Tumor necrosis factor-alpha (TNF-α) is involved in cancer pathogenesis, and TNF-α-308G>A, a single-nucleotide polymorphism, is associated with cancer prognosis; however, different studies have reported inconsistent results. This meta-analysis aimed to determine the correlation between TNF-α-308G>A polymorphism and the survival of cancer patients.PubMed, Web of Science, Embase, Wanfang database, VIP database, and China National Knowledge Infrastructure database were used to obtain articles on association between TNF-α-308G>A polymorphism and cancer survival, published until April 2018. A meta-analysis was carried out using Stata 12.0 software to determine the pooled hazard ratio (HR) and 95% confidence intervals (95% CI). Furthermore, publication bias was assessed, and sensitivity analysis was performed to validate the analysis.P < .001, I2 = 78.1%), GA/GG , and AA/AG+GG  were not associated with the OS of cancer patients. However, interestingly, the HR was greater for patients with the AA genotype than for those with the GG genotype, suggesting an association between TNF-α-308G>A polymorphism and OS among cancer patients .In total, 13 retrospective cohort studies including 2559 cancer patients were reviewed to estimate the association between TNF-α-308G>A polymorphism and overall survival (OS) of cancer patients. The pooled results suggested that within TNF-α-308G>A polymorphism, genotypes GA+AA/GG (HR = 1.39, 95% CI: 0.90–2.14, TNF-α-308G>A polymorphism affects the OS of cancer patients and is a potential therapeutic target for cancer. Gene polymorphisms in regulatory regions can affect protein expression. A G-to-A substitution in the promoter region (−308) of the TNF-α gene (TNF-α-308G>A) upregulates TNF-α expression and is reportedly associated with many diseases including cancer.This study is the first, to our knowledge, comprehensive meta-analysis of available studies for global analysis of an association between TNF-α-308 polymorphism and overall survival of cancer patients.22.1We reviewed the literature from PubMed, Web of Science, Embase, Wanfang database, VIP database, and China National Knowledge Infrastructure database, using the search terms “TNF-α,” “−308,” “cancer,” and “survival” to obtain articles published until April 2018, on genotypes of TNF-α-308 polymorphism (rs1800629) in cancer. After excluding duplicate publications and a careful review of the literature, we finally included 13 retrospective cohort studies for our meta-analysis. All analyses in the current study were based on published studies, so no ethical approval and patient consent were required. Data extraction and literature searches were accomplished and double-checked by 2 individuals.2.2The inclusion criteria for articles were as follows: the use of histological analysis to diagnose and confirm the cancer; evaluation of the correlation between TNF-α-308 polymorphism and overall survival of cancer patients, with an available hazard ratio (HR) and the corresponding 95% confidence interval (95% CI); articles written in English or Chinese; genotyping analysis performed for DNA; studies including exclusively adult subjects without immune diseases. Among studies with overlapping patients, the larger or more comprehensive study would be selected.2.3Initially, we first screened the title and abstract, and then reviewed the full text carefully. Related data were extracted from each eligible study by 2 investigators (FY and XS), independently, including the first author, year of publication, study location, ethnicity of the study populations, number of genotypes, cancer type, genotyping method, HR, and the corresponding 95% CI for overall survival.2.4–13 Overall survival curves in the included articles were imported into Engauge Digitizer version 4.1 (https://sourceforge.net/projects/digitizer/); thereafter, HRs and the corresponding 95% CIs were calculated as reported previously. An I2 value less than 25% and P > .05 indicated no significant heterogeneity among the articles. Publication bias was analyzed using Begg and Egger tests for all genetic models.,16 All statistical tests were performed using Stata version 12.0 .We extracted the HRs and the corresponding 95% CIs for overall survival (OS) either directly from the primary reports or calculated them from the OS curves, using a previously reported method.33.1,17,18 2 were on esophageal squamous cell carcinoma,,20 and the remaining reviews were on pancreatic cancer, bladder cancer, gastro-oesophageal cancer, non-Hodgkin lymphoma, head and neck squamous cell carcinoma, nonsmall cell lung cancer, diffuse B-cell lymphomas, and gastric cancer.,21–27Upon reviewing the literature and excluding duplicate publications, we obtained 13 full-text reviews on the basis of our strict screening criteria    . For the AA/AG+GG genotype, sensitivity analysis revealed that the pooled HR and its 95% CI estimated using the random effects model were significantly different from those estimated using a fixed effects model . Except for genotypes GA+AA/GG and AA/AG+GG, sensitivity analysis for the other 2 genotypes revealed a slight but not significant difference between the random and the fixed effects models, thereby highlighting the reliability of our meta-analysis.The associations between TNF-α-308G>A polymorphism and OS of cancer patients in each eligible study are presented in Table el) Fig. . For GA+3.3Sensitivity analysis performed using fixed and random effects models exhibited a slight but not significant difference between genotypes GA/GG and AA/GG; however, sensitivity analysis including fixed and random effects model analyses of genotypes GA+AA/GG and AA/AG+GG exhibited marked differences between these genotypes, thereby highlighting the reliability of our meta-analysis for the former 2 genotypes. We also evaluated the publication bias of included studies for each model, using Begg and Egger tests. No evidence of obvious asymmetry was obtained in overall analysis of publication bias for TNF-α-308G>A polymorphism in each genetic model.4 Dysregulation of TNF-α production is reportedly implicated in various human diseases including Alzheimer disease, major depression, psoriasis, inflammatory bowel disease, and cancer.,29 Increasing evidence indicates that genetic polymorphisms in the promoter region of TNF-α influences its translation and corresponding malignancies. The TNF-α-308G>A polymorphic site is one of the most well-defined polymorphisms, wherein GG is the wild genotype and the A allele is associated with TNF-α up regulation and poor clinical outcomes among cancer patients.,18,31,32 However, certain studies have also reported the absence of an association between TNF-α-308G>A polymorphism genotypes and breast cancer,,34 although several other studies have suggested an association between TNF-α-308G>A polymorphism and breast cancer risk.,36TNF-α was initially considered to be produced primarily by macrophages and other cells including lymphoid cells, mast cells, endothelial cells, cardiac myocytes and adipose tissue, fibroblasts, and neurons.,18,20,27 (Figs. The present meta-analysis involved the extraction of data strictly based on the defined criteria and grouped the related studies into 4 subgroups in accordance with the reported genotypes: GA+AA/GG, GA/GG, AA/GG, and AA/AG+GG. Overall, our results suggest that only the AA/GG genotype essentially predicted cancer patient survival; patients harboring the AA genotype at TNF-α-308 had a shorter lifespan compared to those harboring the GG genotype, with no obvious heterogeneity (Fig. ,38Despite this study being the first comprehensive meta-analysis on the association between TNF-α-308G>A polymorphism and cancer prognosis, this meta-analysis has some limitations. First, the number of eligible articles and patients was relatively small; hence, the 4 different genotype models should be estimated separately. Moreover, cancer prognosis is very complicated and is associated with numerous factors. For example, some studies have estimated the effects of certain treatments on the therapeutic outcomes of cancer patients, while others have not. Studies not highlighting these effects are indistinguishable; hence, we analyzed them collectively. Moreover, TNF-α-308G>A polymorphism is the only single-nucleotide polymorphism we estimated in the current study; however, others including −238G>A and −857C>T were not included.In conclusion, our study suggests the prediction role of TNF-α-308G>A polymorphism in cancer patient survival. However, owing to limitations in the sample size, future studies are required to assess the association between genotypes including TNF-α-308G>A polymorphism and clinical cancer prognosis.Conceptualization: Fengshuang Yi, Xiuzhi Wu.Data curation: Fengshuang Yi, Xinyu Shi, Xuebin Pei, Xiuzhi Wu.Formal analysis: Fengshuang Yi, Xinyu Shi, Xuebin Pei.Funding acquisition: Fengshuang Yi.Investigation: Fengshuang Yi.Methodology: Fengshuang Yi, Xinyu Shi, Xuebin Pei.Project administration: Fengshuang Yi, Xuebin Pei, Xiuzhi Wu.Resources: Fengshuang Yi, Xuebin Pei, Xiuzhi Wu.Software: Fengshuang Yi, Xinyu Shi.Supervision: Fengshuang Yi.Validation: Fengshuang Yi, Xinyu Shi, Xuebin Pei, Xiuzhi Wu.Visualization: Fengshuang Yi, Xiuzhi Wu.Writing – original draft: Fengshuang Yi, Xinyu Shi, Xuebin Pei, Xiuzhi Wu.Writing – review & editing: Fengshuang Yi, Xiuzhi Wu.


