence intervals. Moreover, we precluded non-human studies, reviews, editorials and published letters. The disagreements were resolved through consensus by all of the authors.Use standardized data collection tables to extract data. The two researchers extracted detailed information from each included article. We extracted the following information: first author; publication year; age; country; sex; cases and participants; the categories of NSAIDs use; relative risk or odds ratio (OR) with 95% confidence intervals. We collect the risk estimates with multivariable-adjusted . QualityWe pooled relative risk estimates as the common measure of association NSAIDs use and head and neck cancer risk; the hazard ratio were considered equivalent to the relative risk . ResultsP value is calculated for linear or non-linear by testing the null hypothesis that the coefficient of the second spline is equal to zero [Due to different cut-off points in the included studies for categories, we performed a relative risk with 95% confidence interval by increase per 2 prescriptions/week using the method recommended by Greenland, Longnecker and Orsini and their colleagues. Dose of NSAIDs using used the median NSAIDs using. If the median NSAIDs using category was not available, the midpoint of the upper and lower boundaries was considered the dose of each category. The midpoint of the category was set at 1.5 times the lower boundary if the highest category was open ended. We use the midpoint of the category if the highest and lowest values are not reported. The midpoint of the category is estimated by assuming that the width of the category is the same as the next adjacent category if the highest or lowest category is open. In addition, we evaluated the non-linear association between NSAIDs using and head and neck cancer risk using restricted cubic splines, with three knots at the 10th, 50th, and 90th percentiles of the distribution. A flexible meta-regression based on restricted cubic spline (RCS) function was used to fit the potential non-linear trend, and generalized least-square method was used to estimate the parameters. This procedure treats nonsteroidal anti-inflammatory drugs using (continuous data) as an independent variable and logRR of diseases as a dependent variable, with both tails of the curve restricted to nonlinear. A  to zero .2-statistic. All analyses were conducted using STATA software 12.0 . P < 0.05 was considered significant for all tests.The between-study heterogeneity was assessed by Q-statistic and the IWe identifed 3088 relevant citations after exclusion of duplicates. After exclusion studies that did not fulfill the inclusion criteria, eleven studies were chosen, and the data were extracted. Results in different subgroups of NSAIDs using and head and neck cancer risk were treated as two separate reports, a total of 33 reports data were included in this meta-analysis. These studies were published update to March 2017. Figure The characteristics of the included studies of nonsteroidal anti-inflammatory drugs using and risk of head and neck cancer are shown in the Tables P < 0.001)  but we observed no evidence of publication bias  (The results of NSAIDs using and HNC risk are shown in Table 1) Table . We foun= 0.245) .P = 0.000), suggesting curvature in the relationship, increase per 2 prescriptions/week of NSAIDs using was associated with a 4% decremental in head and neck cancer risk, the summary relative risk of head and neck cancer risk for an increase per 2 prescriptions/week of NSAIDs using was 0.96   Figure . IncreasP < .001) (Table P < .001) (Table P < .001) (Table P < .001) (Table P < .001) (Table P < .001) (Table P < .001)  Table , COX 2 i1) Table , Ibuprof1) Table  and Othe1) Table  were ass1) Table , Larynx 1) Table  and Hypo1) Table .2 = 0.0%), and the OR for the highest vs lowest category of NSAIDs using was 0.83    and Macf75–0.96) .The results show no obvious evidence of publication bias was found in the associations between NSAIDs using and head and neck cancer risk .NSAIDs as antipyretic analgesic anti-inflammatory drugs have been widely used in clinical, especially in the prevention and treatment of cardiovascular disease. Since the 80s of last century, NSAIDs anti-tumor properties have been widespread concern. Vinogradova found that long-term using of NSAIDs and cyclooxygenase-2 (COX-2) inhibitors can reduce the risk of developing colorectal cancer through a large sample of clinical case-control analysis . AnotherAmong the eleven included studies, eight showed a signifcantly positive association between NSAIDs using and head and neck cancer risk, and have found that NSAIDs use is significantly reduce head and neck cancer risk, while the other were negative. Studies on different NSAIDs using and head and neck cancer risk also remain inconclusive