Purpose: To assess the association of tumor mutational burden (TMB) with clinical outcomes, other biomarkers and patient/disease characteristics in patients receiving therapy for lung cancer. Results: In total, 4,303 publications were identified; 81 publications were included. The majority of publications assessing clinical efficacy of immunotherapy reported an association with high TMB, particularly when assessing progression-free survival and objective response rate. High TMB was consistently associated with TP53 alterations, and negatively associated with EGFR mutations. High TMB was also associated with smoking, squamous cell non-small cell lung carcinoma, and being male. Methods: A systematic literature review based upon an a priori protocol was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane methodologies. Searches were conducted in EMBASE, SCOPUS, Ovid MEDLINE®, and Emcare (from January 2012 until April 2018) and in two clinical trial registries. Conference abstracts were identified in EMBASE, and in targeted searches of recent major conference proceedings (from January 2016 until April 2018). Publications reporting data in patients receiving therapy for lung cancer that reported TMB and its association with clinical efficacy, or with other biomarkers or patient/disease characteristics, were included. Results are presented descriptively. Conclusion: This systematic literature review identified several clinical outcomes, biomarkers, and patient/disease characteristics associated with high TMB, and highlights the need for standardized definitions and testing practices. Further studies using standardized methodology are required to inform treatment decisions.

Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient (Prlr-/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr-/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr-/- females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr-/- females while PRL levels were below 15 ng/mL in control mice (p < 0.01). By comparing pituitary microarray data of Prlr-/- mice and an estrogen-induced prolactinoma model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.

Doublecortin-like kinase 1 (DCLK1) has been found to be involved in malignant biological behavior of cancers and poor prognosis of cancer patients. The aim of this meta-analysis was to systematically clarify the relationships between expression level of DCLK1 and clinicopathological characteristics in tumors and assess its clinical value in cancer diagnosis and prognosis. 18 eligible studies with a total of 2660 patients were identified by searching the electronic bibliographic databases. Pooled results showed that DCLK1 was highly expressed in tissues from cancer patients compared to normal tissues (OR, 10.00), and overexpression of DCLK1 was significantly correlated with advanced clinical stage (OR, 2.48), positive lymph node metastasis (OR, 2.18), poorly differentiated cancers (OR, 1.83) and poor overall survival (HR, 2.15). The overall combined sensitivity and specificity for DCLK1 in distinguishing malignant tumors were 0.58 and 0.90, respectively. The mean diagnostic odds ratio was 12.70, and the corresponding area under the summary receiver operating characteristic curve was 0.78. In summary, our study indicated that DCLK1 could be a risk factor for development of malignant tumors and may serve as a promising diagnostic and prognostic biomarker for malignant tumors.

The value of targeting VEGFR (vascular endothelial growth factor receptor) drugs has demonstrated encouraging anti-cancer activity in advanced solid tumors within current clinical trials. This study aimed to serve as the first systemic review to assess their safety and efficacy according to biochemical characteristics of targeting VEGFR drugs in gastric cancer. We analyzed eight clinical trials on targeting VEGFR drugs in gastric cancer. Results showed that targeting VEGFR drugs significantly improved overall survival (OS) [Hazard Ratio (HR) 0.69, 95% confidence interval (CI) (0.55, 0.83), P < 0.001], progression free survival (PFS) [HR 0.50, 95% CI (0.34, 0.66), P < 0.001], disease control rate (DCR) [Odds Ratio (OR) 3.83, 95% CI (2.39, 6.15), P < 0.001] and significantly decreased the progressive disease rate(PDR)[OR 0.45, 95% CI (0.34, 0.59), P < 0.001], but not objective response rate (ORR) [OR 1.46, 95% CI (0.93, 2.29), P = 0.098]. Further subgroup revealed that VEGFR antibody (VEGFR-Ab) drugs were superior to VEGFR tyrosine kinase inhibitor (VEGFR-TKI) drugs in terms of the OS, PFS and PDR. To determine the toxic effect of targeting VEGFR drugs, the relative risk of adverse events (grade ≥ 3) of special interest(AESIs) were estimated. Most of these were predictable and manageable. Furthermore, less AESIs were observed in the VEGFR-Ab than the VEGFR-TKI drugs. In conclusion, VEGFR drugs were effective targeted therapy in advanced or metastatic gastric cancer, and its toxicity is within a controllable range. VEGFR-Ab drugs were more effective than VEGFR-TKI drugs in terms of the OS, PFS and PDR of gastric cancer patients with little toxicity.