As an important component of miRNA processing genes, RAN gene encodes the ras-related nuclear protein, which is a unique member of the Ras superfamily of GTPases. The mutations in RAN gene are very likely to play a critical role in pathology-related changes to miRNA transport and expression and thus participate in tumor genesis and development. Currently, accumulating studies have explored the association between RAN SNPs and cancer risk. However, the results are conflicting. In the present study, we performed a systematic review for the association of RAN SNPs with overall cancer risk. Meanwhile, a meta-analysis was conducted based on available data, aiming at clarifying the association between RAN SNPs and cancer susceptibility. After literature search and data extraction, 17 studies containing four RAN SNPs were involved in the systematic review. And 12 studies with two highly studied SNPs (RAN rs14035 C>T and rs3803012 A>G) were included in the final meta-analysis, consisting of 7662 cases and 9807 controls. The results showed that the rs14035 polymorphism was linked to a decreased cancer risk in overall subjects and hospital-based (HB) subgroup, while the rs3803012 polymorphism conferred to an increased cancer risk in overall subjects and population-based (PB) subgroup. Our findings suggested that the two SNPs had the potential to be predictive biomarkers for cancer risk. The study would provide novel clues for the identification of miRNA-related genetic biomarkers applied to predicting cancer susceptibility. As a group of endogenous small noncoding RNA molecules, microRNAs (miRNAs) have been implicated in a wide diversity of basic cellular function by downregulating the expression level of their target genes . It has As an important component of miRNA processing genes, RAN gene encodes the ras-related nuclear protein, which is a unique member of the Ras superfamily of GTPases. It is an essential ingredient for the transportation of pre-miRNAs from the nucleus to the cytoplasm through the nuclear pore complex in a GTP-dependent manner , 8. RAN P = 0.011, OR = 1.99, 95%CI = 1.17 − 3.38) [Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in human genomes and also widely exist in the RAN gene. Currently, accumulating studies have explored the association between RAN SNPs and cancer risk. However, the results are conflicted. For instance, Ye et al. conducted a case-control study in Caucasian esophageal-cancer patients and found that the rs14035 polymorphism of RAN was associated with an increased disease risk in a recessive model ( − 3.38) . By cont − 3.38) . The disIn the present study, we performed a systematic review for the association of RAN SNPs with overall cancer risk. Meanwhile, a meta-analysis was conducted based on available data, aiming at clarifying the association between RAN SNPs and cancer susceptibility. The study may provide novel clues for the identification of miRNA-related genetic biomarkers for the prediction of cancer risk.Two investigators (Yanke Li and Fuqiang Zhang) independently performed publication search in the database of PubMed and Web of Science up to July 18, 2019, with the following key terms: ‘RAN/Ras-related nuclear', ‘SNP/polymorphism/variant/variation', and ‘cancer/carcinoma/tumor/neoplasm'. All retrieved articles were initially screened for eligible studies according to several standards: (1) case-control study and (2) focused on the association of RAN SNPs with cancer risk. The exclusion criteria contained (1) duplicate records and (2) records irrelevant to RAN SNPs or carcinoma (3) and with no available original data in the publications with authors failing to be contacted with.https://snpinfo.niehs.nih.gov).The data was independently extracted by two investigators (Yanke Li and Fuqiang Zhang), and a consensus was reached concerning all items. The information obtained from each article consisted of the first author, publication year, country and ethnicity, sample size, cancer type, SNP genotype distribution in the case and control groups, source of the control group, genotyping method, and adjustment factors. The ethnicity was classified into Asian and Caucasian. The source of controls was divided into hospital-based (HB) and population-based (PB) groups. Both cervical cancer and breast cancer were categorized as “hormone-responsive cancer” in stratified analysis. Bioinformatics function prediction was performed for all involved RAN SNPs using SNPinfo Web Server  by scoring them based on previous literature –20. Six P values by using the software NCSS-PASS version 11.0.7 (USA). Then, the FPRP values were figured out followed by the instructions reported in the previous research, and the association with FPRP < 0.5 was considered as a noteworthy finding [The false-positive report probability (FPRP) was tested to assess the level of statistically significant associations. First, we calculated the statistic power of each association based on the number of observations, and reported ORs and  finding .Q statistic test was used to examine the interstudy heterogeneity . The results in the fixed-effect model were selected when no significant interstudy heterogeneity existed; otherwise, the random-effect model was employed. In addition, the dominant and recessive genetic models were defined as heterozygote+variant homozygote vs. wild homozygote and variant homozygote vs. heterozygote+wild homozygote, respectively. Publication bias was assessed using Begg's rank correlation and Egger's linear regression methods. Sensitivity analysis was performed to evaluate whether the pooled results could be robust to some outlying study. All the above-mentioned analyses were conducted by STATA 11.0 software . P < 0.05 was considered to be statistically significant for two-sided tests.The Chi-square test was adopted to evaluate the HWE of SNP genotype frequency distribution in the control group. The association of each SNP with cancer risk was analyzed by calculating the odds ratio (OR) and 95% confidence interval (95% CI). Chi-square-based A total of 165 articles were retrieved through publication search after removing duplicate records. We excluded 148 articles by reading titles and abstracts: 92 were functional studies; 29 were review, meta-analyses, or case reports; 18 were not related to RAN SNPs; 5 were not related to carcinoma; and 4 were focused on cancer prognosis. Therefore, 17 studies were involved in our systematic review. Among them, 5 publications had no available original data, and we failed to contact with their authors. Finally, 12 case-control studies were included in our meta-analysis, consisting of 7662 cases and 9807 controls . The chaPHWE < 0.05) or the limited number of some loci. Consequently, two SNPs were included in the final meta-analysis, which were RAN rs14035 and rs3803012 polymorphisms.A total of four RAN SNPs were involved in the systematic review, including rs14035 C>T, rs3803012 A>G, rs3809142 C>T, and rs7301722 C>A. Their basic information and function prediction results are shown in P = 0.035, OR = 0.85, 95%CI = 0.73 − 0.99). On the contrary, the variant types of rs3803012 conferred to an increased risk , while no remarkable association was shown in the opposite subgroup. Interestingly, the rs3803012 polymorphism could only elevate the risk in PB population rather than HB population . The results showed that both the rs14035 and rs3803012 polymorphisms were associated with cancer risk in overall population and some specific subgroups. To our knowledge, it is the first time to make a comprehensive assessment for the research progress in this field and also the first meta-analysis of cancer-related RAN SNPs.RAN rs14035 SNP, located in the 3′-UTR of the gene, has been widely investigated for its role in carcinogenesis. Although some individual studies reported no significant association between this polymorphism and cancer susceptibility, our meta-analysis suggested that it was linked to a decreased risk of overall cancer. That may result from the limited sample size, ethnic diversity of study population, and complicated environmental factors varied from each study . AdditioSimilar to the rs14035 polymorphism, RAN rs3803012 SNP is also a hotspot 3′-UTR variation with potential biological function. It was suggested to be associated with an increased cancer risk in our study, which was generally consistent with previous research reports. Other than the possible roles, it may exert as a 3′-UTR locus such as rs14035, the A to G changing of rs3803012 might enhance the binding of hsa-miR-199a-3p to the 3′-UTR of RAN. MiR-199a-3p was reported to be a potential candidate for intervention in cancer , which wP = 0.046, OR = 0.68, 95%CI = 0.47 − 0.99), while no association was observed between the variant types of rs3809142 and disease risk [Other than the two highly studied polymorphisms mentioned above, another two RAN SNPs (rs3809142 and rs7301722) were also included in our review. However, the original researches referring to them were insufficient in making quantitative synthesis. They were only reported in a case-control study about breast cancer in Chinese women conducted by Jiang et al. The rs7301722 polymorphism was found to be associated with a decreased risk of breast cancer in a codominant model . The results showed that both of them were associated with cancer risk in overall population and some specific subgroups, suggesting that they could be potential predictive biomarkers for cancer risk. The study would provide novel clues for the identification of miRNA-related genetic biomarkers applied to predicting cancer susceptibility.


GSTM1), glutathione S-transferase T1 (GSTT1) present/null, and glutathione S-transferase pi (GSTP1) Ile105Val polymorphisms, in the susceptibility to nasal or colorectal polyposis (NP or CP). Thus, we aimed to perform a meta-analysis to comprehensively evaluate this association by applying Stata/SE software. After the heterogeneity assumption, Mantel–Haenszel statistics were used to obtain the odds ratio (OR), 95% confidence interval (95% CI) and P-value of the association test (AP). We obtained a total of 235 articles by searching online databases. After screening, ten eligible case–control studies were finally enrolled in our meta-analysis. For the meta-analysis of the GSTT1 gene under present versus null, we observed a decreased risk of NP , but not CP. In addition, we did not detect any evident association between the GSTM1 present/null polymorphism and NP or CP risk. For the meta-analysis of the GSTP1 Ile105Val polymorphism, compared with controls, an increased risk of NP cases was detected under the models of Val versus Ile , Ile/Val versus Ile/Ile  and Ile/Val+Val/Val versus Ile/Ile . In conclusion, the null genotype of the GSTT1 polymorphism may be linked to an increased susceptibility to NP, whereas the Ile/Val genotype of the GSTP1 Ile105Val polymorphism may be associated with a decreased risk of NP.We observed inconsistent conclusions regarding the genetic role of glutathione S-transferase gene polymorphisms, including glutathione S-transferase M1 ( Polyposis refers to a chronic disorder characterized by the presence of polyps, which are neoplasms that grow on the mucosal surface of human organs or tissues, including the nasal cavity, vocal cord, stomach, or colorectal area –3. The tAlthough the exact etiology of polyposis remains to be elucidated, chronic stimulation and genetic factors may partly account for the presence of polyps ,8. GenetGSTM1, GSTT1, and GSTP1 genes, respectively, are the three most common classes  of glutathione S-transferases in the human body ) or Polyp) or Adenomatous Polyps) or Intestinal Polyps) or Colonic Polyps) or Nasal Polyps) or Intestinal Polyp) or Colonic Polyp) or Nasal Polyp) or Adenomatous Polyp)) and ((((((((((((((((Glutathione S-Transferase pi[MeSH Terms]) or Glutathione S Transferase pi) or GST Class-phi) or Class-phi, GST) or GST Class phi) or Glutathione Transferase P1-1) or Glutathione Transferase P1 1) or Transferase P1-1, Glutathione) or GSTP1 Glutathione D-Transferase) or D-Transferase, GSTP1 Glutathione) or GSTP1 Glutathione D Transferase) or Glutathione D-Transferase, GSTP1) or GSTP1)) or ((((((((Glutathione S-transferase M1[MeSH Terms]) or Gstm1 protein, mouse) or glutathione S-transferase, mu 1 protein, mouse) or Gstm1 protein, rat) or glutathione S-transferase, mu 1 protein, rat) or GSTM1 protein, human) or glutathione S-transferase M1, human) or GSTM1)) or ((((((((((glutathione S-transferase T1[MeSH Terms]) or glutathione S transferase theta 1) or glutathione S transferase GSTT1) or Gstt1 protein, mouse) or glutathione S-transferase, theta 1 protein, mouse) or Gstt1 protein, rat) or glutathione S-transferase theta 1, rat) or GSTT1 protein, human) or glutathione S-transferase theta 1 protein, human) or GSTT1)).GSTM1, GSTT1, and GSTP1 gene variants in both polyposis cases and negative controls were available.We designed our screening strategy according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)’ . The maiGSTM1 and GSTT1 genes, the Ile/IIe, Ile/Val, and Val/Val genotype frequencies of the GSTP1 Ile105Val polymorphism, disease