in light of newer evidence.To our knowledge, this is the first study to identify and quantify the potential dose-response association between NSAIDs using and head and neck cancer in a large cohort of both men and women. The primary finding in our meta-analysis is that statistically significant association between nonsteroidal anti-inflammatory drugs using and head and neck cancer. Subgroups analysis indicated that Aspirin, COX 2 inhibitors, Ibuprofen and Other NSAIDs using were associated with a significantly risk of head and neck cancer. Furthermore, nonsteroidal anti-inflammatory drugs using was associated with a significantly lower risk in oral and oropharynx cancer, larynx cancer and hypopharynx cancer. In addition, increasing nonsteroidal anti-inflammatory drugs using (per 2 prescriptions/week increment) was associated with a 4% reduction in head and neck cancer risk, 5% reduction of aspirin using and 6% reduction of other nonsteroidal anti-inflammatory drugs using.Although, we performed this meta-analysis very carefully, some limitations must be considered in the current meta-analysis. Firstly, different sex of population should be included in this meta-analysis to explore the impact of different sex of population on nonsteroidal anti-inflammatory drugs using and head and neck cancer. Secondly, despite we searched all studies describing the association between NSAIDs using and HNC risk, there are only 11 studies about NSAIDs using and HNC risk, the number of eligible studies was still limited.In conclusion, our meta-analysis suggests NSAIDs using was independently associated with deleterious head and neck cancer risk reduction. However, more studies and large sample size are warranted to validate this association.


Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as the potential chemopreventive agents for a number of cancer types, however, previous studies of head and neck cancers (HNC) have yielded inconclusive results. We performed a meta-analysis of observational studies to quantitatively assess the association between NSAIDs use and the risk for HNC.We searched Pubmed, Embase, Google scholar, and Cochrane library for relevant studies that were published in any language, from January 1980 to April 2016. We pooled the odds ratio (OR) from individual studies and performed subgroup, heterogeneity, and publication bias analyses.A total of eleven studies (eight case-control studies and three cohort studies), involving 370,000 participants and 10,673 HNC cases contributed to this meta-analysis. The results of these studies suggested that neither use of overall NSAIDs , aspirin , nor nonsteroidal NSAIDs  were associated with HNC risk. Similar nonsteroidal results were observed when stratified by HNC sites, study design, sample size, and varied adjustment factors. However, we found significant protective effect of ibuprofen  and long-term aspirin use (≧5years)  on HNC risk, with low heterogeneity and publication bias.Our meta-analysis results do not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use. Head and neck cancers (HNC) continues to be an important public health problem, with an estimated 700,000 new cases around the world in 2012 . Other pConvincing laboratory evidence has emerged to demonstrate an association between chronic inflammation and cancer, which makes the anti-inflammatory drugs have emerged as the most potential chemopreventive agents –15. NonsSeveral epidemiologic studies have observed use of aspirin and other NSAIDs have an association with reduced risk for cancers of the colon, stomach, prostate and breast , 20–22. The overview of our search process was illustrated in Figure Table P=0.001; 2I=67.4%). The tests for funnel plot asymmetry by Begg's test and Egger's test identified no publication bias .Figure Table There are six studies provided results on the effect of NSAIDs for specific HNC sites. However, NSAIDs use was not associated with a reduced risk for cancer of oral and oropharynx , 28–30  pooled from eight case-control studies , 30–33 aThe impact of sample size on risk estimates was assessed. The summary ORs were 0.99 (95%CI: 0.85 − 1.15) in eight studies , 28–32 wRecorded prescription database, self-administered questionnaires and standardized interviews were used to obtain information on NSAIDs exposure. The summary ORs were 0.82 (95%CI: 0.73 − 0.92) pooled from six questionnaire-based studies , 31, 33 In subgroup analyses by varied adjustment factors including age, gender, smoking, alcohol drink and body mass index (BMI), the association between NSAIDs use and the risk of HNC were non-significant in all strata Table .The findings from this meta-analysis of eleven observational studies, including 370,000 participants and 10,673 HNC cases, did not indicate overall NSAIDs use was significantly associated