Stathmin has been investigated to be involved in development and progress of malignant tumors. This study was to clarify the relationship between expression of stathmin and tumors and assess its clinical significance. We identified 25 studies with a total of 3,571 individuals from the electronic bibliographic databases and strictly evaluated the quality and heterogeneity of included studies. We analysed the relationship between expression of stathmin and clinical characteristics by the fixed-effects and random-effects of meta-analysis and constructed a summary receiver-operator characteristic curve to estimate the test characteristics. The results showed that patients with cancer displayed a higher stathmin expression than those of non-cancer individuals (OR, 0.31), and overexpression of stathmin correlated with tumor cell differentiation (OR, 0.73), lymph node invasion (OR, 0.80) and high TNM stage (OR, 0.67). The pooled sensitivity of stathmin for distinguishing malignant tumors was 0.73 and the specificity was 0.77. The maximum balance joint for sensitivity and specificity (the Q-value) was 0.7566 and the area under the curve (AUC) was 0.8234. In conclusion, these results showed that overexpression of stathmin intimately correlated with malignant behavior of tumors, suggesting it could be a risk factor of malignant tumors. Stathmin had great sensitivity and specificity indicated it should be a significant molecular biomarker for malignant tumors.

Some studies have reported an association between the Methylenetetrahydrofolate reductase (MTHFR) C667T genetic variant and risk of polycystic ovary syndrome (PCOS), although the results remain controversial. A systematic search was conducted on PubMed, Web of Science, EMBASE, Ovid, Chinese National Knowledge Databases and WanFang databases with relevant keywords. Fourteen studies of sixteen distinct populations involving 1478 PCOS cases and used to conduct a meta-analysis. The T allele was not significantly associated with increased risk of PCOS [OR: 1.08; 95% CI: 0.96-1.21]. In the stratified analysis by ethnicity, the T allele significantly increases risks for the Asian [OR = 1.31; 95% CI: 1.09-1.58] population. No significant associations were detected for the Middle Eastern population [OR = 1.26; 95% CI: 0.96-1.67] and the T allele was found to be protective in the Caucasian population [OR = 0.82; 95% CI: 0.68-0.99]. In conclusion, this meta-analysis suggests that MTHFR C667T variant can increase, decrease, or have no effect on the risks of PCOS depending on the ethnicity.

KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.

D-dimer, one of the canonical markers of hypercoagulability, was reported to be a potential prognostic marker of colorectal cancer. However, an inconsistent conclusion existed in several published studies. Thus, we performed this meta-analysis to provide a comprehensive insight into the prognostic role for pretreatment D-dimer in colorectal cancer. Six databases (English: Pubmed, Embase and Web of Science; Chinese: CNKI, Wangfang and VIP) were utilized for the literature retrieval. Hazard ratio (HR) was pooled by Stata 12.0. A total of fifteen studies (2283 cases) corresponded to this meta-analysis and provided available data to evaluate the prognostic role of D-dimer for colorectal cancer. The pooled HR reached 2.167 (95%. CI (confidence interval): 1.672-2.809, P < 0.001) utilizing random effect model due to obvious heterogeneity among the included studies (I2: 73.3%; P < 0.001). To explore the heterogeneity among the studies, we conducted a sensitivity analysis and found a heterogeneous study. After removing it, the heterogeneity reduced substantially (I2: 0%; P = 0.549) and we obtained a more convincing result by fixed effect model (HR = 2.143, 95% CI = 1.922-2.390, P < 0.001, 14 studies with 2179 cases). In summary, high pretreatment plasma D-dimer predicts poor survival of colorectal cancer based on the current evidence. Further prospective researches are necessary to confirm the role of D-dimer in colorectal cancer.