type, genotyping method, source of control, and sample size. We also evaluated the study quality and asked for missing data by emailing the original authors.We thoroughly extracted the following basic information from each retrieved case–control study via a predesigned table: first author name, publication year, country, ethnicity, gene, present/null frequencies of the P-value of heterogeneity from Cochran’s Q statistic >0.1 or I2 value <50.0%. We obtained the value of the summary odds ratio (OR), 95% confidence intervals (95% CIs), and P-value of the association test (AP). TheA P of less than 0.05 was deemed statistically significant. The present versus null genetic model was used for the GSTM1 and GSTT1 genes, and the allele , homozygote , heterozygote , dominant , and recessive  models were used for the GSTP1 gene.We used Stata/SE software  for our statistical analysis. A fixed-effect model was used for Mantel–Haenszel statistics when the We performed subgroup meta-analyses according to ethnicity (Caucasian/Asian), disease type (NP/CP), source of control , and country (The Netherlands/Germany). We also performed the Begg’s/Egger’s tests to assess the publication bias among the selected studies and sensitivity analyses to measure the statistical stability of the results.GSTM1 and GSTT1 genes and the Ile105Val polymorphism of the GSTP1 gene were tested.As per the flow diagram in GSTM1 and GSTT1 genes and the risk of polyposis. As shown in GSTM1 ; consequently, a fixed-effect model was selected for the Mantel–Haenszel statistics. As shown in GSTM1 present/null polymorphism, while 2840 cases and 3086 controls were available for the GSTT1 polymorphism. In the pooled estimates of the overall meta-analysis, no difference between the case and control groups for the risk of polyposis was observed for GSTM1 [AP=0.838] and GSTT1 (AP=0.914).We first performed a meta-analysis to study the genetic relationships between the present/null polymorphisms of the GSTM1 and GSTT1 genes. As shown in GSTT1 gene in the subgroups ‘NP", OR = 0.65, 95% CI = 0.45–0.93, AP=0.018) and ‘population-based’  under the present versus null model. No differences between the cases and controls were observed for the other subgroups . We also constructed forest plots of the subgroup analysis by disease type for the GSTM1 , source of control , country (The Netherlands/Germany), and ethnicity (Caucasian/Asian) for both the he GSTM1  and GSTT1 . We observed an increased polyposis risk in the models of Val versus Ile , Ile/Val versus Ile/Ile  and Ile/Val+Val/Val versus Ile/Ile  but not in the other genetic models . We obtained a similar conclusion for the subgroup ‘NP’ under the allele (AP=0.027), heterozygote  and dominant  models. Moreover, we detected increased risk in the subgroups ‘P-value of Hardy–Weinberg Equilibrium test (PHWE) >0.05’ and ‘Caucasian’ only in the allele and homozygote models (AP<0.05). Consequently, the Ile/Val genotype of GSTP1 Ile105Val polymorphism is more likely to be associated with an increased risk of NP.Next, we performed the overall analysis involving 298 cases and 477 controls for the association between the tibility . Mantel–P-value of Begg’s test [BP] >0.05; P-value of Egger’s test (EP) >0.05], with the exception of the present versus null model of the GSTT1 gene . We also constructed funnel plots of Begg’s test under the present versus null model of the GSTM1 .Furthermore, we performed a sensitivity analysis to observe the statistical stability of the above conclusions (HLCS), major histocompatibility complex, class II, DR α (HLA-DRA), BICD cargo adaptor 2 (BICD2), V-set immunoregulatory receptor (VSIR), and solute carrier family 5 member 1 (SLC5A1) genes may be linked to the pathogenesis of chronic rhinosinusitis with nasal polyps [GSTT1 gene but not the present/null polymorphism of the GSTM1 gene and the Ile105Val polymorphism of the GSTP1 gene in the Mersin region of Turkey [GSTM1 and GSTT1 polymorphisms on the predisposition for NP was reported [GSTT1, GSTM1, and GSTP1 genes and the genetic tendency of chronic rhinosinusitis with or without nasal polyps in Germany [GSTM1 present/null, GSTT1 present/null, and GSTP1 Ile105Val polymorphisms in the susceptibility towards NP or CP . Our findings suggest that the null genotype of the GSTT1 polymorphism and the GSTP1 Ile105Val polymorphism are more likely to be associated with the risk of NP. However, no association between the GSTM1 present/null polymorphism and the risk of NP or CP was observed.NP is thought to be closely associated with a group of clinical disorders characterized by chronic rhinosinusitis and shows differences in complexity and etiology ,23,24. Al polyps . Anotherf Turkey . Conversreported . There i Germany . AccordiGSTP1 Ile105Val polymorphism and GSTM1 null genotype but not the GSTT1 null genotype seem to increase the risk of Alzheimer’s disease [GSTM1 null genotype but not the GSTT1 null genotype may be linked to the risk of juvenile open-angle glaucoma (JOAG) [GSTM1 and GSTT1 genes and the combined GSTM1/GSTT1 gene may be risk factors for endometriosis [GSTT1 null genotype and the Ile/Val genotype of the GSTP1 Ile105Val polymorphism in the risk of NP. Individuals with the GSTT1 null genotype may show partial gene deletion, followed by enzymatic activity deficiency and decreased detoxification capacity. The Ile105Val polymorphism of the GSTP1 gene leads to an amino acid change from Ile to Val at residue 105 of the GSTP1 protein, which also may decrease the catalytic activity of the enzyme. Such a change may reduce the efficient detoxification of stress-induced intermediates, which has been implicated in the presence of an inflammatory response and nasal polyps in response to increased levels of electrophilic compounds or reactive oxygen species.Human glutathione S-transferases are a family of multifunctional enzymes with antioxidant activity that are involved in oxidative stress, cell differentiation, inflammatory responses, drug detoxification, and chemotherapy resistance . Some me disease . Similara (JOAG) . Howeveretriosis . Our metGSTP1 gene, and we were unable to explore the roles of other variants within the GSTP1 gene, such as the Ala114Val polymorphism. The possible distinct effects of different haplotypes merits further evidence. In addition, the joint effects of GSTM1, GSTT1, GSTP1, and other genes, such as cytochrome P450 family 1 subfamily A member 1 (CYP1A1), is worthy of analysis upon publication of sufficient data.There are some limitations of the present study that should be fully discussed. We endeavoured to search relevant publications by using search terms for different polyps, such as adenomatous polyps, intestinal polyps, colonic polyps, nasal polyps, and intestinal polyps, without language or region restrictions. However, only the data on nasal and colorectal polyps permitted synthesis of the data. Detailed data on genotype frequencies in both cases and controls are required to perform the overall meta-analysis and subsequent subgroup analyses. Due to restrictions of data availability, only the Ile105Val polymorphism was analyzed in our meta-analysis of the GSTM1, GSTT1, and GSTP1 polymorphisms was detected in our study. For the meta-analysis of the GSTP1 Ile105Val polymorphism, we included five case–control studies from four articles [No high degree of heterogeneity in the comparisons of the articles ,15,16,19GSTT1 present/null polymorphism in the risk of NP, the limitation of small sample size weakened the statistical power of our analysis to some extent. In addition, hospital-based controls were included in some studies. The genotype distribution of the GSTP1 Ile105Val polymorphism in the control group of one article [Although we obtained a positive result for the role of the  article  did not GSTT1 null genotype may serve as a protective factor against NP, whereas the Ile/Val genotype of the GSTP1 Ile105Val polymorphism is more likely to be associated with an increased risk of NP. More genomic tests in the future are warranted to further determine the roles of glutathione S-transferase gene polymorphisms in the genetic susceptibility to different types of polyposis.In summary, we pooled published relevant data and concluded that the


NFKB1 gene rs28362491 polymorphism and NFKBIA gene rs2233406 polymorphism in the development of head and neck cancer (HNC) remains controversial. This meta-analysis was performed to assess the relationship between the gene polymorphisms and HNC quantitatively.  The role of the  PubMed, Embase, Web of Science, WanFang Data, and China National Knowledge databases were used to search for eligible articles. The relationship was evaluated by STATA 11.0.  Eight eligible articles were included in our study. Nine case-control studies from the eight included articles were correlated with rs28362491 polymorphism. Four articles were related to rs2233406 polymorphism. Overall, a significant correlation was observed between the rs28362491 polymorphism and a decreased risk of HNCs . In subgroup analyses, the rs28362491 polymorphism was associated with the risk of nasopharyngeal carcinoma (NC), but not with oral cancer (OC). In addition, no statistical correlation was found between the polymorphism of rs2233406 and HNCs.  rs28362491 polymorphism was significantly associated with the risk of HNCs, especially with NC. Additionally, our results showed that no association was discovered between rs2233406 polymorphism and HNCs. Head and neck cancer (HNC) is the sixth most common cancer , which aκB (NF-κB), which was identified initially in 1986, acts as an essential transcription factor associated with cell survival, cell growth, cell replication, and cell apoptosis [κB also plays an important role in the development of carcinogenesis and tumor cell's resistance to radiotherapy and chemotherapy [κB family consists of five members: p65/Rel A, p50/p105, p52/p100, c-Rel, and Rel B. The heterodimer of the p65/Rel A and p50/p105 subunits, encoded by the NFKB2 and NFKB1 genes, respectively, is the most common form of NF-κB. Moreover, NF-κB activity would be influenced by NF-κB inhibitor alpha (NFKBIA) [κB has been reported in certain human tumors, such as colorectal cancer, breast cancer, colon cancer, multiple myeloma, melanoma, prostate cancer, and Hodgkin's lymphoma [Nuclear factor-poptosis –15. NF-κotherapy . The NF-(NFKBIA) –19. Inaplymphoma –24.NFKB1 and NFKBIA genes, located on chromosome 4q24 and 14q13, respectively, are associated with the development of cancers, including oral cancer (OC) [NFKB1 gene (rs28362491) and NFKBIA gene (rs2233406) might be associated with HNCs [NFKB1 and NFKBIA genes and HNCs. Additionally, trial sequential analysis (TSA) was also conducted to minimize random errors and strengthen the reliability of our conclusions.The cer (OC) , gastriccer (OC) , coloreccer (OC) , and Hodcer (OC) . In receith HNCs , 29–35. The meta-analysis was designed and implemented according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement .κB”, or “Nuclear factor kappa B”, or “NF-κB”, or “NFKB1”, or “rs28362491”, or “NFKBIA”, or “Nuclear factor kappa B inhibitor”, or “rs2233406” AND “carcinoma”, or “cancer”, or “neoplasm”, or “tumor”, or “carcinogenesis” AND “polymorphism”, or “variants”, or “variant”, or “mutation”, or “mutations”, or “polymorphisms” AND “head and neck”, or “HNC”, or “oral”, or “oral cavity”, or “pharyngeal”, or “laryngeal”, or “nasopharyngeal”, or “oropharyngeal”, or “laryngopharyngeal”, or “hypopharyngeal”. Finally, references cited by all the included studies were scanned to identify relevant articles.PubMed, Embase, Web of Science, WanFang Data, and China National Knowledge databases were searched comprehensively prior to May 1, 2019 with the following terms: “Nuclear factor-NFKB1 gene and/or the rs2233406 polymorphism of the NFKBIA gene; and (3) information provided by the paper was sufficient to estimate the correlation. Articles which satisfied one of the following criteria were excluded: (1) duplicated papers, reviews, editorials, case reports, commentaries, and nonhuman studies; (2) full-text was not found; and (3) no sufficient data were reported.No limitations were imposed on language or publication date. Articles were enrolled if they met all the following criteria: (1) the paper was case-controlled; (2) the paper assessed the risk of HNC and the rs28362491 polymorphism of the Two writers collected the information of each enrolled article according to the inclusion and exclusion criteria independently. First author, year of publication, country, ethnicity, genotyping method, source of control, distributions of genotype, and cancer type were fetched. Quality assessment of the enrolled papers in the analysis was conducted by the Newcastle-Ottawa Scale (NOS) criteria .Z-curve crossed with the TSA monitoring boundary before the RIS was reached or total sample size included in the study reached the RIS, a robust conclusion might have been affirmed and further study would be unnecessary.Considering that meta-analysis might result in false positive (type-1 error) or false negative (type-2 error) results due to the sparse data , TSA wasWe calculated