with a decreased risk for HNC.When stratified by type of drugs, there was no association between use of aspirin or NA-NSAIDs and the risk of HNC. However, we observed a significant risk reduction of 15% in HNC risk for users of ibuprofen alone . It was suggested that different types of NSAIDs might have different effects due to biological mechanisms , 35. AndIt is widely accepted that any potential protective effects of NSAIDs use against cancers are likely to involve a considerable duration . PreviouA significant preventive effect of NSAIDs use on HNC risk was observed in questionnaire-based studies but not in prescription-based studies. Studies that use prescription databases have their own shortcomings. Generally, no data were available regarding the use of over-the-counter medications including aspirin and NSAIDs, which will have underestimated exposure to these drugs. However, results from questionnaire-based studies should be interpreted cautiously for recall bias or selection bias. If the relatively healthy aspirin users were more likely to participate in the study than non-users, and an overestimate inverse association could be observed.The previous systematic review including 2 cohort studies , 29 and There were some potential limitations that have to be considered when interpreting these results. First, this meta-analysis is based on observational studies, which are more susceptible to recall and selection biases, and could result in an underestimation or an overestimation of the true effect. However, It may be unfeasible to evaluate the long-term protective effects of NSAID from randomized clinical trials due to the large sample size required; Second, we did not take into account possible interactions with other drugs due to absence of data. Use of NSAIDs are often associated with other drugs use, which could have concealed a possible association with NSAIDs . Third, In conclusion, our meta-analysis does not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use. Further large-scale robust studies are required, in particular, those evaluating the duration of aspirin use that may be take a protective effect.This meta-analysis was conducted according to the meta-analysis of Observational Studies in Epidemiology (MOOSE) Guidelines . We systStudies that met the following criteria were eligible for inclusion: (1) use a case–control or cohort study design; (2) evaluate the association between NSAIDs use and the risk of HNC; (3) provided the odds ratio (OR) or relative risk (RR) with corresponding confidence interval (CI) or sufficient data to calculate them. When the same author reported results obtained from the same population in more than one publication, only the most recent report, or the most complete one, was included in the analysis. Data from review articles, case reports, abstracts, and letters were not included.Two investigators (Lanhua Tang and Huabin Hu) extracted the following information from each eligible studies independently: the last name of the first author, year of publication, study design, country where the study was performed, enrollment periods, HNC sites, sample size (numbers of case patients and control subjects), types of NSAIDs use, the source of NSAIDs exposure information, the source of HNC diagnosis, the ORs or RRs with corresponding 95%CI and adjustment for covariates. Differences in data extraction were resolved by consensus, referring back to the original article.The methodological quality of the included studies was assessed using the 9-star Newcastle–Ottawa scale for quality of nonrandomized studies in meta-analyses . The NewP <0.10 level of significance [I2 that describes the percentage variation across studies that is attributed to heterogeneity [P <0.10 was considered to represent statistically significant publication bias.Odds ratio (OR) was used as a measure of the association between use of NSAIDs and risk of HNC. Because the absolute risk of HNC is low, the OR in case–control studies was considered reasonable approximations of the corresponding rate ratios in cohort studies . The hetificance . We alsoogeneity , 50. Wheogeneity . Otherwiogeneity . Publicaogeneity , and theogeneity . P <0.10When study reported results separately for aspirin and non-aspirin NSAIDs (NA-NSAIDs), to avoid double counting of the cases, we included only the results for aspirin in the overall summary estimate. Use of NSAIDs has the definition as follows:“overall use” was all the reported intake levels of NSAIDs use,“long-term use” was defined the duration of NSAIDs use or the time between last and first prescription more than 5 years. We only calculated the results for combined sites of HNC in the overall estimate, if studies had results for specific site and combined sites of HNC.Analysis was performed using the STATA version 11.0 .