Transducin (β)-like 1 X-linked receptor 1(TBL1XR1) has been reported to be overexpressed in various human cancers, as well as contributing to carcinogenesis and progression. This synthetic analysis was performed to assess whether TBL1XR1 protein could act as a potential prognostic molecular marker for human cancers. Several online databases (PubMed, Web of Science, Embase together with Wanfang and China National Knowledge Internet database) were retrieved to identify TBL1XR1-related publications. A total of ten studies with 1837 cancer patients were included in this meta-analysis. Hazard ratios (HR) with 95% confidence intervals (CI) were applied to assess the association between TBL1XR1 expression and cancer prognosis. Odds ratios (OR) were calculated to determine the relationship between TBL1XR1 expression and clinicopathological characteristics. The overall results revealed that the overexpression of TBL1XR1 was correlated with poorer overall survival (OS) (HR: 1.77, 95% CI: 1.49-2.06, p < 0.001) and worse disease-free survival (DFS) (HR: 1.51, 95% CI: 1.19-1.84, p < 0.001) in human solid cancers. Statistical significance for OS was also found in subgroup analysis stratified by the cancer type, analysis method and follow-up time. Furthermore, elevated TBL1XR1 was associated with unfavorable clinicopathological characteristics including tumor size, depth of invasion, lymph node metastasis and TNM stage. Our meta-analysis suggested that TBL1XR1 might be served as a novel and promising biomarker to predict prognosis and clinicopathologic characteristic for cancer patients.

As a common antagonist of Wnt/β-catenin signaling, Wnt inhibitory factor 1 (WIF1) plays an important role in the tumor progression. The aim of our meta-analysis was to summarize the diagnostic value of WIF1 methylation in colorectal cancer (CRC). Eligible studies were retrieved by a systemic search among PubMed, Embase, CNKI, and Wanfang literature databases. The diagnostic value of WIF1 methylation for CRC was assessed by the summary receiver operating characteristics (SROC) test. Our meta-analysis of 12 studies between 1420 CRC samples and 946 control samples showed that WIF1 hypermethylation was significantly associated with CRC (P < 0.001, OR = 30.10, 95% CI = 19.48-46.50). WIF1 hypermethylation, as a diagnostic biomarker for CRC, has a pooled sensitivity of 0.40 (95% CI: 0.37-0.42), a pooled specificity of 0.95 (95% CI: 0.93-0.96), a pooled positive-likelihood ratio (PLR) of 8.65 (95% CI, 4.47-16.73), and a pooled negative-likelihood ratio (NLR) of 0.41 (95% CI, 0.30-0.55), a diagnostic odds ratio (DOR) of 26.86 (95% CI: 15.73-45.89), and an area under the curve (AUC) of 0.9115. In conclusion, our study established that WIF1 hypermethylation might be a promising diagnostic biomarker for CRC.

Some studies have reported an association between the zinc-finger protein 350 (ZNF350), also known as zinc-finger and BRCA1-interacting protein with a Kruppel-associated box (KRAB) domain (ZBRK1), and risks of breast cancer, although the results remain controversial. A systematic search was conducted on PubMed, Web of Science, EMBASE, Ovid, Chinese National Knowledge Databases, and WanFang databases with relevant keywords. Four studies of five distinct populations involving 5824 breast cancer cases were used to conduct a meta-analysis that summarizes the current evidence of 5 genetic polymorphisms: Asp35Asp, Leu66Pro, Pro373Pro, Ser472Pro, and Ser501Arg in the ZNF350 gene. The T allele in Asp35Asp polymorphisms not significantly associated with increased risk of breast cancer (OR: 1.08; 95% CI: 0.96-1.21). The minor C allele of the Asp35Asp polymorphism is protective in the overdominant model (OR = 1.14; 95% CI: 1.02-1.28). The Pro allele in the Leu66Pro polymorphism is protective in all of the models examined (allelic, dominant, recessive, and overdominant). The Pro373Pro is not associated with breast cancer in all of the models tested. The Pro allele of the Ser472Pro polymorphism is protective using the dominant model (OR = 0.10; 95% CI: 0.04-0.23) but deleterious using the overdominant model (OR = 1.14; 95% CI: 1.02-1.28). The Ser501Arg polymorphism is deleterious only when using the recessive model (OR = 1.21; 95% CI: 1.02-1.44). In conclusion, this meta-analysis suggests that genetic polymorphisms in the ZNF350 variant can increase, decrease, or have no effect on the risks of breast cancer depending on the polymorphism and genetic model used. Further studies will be required to validate these findings.