the false-positive report probability (FPRP)  to assesZ-test, and a value of P < 0.05 was regarded as statistically significant.Statistical analysis was performed using STATA 11.0 . The strength of correlation between the gene polymorphisms and HNCs was evaluated through pooled odds ratios (ORs) along with the corresponding 95% confidence intervals (CIs). The ORs and CIs of each gene polymorphism were calculated for the allelic, homozygote, heterozygote, dominant, and recessive genetic models of each article, respectively. The combined ORs were calculated by Q-test and I2 statistics. If the P value in the Q − test > 0.10 and I2 < 50%, the Mantel-Haenszel fixed-effects model was used to estimate the pooled ORs. Otherwise, the DerSimonian and Laird random-effects model was performed to evaluate the correlation between the polymorphisms of the NFKB1 gene (rs28362491), NFKBIA gene (rs2233406), and HNCs. Hardy-Weinberg equilibrium (HWE) in the controls was calculated by the chi-square test [The between-article heterogeneity was estimated by Cochran's are test . In ordeEight articles , 29–35 iNine case-control studies from eight included articles , 29–35 wThe results of the overall analyses and subgroup analyses for gene polymorphisms (rs28362491 and rs2233406) with HNCs are shown in Q-test , the random-effects model was performed to analyze the correlation between rs28362491 polymorphism and HNCs under all genetic models. Overall, rs28362491 polymorphism was significantly correlated with a decreased risk of HNCs under homozygote and recessive genetic models . We discovered that there was no relationship between the rs2233406 polymorphism and the risk of HNCs under all genetic models . In the stratified analyses by genotyping method and tumor type, no association was observed in all genetic models (P > 0.05).With respect to rs2233406 polymorphism, the random-effects model was conducted under all genetic models except the recessive model because the statistical heterogeneity between the articles was substantial  and Begg's funnel plot for rs28362491 and rs2233406 polymorphisms.In the sensitivity analyses, no substantive change was discovered in the combined ORs after excluding one paper at a time. Egger linear regression tests and Begg's funnel plots were conducted to evaluate publication bias. In all the genetic models, no remarkable publication bias was found by the Z-curve had not crossed the trial monitoring boundary before the RIS was reached .Nine trials were used to evaluate the association between the rs28362491 gene polymorphism and the HNC susceptibility. The results of TSA analysis (taking the homozygous model data for example) showed that the cumulative  reached , indicatThe FPRP values for all the discovered significant results are demonstrated in κB plays an essential role in immune response, cell apoptosis, cell proliferation, and the development of cancers [α would be influenced by NF-κB in regulating their biological effects. Therefore, an abnormality in NF-κB function would disturb these various biological behaviors and eventually lead to tumorigenesis [NF- cancers –44. Moreigenesis .NFKB1 gene encoding p50/p105 subunit of the NF-κB family could modulate the transcription, production, and function of the p50/p105 subunit [κB inhibitor I kappa B (IκB) would inhibit the function of NF-κB by binding to it. NF-κB inhibitor alpha (NFKBIA), which is the most common protein of the IκB family, is encoded by the NFKBIA gene. As a functional polymorphism of the NFKBIA gene, the -826 C/T (rs2233406) polymorphism might play an important role in influencing the function of NF-κB. Recently, various articles have explored the relationship between rs28362491 and rs2233406 polymorphisms and HNCs [The -94 ins/del ATTG (rs28362491) promoter polymorphism of the  subunit , 46. NF-and HNCs , 29–35. κB in the development of cancer, we hypothesize that the possible mechanisms are as follows. NF-κB plays a critical role in various biological pathways, which brings us to the idea that ATTG deletion results in the loss of binding to nuclear proteins, which causes lower promoter activity [To the best of our knowledge, this is the first meta-analysis to evaluate the association between rs28362491 and rs2233406 polymorphisms and HNCs. In the present study, nine case-control studies from eight eligible papers were enrolled to assess the correlation between -94 ins/del ATTG polymorphism and HNCs. Overall, the results showed that -94 ins/del ATTG (rs28362491) polymorphism was significantly correlated with a decreased risk of HNCs under homozygote and recessive genetic models  showed that the cumulative evidence might be insufficient and further studies would be needed to strengthen the conclusion of rs2233406 polymorphism and the homozygous model in rs28362491 polymorphism. Therefore, further studies with a larger sample size and more information are required to observe the role of rs28362491 and rs2233406 polymorphisms in HNCs.Despite these shortcomings, our meta-analysis has several highlights. To our knowledge, this present meta-analysis is the first one to conclude a relationship between rs28362491 polymorphism and HNCs and discover that rs28362491 polymorphism is associated with the development of HNCs, especially NC, although there were four meta-analyses  which foIn conclusion, this meta-analysis explored that the risk of HNCs was significantly correlated with rs28362491 polymorphism, but not with rs2233406 polymorphism. Moreover, the significant correlation between rs28362491 polymorphism and the susceptibility to NC was identified for the first time. However, more gene-environment and gene-gene interaction papers with larger sample sizes should be addressed to evaluate the relationship between rs28362491 and rs2233406 polymorphisms and HNCs.


Although studies have consistently found an association betweenchildhood leukaemia risk and magnetic fields, the associations between childhoodleukaemia and distance to overhead power lines have been inconsistent. We pooleddata from multiple studies to assess the association with distance and evaluatewhether it is due to magnetic fields or other factors associated with distancefrom lines.We present a pooled analysis combining individual-level data  from 11 record-based studies.There was no material association between childhood leukaemia anddistance to nearest overhead power line of any voltage. Among children living< 50 m from 200 + kV power lines, the adjusted odds ratio for childhoodleukaemia was 1.33 (95% CI: 0.92–1.93). The odds ratio was higher among childrendiagnosed before age 5 years. There was no association with calculated magneticfields. Odds ratios remained unchanged with adjustment for potentialconfounders.In this first comprehensive pooled analysis of childhood leukaemiaand distance to power lines, we found a small and imprecise risk for residences< 50 m of 200 + kV lines that was not explained by high magnetic fields.Reasons for the increased risk, found in this and many other studies, remains tobe elucidated. Analyses that have pooled data from multiplestudies5 report a small but consistent increased risk ofchildhood leukaemia associated with exposures above 0.3 or 0.4 μT. In one of theseanalyses, Kheifets et al.4 pooled six studies for an analysis of theassociation between distance from power lines and childhood leukaemia. They found anodds ratio (OR) of 1.59 : 1.02–2.50) for the closestdistance category, which was comparable to the result for MF. High MF can occurclose  to high voltage power lines6. However, distance is known to bea poor predictor of MF exposure7 and therefore the question arises as to whetherthe association of increased childhood leukaemia risk with distance is due to MF orto other factors associated with distance from overhead power lines that areunrelated to long-term average MF. Unlike MF, there has not yet been a comprehensivepooled analysis on childhood leukaemia and distance to power lines, which could helpto answer this question.Thirty-five epidemiologic studies have examined the associationbetween exposure to extremely low-frequency magnetic fields (MFs) and childhoodleukaemia8, reporting on a study in the United Kingdom (UK)using diagnosed cases from 1962–1995, found an association between childhoodleukaemia and the distance between home address at birth and the nearesthigh-voltage overhead line8 with the apparent risk extending out to 600 m, adistance greater than would be expected for MF from high-voltage lines, because MFrapidly decline with distances and are very weak at distances beyond100 m10. Whether the risk trulypersists at greater distances from power lines and what might be an explanation forthis observation is unclear. Several explanations have been proposed, includingselection of controls, but none are fully satisfactory11, leaving open the possibilitythat some factor associated with distance other than MF is responsible.Draper et al.8 was extended to cover more recent time periods(diagnoses during 1962–2008) and lower line voltages12. The updated study confirmedthe raised leukaemia risks reported for the earlier decades, but found that riskdeclined in the latest decades. A small Danish study of calculated fields also foundhigher risks in earlier decades (1968–1986) compared with more recent cases(1987–2003)13. Two large studies in France and the UnitedStates, specifically California, reported that living within 50 m of a 200 + kV linemay be associated with a small increased risk of childhoodleukaemia15.In these studies, no increase in risk was observed beyond 50 m from 200 + kV linesor within 50 m of lower voltage lines. Both studies covered more recent time periodsonly (diagnosed in 1988 or later). Thus, the existence of similar temporal trends inrisk in other countries is unresolved.The study by Draper et al.16, each with varying degrees ofaccuracy. In addition, the point of the home chosen for the start of measurement ofthe distance varied from study to study; some used the centre of thebuilding17, whereas others used the corner closest to thepower line19 or where the mailbox waslocated14. Some studies identified observations with poorgeocoding accuracy and excluded them from analyses. If the association were real,one would expect it to be stronger when data with problematic geocoding are excludedfrom the analysis. On the other hand, such exclusions might inadvertently introducebias.Geographic information systems, maps and on-site measurements have allbeen used to assess proximity to power lines18, the MF association with childhood leukaemia waslimited to single-family homes, although calculated MF levels were somewhat higherin apartments mainly due to fields from sources other than power lines, as verifiedby spot measurements. This resulted in lower correlation between calculated fieldsand spot measurements for apartments compared with single-family homes, which mayexplain why the association between calculated fields and childhood leukaemia waslimited to homes with better exposure prediction .In Sweden24.Study participants often differ in SES and other factors from non-participants,possibly resulting in selection bias27, but this is less of an issuein the record-based studies that comprise this analysis, which do not require activeparticipation. Indeed, Poole et al.22 argues that individual measures of SES oftencome from case–control studies requiring participation, whereas ecological measuresoften come from record-based studies less prone to this bias. In addition, residencein single-family homes may be associated with higher SES and with various exposures(including both distance and MFs) and thus potentially confound anassociation.The association between socioeconomic status (SES) and leukaemia iscomplex and varies based on the specific measures used. Individual measures such ashigh family income tend to be associated with a lower risk of childhood leukaemia inmost studies, whereas the opposite is true for ecological measures such as percentof neighbourhood unemployment or deprivation index29or specifically higher nitrogen dioxide exposure fromtraffic30. Several studies have reported associationsbetween childhood leukaemia and traffic density, proximity to major roads orhighways, or exposure to air pollutants caused by traffic. A meta-analysis by Bootheet al.31assessing childhood leukaemia in relation to multiple pollutants found an increasedrisk for post-natal exposure but no association with pre-natal exposure. Moststudies found an association with childhood leukaemia overall, but the associationtended to be stronger when examining just acute lymphoblastic leukaemia (ALL) oracute myeloid leukaemia (AML) for specific pollutants32.Power lines may be co-located with other potential risk factors suchas motorways or railways, resulting in higher traffic-related air pollution exposurein proximity to power lines33.Studies of childhood leukaemia and distance from power lines haveassessed exposure at the birth home and/or diagnosis home. The critical time-periodof exposure for a potential effect on leukaemia development is unknown and it isunclear whether birth home or diagnosis home is more representative of a child’slifetime exposure, and/or which exposure period is more relevant biologically. Ofcourse, the former depends on the pattern of movement of the family betweenpregnancy and diagnosis. Residential mobility can manifest as selection bias,confounding or increased measurement error, or it could also be a potential riskfactorThere are many unresolved issues regarding the association betweenchildhood leukaemia risk and distance from overhead power lines that are difficultto resolve in any single study. In this study, we pool data from multiple studies toprovide a more comprehensive assessment of the association between childhoodleukaemia risk and distance to power lines than previously attempted. We also assesswhether the association is due to MF or other factors, and further consider whetherbias, confounding or other methodologic challenges inherent in these studies havesubstantial influence on the results using available data.35. We searched the published literature throughPubMed and a database of MF literature  to identify studies on childhood leukaemia and proximity tooverhead transmission lines. To locate studies potentially missed in our initialsearches, we also searched the reference lists in identified papers and conductedan informal survey of epidemiologists involved in MF research. To be included inour analysis, a study must have used record-based exposure assessment, i.e., notrequiring active participation of study subjects, with exposure  determined at the individual level; thus, studies with ecologic orarea-based exposure assessment were excluded. We excluded wire codestudies43. Although wire code studies use distance, theydocument only the power lines closest to the home, and thus higher voltage powerlines might not have been recorded if there were any distribution lines that werecloser. Studies with hospital controls were also excluded, because such controlsmay not be representative of the source population from which cases arose. Weidentified 21 studies on distance to power lines published between 1993 and 2016,of which 13 met our inclusion criteria  meta-analysisix Table 52–59.Tab44.Table 47. All studies provided information on sex, ageand SES (with the exception of France with no information on sex for controls),five studies provided information on mobility (whether subjects moved betweenbirth and diagnosis dates) and four studies provided data on type of dwelling andtraffic exposure. We collected available MF information to examine potentialimpact from adjustments for calculated fields on distance. Most studies providedcalculated MF (Brazil provided measured fields), whereas France, Switzerland andTasmania had no measured or calculated fields available.Among the three largest studies, accounting for 88% of all casesand 76% of cases closest to lines, two (United Kingdom and United States) werebased on birth residencies and one (France) on the residence at time of diagnosis;most of the other studies focused on the residence at time of diagnosis in theiroriginal publications, but nearly all had some information available on birthhomes as well. To focus on populations with higher exposure prevalence, somestudies (Norway and Sweden) captured data from the time the child entered an areadefined as homes within specified distances to overhead power lines. For Italy 2,we received data for 1998–2013 for the Modena and Reggio Emilia provinces, whichis a broader time period than in their originalpublicationAll variables were recoded to make them as compatible as possible.Distance to power lines was coded into four categories as the primary analysis;these cut points were selected based on available data and previousliterature.The primary analyses estimated risk of any type of childhoodleukaemia associated with distance of residence from power lines and wasrestricted to participants who had study-defined accurate geocoding. A mixture ofbirth and diagnosis homes was used, based on available data, with the home used inprior publications given preference. We estimated risk for distance from closestoverhead power line of any voltage and from closest power line with voltage of≥ 200 kV. Analyses were adjusted for age at diagnosis, sex (except for Francewhere a dummy variable was used) and SES , all of which were coded as categoricalvariables.60. In the one-stage approach, a traditionalpooled analysis, data from all studies were entered simultaneously into a singlemixed-effects logistic regression model with random intercepts for study. In thetwo-stage approach, effect estimates (log ORs) were obtained for each studyseparately and then combined using a random-effects meta-analysis model. Asensitivity analysis using the two-stage approach included Japan and Finland forwhich only summary data were available. The risk estimate for Finland comes fromunpublished data from a previous pooled analysis2 and provided estimates based onliving < 50 m to any voltage line. For the primary analyses, estimates fromthese two methods were compared. For all further analyses, we used the one-stageapproach.We used two statistical approaches: one-stage meta-analysis andtwo-stage meta-analysis50,except that due to small numbers, we grouped the decades as 1960–1980, 1980–2000,and 2000 and later. The latter analysis was conducted both with and without the UKstudy, because it was the hypothesis generating study.Additional subgroup, confounder and sensitivity analyses wereperformed. We fitted models for various subgroups: comparing subtypes of leukaemia(ALL and AML), excluding children with Down syndrome, and comparing subjectsyounger than 5 years with those who were 5 years or older at diagnosis. Toevaluate whether the strength of the association changed over time, we stratifiedby decade of diagnosis in a manner similar to that of Bunch etal.We examined the effects of confounder adjustments on riskestimates. Confounders examined included residential mobility (moving between thetime of birth and diagnosis) for five studies, type of dwelling (single-familyhome or other) for four studies, traffic exposure  for fourstudies, urban vs. rural setting for seven studies, ecological measures of SES forsix studies, individual measures of SES for five studies and MF for eight studies.The latter analysis was performed both with and without Brazil, the only countrywith measured rather than calculated fields. Completeness of collected confounderinformation varied across studies; many studies with confounder information hadsubstantial subject-level missing data. We further analysed the associationbetween childhood leukaemia risk adjusting for each confounder individually,controlling for age, sex and SES. As confounder information was available only forsubsets of studies, we present ORs from both minimally adjusted models  and models with confounders fit to the same subset ofdata.Sensitivity analyses included comparing the association based onbirth homes with that in diagnosis homes, as well as the choice of the referencecategory . To assess how geocoding accuracy may resultin exposure misclassification, we conducted an analysis of all observations,regardless of geocoding quality, compared with one including only observationswith good geocoding. Finally, we repeated the primary analysis using alternativecontrols. These analyses used data from studies that assessed other cancers inaddition to leukaemia . We used controls matched to cases of other cancers  and conducted an analysiscombining all alternative controls.Analyses were conducted using SAS 9.3 and Stata 14.2.Our pooled data set included 30,200 childhood leukaemia cases and69,594 controls. After restriction to participants with study-defined accurategeocoded distances from overhead power lines to the home, we were left with 97,280participants . After removing observations withmissing data on age, sex or SES, there were 27,143 cases and 65,265 controlsavailable for the primary analysis. Studies included cases diagnosed as early as1960s and as late as 2014; a larger percentage of cases and controls came from thetime periods between 2000 and 2015, as shown in Fig. Table I2 24.6%, p = 0.25 for children living < 50 m from a 200 + kV power line compared with those≥ 300 m away  Table . WhenexTable Table Analyses of the association between distance and leukaemia riskstratified by various covariates revealed stronger associations with distance forparticipants who had ever moved and for participants from both single-family homesand other dwelling types, suggesting potential interaction effects between thesecovariates and proximity to power lines Table . HoweverThe association between distance (< 50 m compared with ≥ 300 m)to 200 + kV power lines and childhood leukaemia was stronger for diagnosis homes compared with birth homes , although the CIs overlap Table . This waWe conducted a pooled analysis assessing proximity to overhead powerlines and its association with childhood leukaemia using individual-level data from11 case–control studies. We found virtually no increase in risk of leukaemia amongchildren who lived within any distance (including < 50 m) to power lines of allvoltages combined. We found a small, but imprecise, increase in risk of leukaemiaamong children who lived in homes < 50 m from higher voltage (200 + kV) powerlines. We found no material association between childhood leukaemia and MF in thisset of studies.23 found that SES, as an individual or ecologicalmeasure, was not clearly associated with the risk of childhood leukaemia or itsmajor subtypes.We did not find any association between childhood leukaemia and urbanvs. rural, type of dwelling, traffic density or SES in this set of studies. Further,adjusting for SES did not alter the associations whether ecological or individualmeasures of SES were used. Unfortunately, only the US study measured both types ofSES; thus, we were unable to compare these measures of SES in the pooled analysis. Aprevious analysis of the US dataOf the potential confounders that we examined, only mobility wasassociated with childhood leukaemia. Brazil obtained some of their data throughinterviews  andtherefore the data on mobility were prone to non-responder bias (9.5% of cases and12% of controls refused participation). The stratified analyses showed a muchstronger association between proximity to power lines and childhood leukaemia forthose who moved compared with those who never moved, but both strata had smallnumbers in their highest exposed categories Table . Given tWe found higher ORs for distance when only studies with informationon mobility, type of dwelling or traffic were included; however, adjustments forthese confounders had no effect on the estimates. Thus, these variables did notappear to confound the associations, but rather indicated potential selection ofstudies with higher ORs for close distance, perhaps due to higher quality of studieswith more detailed examination of potential confounders and more accurategeocoding.Nevertheless, the role of mobility in the studies of childhoodleukaemia is not fully understood. Assessment of that role is complicated, becauseit might be related to the age of the child, SES, type of housing (single-family vs.apartments), likelihood of successful geocoding, inclusion into the measurementcomponent of the study or exposure misclassification. Further exploration of therole of mobility on the association between proximity to power lines and childhoodleukaemia is warranted, whether it is through selection bias, confounding ormeasurement error or as a risk factor itself.In the age-stratified analyses, excess leukaemia risk associated withclose distance to power lines was limited to the younger age group, for whom anyaddress might be more indicative of lifetime exposure and/or exposure during acritical time period. On the other hand, although we might expect exposure in birthhomes to be more representative of exposure during the critical developmental timeperiod, power line proximity to diagnosis homes was more strongly associated withchildhood leukaemia than proximity to birth homes. This was the case when allstudies were considered and when limiting to studies that had information on bothbirth and diagnosis homes Table .Another12 with some support from theDanish study13. When the UK data were excluded, the associationsby period of diagnosis were similar  allowed us to standardise inclusion criteria and analyses across studies,and conduct analyses that were not done or possible in the individualstudiesThere are inherent limitations when pooling data. First, the pooleddataset is only as good as the underlying data. Second, each study collecteddifferent information, which limited the adjustment and confounder analysis orrequired excluding studies. Restrictions to smaller subsets of studies in thesensitivity analyses are likely selective and not generalisable to the broader setof data.5 in that the elevated risk we found was limited to< 50 m of a 200 + kV lines, a distance at which MF are more likely to beelevated. On the other hand, the lack of association with MF and the fact thatadjusting for MF did not weaken the association for distance supports alternativeexplanations for the associations observed between residential distance from powerlines and leukaemia risk, such as other correlates of distance or unmeasuredconfounders. Furthermore, although we included only record-based studies, which areless prone to bias, our results are somewhat weaker and less precise than that ofprevious MF pooled analyses, again arguing against MF as an explanation.Although the studies we have included do not show an association withMF, our results are broadly consistent with previous pooled analyses of MF andchildhood leukaemiaIn conclusion, we found a small, imprecise association betweenchildhood leukaemia and residence located within 50 m of 200 + kV lines, which wasstronger for younger children, in our individual-data pooled analysis of 11 studies.This association was not explained by exposure to high MF levels or by othermeasured confounders. We found no evidence for bias as a potential explanation andin particular, we only included record-based studies, making selection biasunlikely. Although exposure misclassification is likely to be present, the risk ofbias due to distance misclassification is quite small. The previous UK findings ofrisk estimates for distances beyond 200 m are not supported by the pooled data fromother countries. The decrease in effect over time are not clearly supported by thepooled data from other countries, although numbers of exposed cases and controls forthe earlier time period are small for both the United Kingdom and for othercountries combined. Although pooled analysis is a powerful approach to integratingdata, it is only as good as the underlying data. Reasons for the small yet fairlyconsistent increase in the risk of childhood leukaemia in relation to proximity topower lines found in many studies remain to be elucidated.Table S1Table S2Table S3Table S4Table S5Table S6Figure S1Figure S2