This meta-analysis of 23 eligible articles comprehensively and quantitatively evaluated the effects of tumor necrosis factor-α (TNF-α) rs1800629 and rs361525 polymorphisms on sepsis risk. We found that TNF-α rs1800629 was associated with increased sepsis risk in the overall population in four genetic models, including A vs. G (P<0.001, odds ratio (OR)=1.32), GA vs. GG (P<0.001, OR=1.46), GA+AA vs. GG (P<0.001, OR=1.46), and carrier A vs. carrier G (P<0.001, OR=1.32). Subgroup analyses showed a similar result for Asian patients (all P<0.05, OR>1). TNF-α rs361525 was also associated with increased sepsis risk in Asian patients in the four genetic models (all P<0.05, OR>1). Begg's and Egger's tests excluded large publication bias, and sensitivity analysis indicated stable results. Our results suggest that the G/A genotype of TNF-α rs1800629 and rs361525 increases sepsis risk in an Asian population.

We attempted to explore the prevalence of HBV and HCV infections in patients with systemic lupus erythematous (SLE) via a systematic review. Articles published before June 2017 and, related to prevalence rates for HBV and HCV infection in SLE patient were identified in PubMed, Embase, CNKI, and Wanfang databases. Based on these searches 22 studies were selected for further analysis. The OR of HBsAg positive rate in SLE patients compared with control population was 0.28, with significant heterogeneity identified among the studies (I2 = 92%, P < 0.00001). Following exclusion of one study, the adjusted OR of HBsAg in patients with SLE was 0.24, and no significant heterogeneity was observed (I2 = 32%, P = 0.15). The adjusted OR of HBcAb positive rate in SLE patients compared with control population was 0.40, with no significant heterogeneity between studies (I2 = 0%, P = 0.56). The risk of having HCV infection by SLE patients was higher compared with the control subjects (OR = 2.91). In conclusion, this meta-analysis suggested that SLE might exert a role of protection against HBV but not for HCV infection. Further epidemiological and experimental studies are necessary to explore the role and mechanisms by which SLE affects HBV/HCV infections.

The inflammatory potential of diet has been inconsistently linked to colorectal cancer (CRC) risk. This meta-analysis aimed to evaluate the association of the inflammatory potential of diet, as estimated by the dietary inflammatory index (DII) score, with CRC risk.

MicroRNA-494 was revealed as an attractive prognostic biomarker in recent studies. Nevertheless, the prognostic value of microRNA-494 in cancers remains controversial. Current meta-analysis aims to elucidate the precise predictive value of microRNA-494 in various cancers. Eligible studies were identified through multiple search strategies, the hazard ratios (HRs) and their confidence interval (CI) for patient prognostic outcomes were extracted and estimated. The pooled results of fifteen studies indicated that elevated expression of microRNA-494 implies a good overall survival of cancer patients (HR = 0.58, 95% CI: 0.36-0.91); While no significant association was found between the high expression of microRNA-494 and clinicopathological characteristic. Additionally, subgroup analysis revealed that overexpression of microRNA-494 predicted a worse overall survival in non-small cell lung cancer (HR = 2.35, 95% CI: 1.05-5.24) and colorectal cancer (HR = 2.59, 95% CI: 1.62-4.14). As per the subgroup analysis, the cancer type, the anatomy system classification and the ethnic background had influence on the overall survival result. Our findings indicate that elevated expression of microRNA-494 might predict a good overall survival in most cancers, while in non-small cell lung cancer and colorectal cancer, overexpression of microRNA-494 might predict a worse overall survival.