Airline crew are exposed to ionizing radiation as part of their occupation and have a documented increased risk of melanoma and cataracts. However, whether their occupation predisposes them to an increased risk of thyroid cancer is not established. The purpose of this systematic review and meta-analysis was to assess the risk of thyroid cancer in airline cockpit and cabin crew compared with the general population.The MEDLINE database accessed via PubMed and Cochrane Database were searched. We included cohort studies reporting the standardized incidence ratio (SIR) or standardized mortality ratio (SMR) of thyroid cancers in any flight-based occupation.p = 0.613; 6 records). The summary SIR for cockpit crew was 1.21  and the summary SIR for cabin crew was 1.00 . The overall summary standardized mortality ratio for airline crew was 1.19 .Of the 1777 citations retrieved in PubMed, eight studies with a total of 243,088 aircrew members and over 3,334,114 person-years of follow-up were included in this meta-analysis. No relevant studies were identified on Cochrane Database. The overall summary SIR of participants in any flight-based occupation was 1.11  contains supplementary material, which is available to authorized users. Commercial airline crew spend hundreds of hours per year working at cruising altitudes around 9–12 km near the tropopause , high-enAirline crews may represent a natural experiment due to work conditions that increase circadian disruption and radiation exposure. Historically several cancers such as melanoma  and breaRadiation poses a theoretical health risk because of its potential to damage DNA and foster mutagenesis , 16. ThoAmong organs susceptible to radiation, the thyroid is particularly sensitive. Previous reports have confirmed an increased incidence of thyroid cancer in individuals exposed to high levels of radiation during childhood or adolescence –23. ThesThe incidence of thyroid cancer continues to climb , and theThis study was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines .Relevant studies were identified by searching PubMed and Cochrane Database and scanning reference lists of articles. The following search terms were used: (Flight crew* OR Flight attendant* OR Air*crew* OR Airline* OR Airplane* OR Flight* OR Pilots* OR Steward* OR Stewardess OR Cabin crew* OR Cabin attendant* OR Aviat*) AND cancer AND . The date of the last search on PubMed and Cochrane Database was March 13, 2017. We also evaluated related review articles to identify studies that were missed by searching PubMed and Cochrane Database.Studies that reported a SIR or a SMR for thyroid or endocrine cancer in cockpit or cabin crew or that reported observed and expected counts that could be used to calculate a SIR or SMR were considered eligible for inclusion. Some studies reported a SIR or SMR of “thyroid and other endocrine cancers” or “endocrine cancers”. We included these studies because thyroid cancer is the most common endocrine malignancy, and constitutes the majority of new diagnoses and deaths among endocrine malignancies each year . We alsoTwo authors (A.C. and M.R.) assessed the eligibility of studies, with any disagreements settled by consensus with a third author (G.S.L.). Initial screening was done using the article title and abstract to generate a list of potentially relevant studies. Each study in the list then underwent full text review to determine eligibility by our inclusion criteria. If different publications reported on subsets of duplicative data, we included the study with the largest amount of data, e.g. the study that followed the same cohort for the longest period of time.For each included study, we extracted data available about the study participants’ characteristics ; data collection period; person-years of follow up; outcomes; and whether the outcomes were attributed to thyroid cancer specifically, thyroid and other endocrine cancers, or endocrine cancers in general (unspecified). Mean follow up was calculated by dividing person-years of follow up by the number of participants.We calculated the summary SIR and SMR for all airline crew, and also calculated these values for airline crew stratified by location on the plane. The two location groups were cockpit crew (e.g. pilots) and cabin crew (e.g. flight attendants).p = 0.10. Funnel plots were created using Stata to assess for potential publication bias across studies. To assess the goodness of fit of linear regressions, the Pearson correlation coefficient R2 was calculated using Microsoft Excel 2013.We used Stata version 13.1 (StatCorp) to perform random effects model and fixed effects model meta-analyses, producing summary relative risks and 95% confidence intervals. Unless otherwise specified, reported SIR and SMR results were obtained using the random effects model. All statistical tests were 2-sided. The I-squared measure of heterogeneity  was consOur search terms on PubMed produced 1774 results. Our search terms on Cochrane Database produced two systematic reviews and 26 controlled trials, all of which were excluded on initial screening. We also searched reference lists and review articles to identify an additional three publications –41. We pThis review included 8 studies published between 1996 and 2014, incorporated data collected between 1943 and 2008 from 11 countries , and included 243,088 airline crew members . The summary SIR for cockpit crew was 1.21  and the summary SIR for cabin crew was 1.00   was 1.11 . The summary SMR for cockpit crew was 0.96  .R2 = 0.29, p = 0.31). There was also no significant association between SIR and total person-years of follow-up  or duration of data collection . These statistical analyses are presented in Additional file Thyroid cancer is indolent relative to breast cancer, leukemia, and melanoma . PresentWe conducted, to our knowledge, the first meta-analysis to investigate the risk of thyroid cancer in airline cockpit and cabin crew members. We found no significant increase in incidence of or mortality due to thyroid cancer relative to the general population. However, the measurement of accumulated radiation exposure in flight is imprecise and childhood exposure windows are not captured in the studies included in this meta-analysis. Assigning equal exposures to all airline crew could mask a threshold effect in which only airline crew members with the highest radiation exposure levels or some lifetime combination of childhood and adult radiation exposure levels experience increased thyroid cancer risk. It is also possible that, in contrast to findings that childhood radiation exposure is clearly associated with thyroid cancer risk later in life, when the thyroid is exposed to radiation during adulthood , 61 the We were unable to assess risk by gender given the data provided in the publications. Gender is an important factor given the three-fold higher incidence of thyroid cancer in women compared with that in men in the general U.S. population  and docuOur results may reflect the inability to consider these specific variables and a small number of studies with insufficient person-years of follow-up to detect small to moderate increases in risk. Unlike the studies for melanoma and breast cancer for example, the number of cases of thyroid cancer remain small in comparison requiring larger datasets with extensive person-years of follow-up. Identifying more studies or including additional person-years of follow-up in existing studies would produce narrower confidence intervals of outcome estimates to detect small increases in risk. In order to assess small or moderate risks of radiation-associated thyroid cancer in airline crew, future meta-analyses would need to include more studies than the number included here, especially if the studies included were of low or moderate power and hindered by lack of detail on other key variables.This study has several other limitations. To more thoroughly understand the risk of radiation exposure among adults, lifetime individual radiation exposure levels should be captured based upon childhood exposures and adult occupation-based exposures, perhaps by using innovative means for analyzing flight frequency, duration, and elevation data that would require industry participation. Changes in screening, incidence, and mortality of thyroid cancer over different time periods, as well as clinical practice differences in countries outside the United States, were not adjusted for when calculating the SIR and SMR. We considered multiple hypothesis testing from including and excluding other endocrine cancers, and regard it as unlikely to have affected our conclusions given the insignificant results. Our meta-analysis of thyroid cancer mortality is also limited because the published studies reported SMR data for thyroid cancer that included other endocrine malignancies.p > 0.10). Another strength is that participants were stratified by airline crew occupation (i.e. cockpit or cabin crew) to assess whether location on the airplane was a confounding factor. We did not find a significant difference in thyroid cancer SIR or SMR between the two airline crew occupation groups, suggesting that location on the airplane was not a confounding factor. We also addressed the potential limitation of insufficient follow-up, given that indolent thyroid cancers may present later and require a greater duration to effectively monitor. We did not find evidence supporting a trend between mean follow-up and reported SIR across studies, suggesting that insufficient follow-up is less likely to be a concerning factor in the analysis.There are a number of strengths of this study. One is that significant heterogeneity was not observed in the overall SIR and SMR


To gain further insight on the association between human toxocariasis and epilepsy in light of the new evidence in the last years.A systematic review was conducted without date and language restriction in the following electronic databases: MEDLINE (PubMed), Ingenta Connect, Science Direct (Elsevier), RefDoc, Scopus, HighWire, Scielo and the database of the Institute of Neuroepidemiology and Tropical Neurology of the Limoges University (IENT). Two investigators independently conducted the search up to November 2017. A pooled odds ratio (OR) was estimated using a random effects model. Meta-regression was conducted to investigate potential sources of heterogeneity.Toxocara spp. seropositivity. A positive association was constantly reported in the restricted analysis . Meta-regression showed no statistically significant association between covariates and outcome.Database search produced 204 publications. Eleven case-control studies were included that were carried out in 13 countries worldwide. A total number of 4740 subjects were considered (2159 people with epilepsy and 2581 people without epilepsy). The overall pooled OR was 1.69 (95% CI 1.42–2.01) for the association between epilepsy and Toxocara seropositivity and epilepsy. New surveys supported the association, mainly population-based studies. On this basis, health strategies to reduce the impact of Toxocara spp are strongly advised. Further research should be performed to understand the physiopathological mechanisms of toxocara-associated epileptogenesis.The updated meta-analysis provides epidemiological evidence of a positive association between  Toxocara canis (T. canis), the common roundworm of dogs, and by the roundworm of cats, Toxocara cati (T. cati). Toxocariasis is one of the most prevalent helminthiasis worldwide. Humans become infected by the ingestion of contaminated food or soil or by direct contact with dogs and cats. Epilepsy is the most common chronic neurological disorder worldwide with a global estimate of about 70 million cases of lifetime epilepsy. Early studies suggested high rate of toxocara exposure (toxocara seropositivity) among people with epilepsy. Despite several studies support the possible role of toxocariasis in the incidence of epilepsy, this association is still debated. We updated our previous research to gain further insight on the association. This study provides new evidence of a positive association between the two diseases. On this basis, health strategies to reduce the impact of Toxocara spp are strongly advised. Further studies are necessary to clarify the role of certain parasites in epilepsy.Human toxocariasis is a parasitic zoonosis caused by the larval stages of  Toxocara canis and Toxocara cati, the common roundworms of dogs and cats, respectively.Toxocariasis is a parasitic zoonosis caused by larvae of Toxocariasis is one of the most prevalent helminthiasis worldwide. Even if the parasite tends to be more prevalent in tropical settings where seroprevalence reaches up to 80–90%, in Western countries seroprevalence ranges from 35 to 42% in rural areas and from 2 to 5% in urban areas .Toxocara is a nematode that usually inhabits the small intestine of the host. The female Toxocara produces up to 200,000 eggs per day, releasing them to the environment through the feces  , one in The large majority of the surveys were hospital-based studies –31,35,39Edwards et al. in 2008 [Glickman et al. [Alter [Arpino et al. [Winkler et al. [Four studies –25,27 us in 2008 , based on et al.  consider. [Alter  in 1972.o et al.  considerr et al.  defined r et al. . Cryptogr et al. ,35,39.Considering the type of seizures, five studies –25,35,39A neurologist, or an epileptologist, confirmed the epilepsy diagnosis in six studies through anamnesis and complete neurological examination –27,32. AControls have been recruited from the general population in the population-based surveys ,27,32. CSociodemographic variables and possible risk factors were collected in eight studies ,29–32,39Toxocara spp. antibodies in sera as antibodies-ELISA (Ab-ELISA) commercial or in-house kits [Several technical approaches were used to assess the presence of anti-use kits –32,39, ouse kits ,25 or Abuse kits ,26,27,35use kits –25.Toxocara spp. seropositivity and epilepsy was found in five surveys [A posteriori statistical power was higher than 80% in only three studies [A priori and a posteriori statistical power and crude ORs of the included studies are shown in Statistical significant association between  surveys ,29,30,32 surveys ,35. A po studies ,25,32. AToxocara spp. seropositivity  for the association between epilepsy and sitivity . The tesFive studies used Western Blot as diagnostic or confirmatory test –27,35, wTo assess the publication bias, the funnel plot is shown in the 2 = 0.00, p = 0.132), continent , technique to assess Toxocara exposure (tau2 = 0.015 p = 0.718), age group population , case and control ascertainment source , epilepsy diagnosis confirmation by a neurologist  and epilepsy definition used . Meta-regression showed no statistically significant association between covariates and outcome.In order to explore the sources of heterogeneity, the following study level co-variables were considered: time period . The association is consistent but slightly lower than the previous published meta-analysis  [Today, the association between toxocariasis and epilepsy is still debated which is related to different results found in the literature and the lack of understanding of physiopathological mechanisms between toxocariasis and epileptogenesis. This updated meta-analysis provides epidemiological evidence of the association between We updated our previous meta-analysis  to gain The four new articles included explicitly investigated the association between epilepsy and toxocara exposition using a case-control design. Case recruitment was performed in a general population setting in two studies ,32, adopThe new evidence allowed us: i) to consider more than twice as many cases and controls compared to our previous study improving the statistical power to estimate more accurately the pooled OR of the association, ii) to include eight additional countries worldwide which strengthens the consistency criterion for causality, iii) to conduct restricted analysis considering population-based case-control studies.Toxocara spp seropositivity has been showed to be associated with focal seizures  [a-priori and a posteriori statistical power [Overall, the majority of the studies included were performed in a hospital setting. Hospital based studies are frequently prone to selection bias, as the cases being followed in the hospital probably present more severe form of epilepsy compared to the general population. Children suffering from severe encephalopathies, or patients with a history of tonico-clonic generalized seizures more frequently need specialized care in a hospital setting, while subjects presenting milder symptomatology or focal seizures without secondary generalization, might be underrepresented. The difference is even more striking in low and middle-income countries, where the elevated costs of access to specialized care further reduce the representation of milder forms. This bias may partially account for the lack of association found in some of the hospital-based studies, because 24–9.80) . Further24–9.80) ,27,32, fToxocara spp, the analysis has been restricted to the studies investigating a young population (<18 years), giving a common OR of 1.71 (95% CI 1.02–2.87), a result now borderline significant when compared to the previous meta-analysis of 2.23 (95% CI 1.36-3-69) [Toxocara spp antibodies rate between cases and controls [Toxocara spp positive subjects in the control group as living in rural setting increases the possibility of being exposed to T. canis eggs, especially in a country with a high soil contamination rate such as Egypt [a posteriori statistical power was 4.3%, which increases the probability of making a type II error. Age has also been used as matching criteria in all the included studies because it seems to contribute to Toxocara spp. exposure. Generally the chance of being exposed to an infectious agent increases with age, however it has also been demonstrated that younger age is associated with higher Toxocara spp seropositivity [Toxocara spp eggs infected soil (such as playgrounds). Interestingly, toxocariasis is more common in childhood, while neurotoxocariasis cases are observed more frequently in adults [To take in account the possible effect of age on the exposure to controls . Neverthas Egypt . MoreoveToxocara spp should be associated with focal seizures, with or without secondary generalization rather than generalized seizures. However only few studies provided a stratified analysis according the type of seizures. This association has been confirmed in two of the studies included [Zibaei et al. (2013) found a borderline significant association in a population comprised largely by patients with partial seizures (82.4%) [Another factor that affects the interpretation of the association between epilepsy and toxocariasis depends on the lack of a clear classification of the etiologies of epilepsies and the different types of seizures. It should be expected, according to the hypothesized physiopathology, that included ,25, whil (82.4%) . FurtherToxocara canis larvae of the second stage [Ascaris lumbricoides, Stronglyloides), reduce its specificity, particularly in tropical areas [Another possible limitation is due to the heterogeneity of techniques  and kits  used in the different studies to evaluate toxocariasis seropositivity. The standard serological test for the diagnosis of toxocariasis is an ELISA based on secretory-excretory antigens (TES) from nd stage  and it ial areas . The useal areas  thus scral areas . Therefoa posteriori statistical power over 80%, a value usually considered as appropriate when planning research studies, and they all found the association to be significant [A possible explanation for the lack of association on some of the included studies may rely upon the low statistical power that these studies possessed to find a significant association between epilepsy and toxocariasis. In fact, only three studies had nificant ,25,32. Nnificant ,30,35, wnificant ,27,31,39Toxocara spp antibodies) and the outcome (epilepsy). This does not allow us to exclude a reverse causality in which the development of epilepsy acts as a risk factor for the infection with Toxocara spp. In fact, epilepsy itself is a risk factor for frequent falls to the ground that increase the chance of Toxocara spp infection especially in areas with high levels of soil contamination. Children with epilepsy and mental retardation, such as those suffering from severe perinatal encephalopathies, may have abnormal behaviors (e.g. pica) that increase the chance of Toxocara spp infection [Toxocara spp antibodies in a population of incident patients with epilepsy, however no case control study considering incident PWE has been performed to assess the association. A prospective population-based survey including new cases will provide the most reliable epidemiological evidence of association but this does not necessarily imply causation [Wagner and Newton (2009) that causal relationship can be established only by measuring the reduction in the incidence of epilepsy following the eradication of the putative helminth (Toxocara spp) [A major limitation in the interpretation of the association is due to the fact that all the studies included in our meta-analysis have been conducted on prevalent epilepsy cases, thus considering a cross-sectional approach at the same time of both the exposure (anti-nfection . To clarausation . Therefoara spp) .Toxocara spp and the development of epilepsy is still a matter of debate. While it has been demonstrated that the parasite can migrate to the CNS and cause a variety of clinical manifestation [Toxocara larvae could induce a granulamotous reaction. An acute granulomatous reaction may cause acute symptomatic seizures, and may leave fibrous scars after resolution and chronic granulomatous lesions maybe could lead to epilepsy [Toxocara spp larvae in the brain is responsible for an increase in the permeability of the blood brain barrier, and the production of proinflammatory cytokines leading to neuronal damage [The role of exposition to estation , there aepilepsy . Granuloepilepsy . Second,l damage . Similarl damage  suggestil damage ,54. Cluel damage ,56. Toxol damage , howeverThis work relies on certain strengths. First, the broad literature search in eight large databases without date and language restriction, which allow us to screen the available literature in the subject. Second, international guidelines on meta-analysis of observational studies were followed. Third, this update included studies carried out in rural and urban settings in different geographic areas worldwide. Lastly, no apparent publication bias exists in the studies included in the meta-analysis. However, we recognize that the funnel plots should be interpreted with caution when the studies are few.Some limitations could be discussed. First, only few new studies were performed to evaluate the association, however, this update considers more than twice as many cases and controls compared to our previous study . Second,Toxocara infection in definitive hosts [Human toxocariasis is a cosmopolitan and preventable infection that may have a role in the global burden of epilepsy. There are however many available strategies to reduce the impact of this neglected diseases: public health policies could limit soil contamination and control ve hosts  and enhave hosts . As an ave hosts .We provide epidemiological evidence of a positive association between epilepsy and toxocariasis seroprevalence. New surveys supported the association, mainly population-based studies. We showed that research interest is slightly increasing in the field and studies with appropriate methodological approach have been produced in the last years. We also highlighted the presence of several knowledge gaps that have not been addressed. We strongly encourage researchers to perform further studies in the field to answer these questions. Further research should be performed; ideally, including new cases in a general population settings, to better explore the association or assessing the reduction in the incidence of epilepsy following the eradication of Toxocariasis. Increasing the understanding of physiopathological mechanisms of epileptogenesis will clarify the role of certain parasites in epilepsy.S1 File(DOC)Click here for additional data file.S1 Fig(EPS)Click here for additional data file.S2 Fig(EPS)Click here for additional data file.


It remains unknown which is the most preferable regimen used concurrently with thoracic radiation for locally advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue.PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Overall survival (OS) data was the primary outcome of interest, and progression-free survival (PFS), and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs).14 RCTs with a total of 2975 patients randomized to receive twelve categories of treatments were included in the meta-analysis. Direct comparison meta-analysis showed that etoposide-cisplatin (EP) was more effective than paclitaxel-cisplatin/carboplatin (PC) in terms of OS  and PFS . In network meta-analysis, all regimen comparisons did not produce statistically significant differences in survival. Based on treatment ranking of OS and the benefit-risk ratio, S-1-cisplatin (SP) was likely to be the most preferable regimen for its best efficacy and low risk of causing SAEs. Uracil/tegafur-cisplatin (UP) and pemetrexed-cisplatin/carboplatin (PP) were ranked the second and third respectively. Gemcitabine-cisplatin (GP) and PC + Cetuximab (PC-Cet) appeared to be the worst and second-worst regimens for their poor efficacy and poor tolerability.Based on efficacy and tolerability, SP is likely to be the most preferable regimen used concurrently with thoracic radiation for locally advanced NSCLC, followed by UP and PP. Further direct head-to-head studies are needed to confirm these findings.The online version of this article (10.1186/s13014-019-1239-7) contains supplementary material, which is available to authorized users. Lung cancer remains the leading cause of cancer-associated deaths globally. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases  and abouNetwork meta-analysis is the best way to solve aforementioned questions, which enable indirect comparisons to account for missing head-to-head data and multiple regimen comparisons. The study aimed to perform a network meta-analysis to estimate the relative efficacy and tolerability of different agents based concurrent chemotherapy regimens, attempting to identify the most preferable regimen used concurrently with thoracic radiation for locally advanced NSCLC.This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria . PubMed,Studies were included if they met the following criteria: (1) types of studies: randomized controlled trials (RCTs); (2) types of participants: participants with a histopathological diagnosis of locally advanced NSCLC; (3) types of interventions: one or more regimens for experimental arm, and the presence of a control for comparison; and (4) outcome: reported overall survival (OS) and/or progression-free survival (PFS) data. Studies were excluded if any of the following criteria were applied: (1) letters, editorials, case reports, and reviews; and (2) survival data could not be extracted from the literature.The data were extracted by two investigators independently. The following data were extracted from each study: first author, years of publication, duration of the study, country of origin, treatments, numbers of patients , data of OS, PFS, objective response rate (ORR), and serious adverse events (SAEs).The methodological quality of RCTs was assessed by Cochrane risk of bias tool , which cχ2) and I-square (I2) tests with the significance set at I2 > 50% or P < 0.10.The primary outcome was OS, and the secondary outcomes were PFS, ORR, and SAEs. Hazard ratios (HRs) or odds ratios (ORs) and their 95% confidence intervals (CIs) were used as summary statistics. For direct comparisons, standard pairwise meta-analysis (PWMA) was performed. A statistical test for heterogeneity was performed using the chi-square (https://drugis.org/software/r-packages/gemtc). For each outcome measure, four independent Markov chains were simultaneously run for 20,000 burn-ins and 100,000 inference iterations per chain to obtain the posterior distribution. The traces plot and Brooks-Gelman-Rubin method were used to assess the convergence of model [The Bayesian network-meta analysis (NMA) was performed in a random-effect model using Markov chain Monte Carlo methods , 21 in Jof model . TreatmeSAEs) in the ranking plot. Lastly, comparison-adjusted funnel plot was used to detect the presence of small-study effects or publication bias [Network consistency was assessed with node-split models by statistically testing between direct and indirect estimates within treatment loop . To rankion bias .The literature search results and study selection process are shown in Fig. The risk of bias in included RCTs was summarized in Additional file P = 0.08).Results of single trial and direct comparison meta-analysis are shown in Table P = 0.05). Other regimen comparisons did not produce statistically significant differences. With regard to PFS and ORR, no significant differences were observed for all regimen comparisons. As for overall SAEs and RP, MVP showed significantly higher risk of SAEs in comparison to each regimen except GP and PC-Cet. DP was more likely to cause SAEs than SP  and UP . NP resulted in a higher and a trend higher risk of SAEs than UP  and SP , respectively. PC had a trend higher risk of grade≧3 RP than PP  and EP .The network plot established for NMA is shown in Fig. There were three independent closed loops in the network for OS, ORR, overall SAEs: EP-NP-PP, PC-DP-MVP, and PC-DP-SP-NP-EP; two independent closed loops for PFS: PC-DP-MVP; and PC-DP-SP-NP-EP. Analysis of inconsistency showed that the NMA results were similar to the PWMA results for the four outcomes, which suggested the consistency between the direct and indirect evidence  in the ranking plot . In our NMA, PP was ranked third-best regimen in term of the benefit-risk ratio. The addition of Cetuximab did not demonstrate a survival advantage compared with PP alone. It should be noted that all included patients  were with mixed histological types. In a phase III trial comparing PP and GP in patients with advanced NSCLC, PP resulted in a superior OS in non-squamous patients but did a worse survival for patients with squamous histology tumors compared with GP [PP has been the standard first-line treatment option in patients with metastatic non-squamous NSCLC. However, no clear survival advantages are reported for locally advanced case. A phase III trial (PROCLAIM) compared concurrent chemoradiation using PP vs. EP in stage III non-squamous NSCLC . No stat with GP . FurtherEP and PC, two most common regimens administered currently with radiation to date, have recently been compared directly in several clinic trials. In a most recent multicenter randomized phase III trial  comparinP = 0.09). Data from a large meta-analysis of predictors of RP showed that concurrent PC resulted in five times the risk of grade ≥ 2 RP compared with EP [RP remains one of the most common side effects for patients treated with chemotherapy concurrently with thoracic radiation, and different chemotherapy regimens have been reported to be related to the differences in RP risk , 31. In P < 0.001). However, the sample size is relatively small (21 in EP arm and 20 in erlotinib arm). These findings need a large sample size of phase III study to confirm. Morever, a recent phase III trial (PACIFIC) [Molecularly targeted agents and immunotherapy have a defined role for metastatic NSCLC. The efficacy of these new classes of agents for locally advanced disease is undergoing investigation. In the 2017 Annual Meeting of the American Society of Clinical Oncology, Yu et al. reported a multicenter phase II trial of erlotinib vs. EP with concurrent thoracic radiotherapy for stage III NSCLC with epidermal growth factor receptor activating mutation . CompariPACIFIC)  comparedThis network meta-analysis has a number of limitations. Firstly, in common with other meta-analyses, data were collected and analyzed basis of results reported from trials, instead of individual patient data. Secondly, all studies except PROCLAIM trial included patients with mixed histological types. Thus, we could not assess survival differences between regimens according to histological types. Thirdly, different toxicity criteria were used, and radiotherapy features  were inconsistent in individual RCTs. Moreover, chemotherapy regimens used in different countries were studied togheter in the meta-analysis. These might lead to heterogeneity and inconsistency. Finally, some HRs of OS or PFS were calculated from the Kaplan–Meier curve due to that they were not directly reported in the articles. This may result in bias.Based on efficacy and tolerability, SP is likely to be the most preferable regimen used concurrently with thoracic radiation for locally advanced NSCLC, followed by UP and PP. GP and PC-Cet appeared to be the worst and second-worst regimens for this population. Further direct head-to-head, well-designed, prospective studies are needed to confirm these findings.Additional file 1:Table S1. Search strategy (DOC 62 kb)Additional file 2:Figure S1. Assessment of risk of bias. A: Methodological quality graph: authors’ judgment about each methodological quality item presented as percentages across all included studies; B: Methodological quality summary: authors’ judgment about each methodological quality item for each included study, “+” low risk of bias; “?” unclear risk of bias; “-” high risk of bias. (JPEG 17793 kb)Additional file 3:Figure S2. Comparison-adjusted funnel plots of publication bias test for overall survival. SP, S-1-cisplatin; UP, uracil/tegafur (UFT)-cisplatin; PP, pemtrexed-cisplatin/carboplatin; EP, etoposide-cisplatin; PC, paclitaxel-cisplatin/carboplatin; NP, vinorelbine-cisplatin; DP, docetaxel-cisplatin; IC, irinotecan-carboplatin; MVP, mitomycin-vindesine-cisplatin; GP, gemcitabine-cisplatin; Cet, cetuximab. (JPG 6940 kb)Additional file 4:Table S2. Results of network meta-analysis (DOC 117 kb)Additional file 5:Figure S3. Inconsistency evaluation by node-splitting analyses. (a) overall survival; (b) progression-free survival; (c) objective response rate; (d) serious adverse events. EP, etoposide-cisplatin; PC, paclitaxel-cisplatin/carboplatin; PP, pemtrexed-cisplatin/carboplatin; MVP, mitomycin-vindesine-cisplatin; SP, S-1-cisplatin; NP, vinorelbine-cisplatin; DP, docetaxel-cisplatin. (JPG 9280 kb)