Glucose transporter 1 (GLUT1) plays an important role in the transport and metabolism of glucose in cancer cells. An increasing number of studies have explored the connection between GLUT1 expression and prognosis in non-small cell lung cancer (NSCLC), but the results have been controversial. Therefore, we conducted a meta-analysis to obtain a comprehensive evaluation of the prognostic value of GLUT1 in NSCLC. Relevant studies from PubMed, Embase, and Web of Science were searched. Hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were used as the effective measures. A total of 10 studies involving 1,665 patients were included in this meta-analysis. The results showed that GLUT1 overexpression was associated with poor overall survival (HR = 2.21; 95% CI, 1.42-3.42; p < 0.001) and disease-free survival (HR = 1.73; 95% CI, 1.35-2.23; p < 0.001). Furthermore, elevated GLUT1 expression correlated with sex (OR = 2.29; 95% CI, 1.17-4.49; p = 0.015), advanced tumor stage (OR = 2.46; 95% CI, 1.79-3.38; p < 0.001), histology (OR = 6.99; 95% CI, 4.71-10.38; p < 0.001), and large tumor size (OR = 2.77; 95% CI, 1.73-4.44; p < 0.001). This meta-analysis revealed overexpression of GLUT1 to be a biomarker of worse prognosis in NSCLC.

Excess body weight has a positive association with risk of liver cancer, but the gender difference in the relationship between body mass index and liver cancer risk remains uncertainty. In this work, we performed meta-analysis for excess body weight and risk of liver cancer incidence to identify the gender difference. We searched the English-languages database and the Chinese literature databases to May 12, 2017. Overall, a total of 17 studies were included. Relative risks (RRs) with 95% confidence intervals was used to evaluate the strength of these associations. The RRs of liver cancer incidence for obese men and women were 2.04 (1.70-2.44) and 1.56 (1.37-1.78). The former one was significantly higher than the later one (P for interaction = 0.02). Notably, the RR of liver cancer incidence in non-Asian obese men was even higher than their counter part (2.31(1.85-2.91) vs. 1.56 (1.31-1.86), P for interaction = 0.01). Similar gender difference was observed in the dose-response curve. As example, at the point of BMI = 32 kg/m2, the RRs for men and women were 1.61 (1.45-1.79) and 1.41 (1.02-1.94) respectively. Findings from this meta-analysis indicate that obesity is associated with a higher risk of liver cancer incidence in men, especially in non-Asian men, which might partially contribute to the male dominance of liver cancer incidence.

In numerous studies, Flotillin-1 was reported to be involved in tumor progression, indicating prognosis in various types of cancer. However, the results were inconsistent.

CXC chemokine receptor-2 (CXCR2) expression is associated with the prognosis of multiple cancers. We performed a meta-analysis to determine the association between the CXCR2 expression in tumor tissue and patient prognosis. We compiled related literature from PubMed, Embase, and Web of Science (last updated July 31, 2017). A total of 4012 patients with solid tumors from 21 studies were included to evaluate the association between CXCR2 and overall survival, recurrence-free survival, or disease-free survival. High CXCR2 expression was significantly associated with poor overall survival (pooled HR = 1.82; 95% CI = 1.63-2.03; P < 0.001), recurrence-free survival (pooled HR = 1.40; 95% CI = 1.21-1.62; P < 0.001), and disease-free survival (pooled HR = 1.89; 95% CI = 1.05-3.40; P = 0.033), especially in patients with digestive system neoplasms. Thus high CXCR2 expression in tumor tissue appears predictive of a poor prognosis in patients with solid tumors. Further studies will be required to determine whether CXCR2 blockade has a favorable effect on the prognosis of patients with cancer.

The objective of this study was to provide an up-to-date summary of the current evidence that may be useful for updating guidelines. We comprehensively searched the published literatures and conferences for studies that compared curative with palliative treatments in colorectal cancer patients with peritoneal metastasis. The primary outcomes considered in this study were three- and five-year overall survival rates. We pooled data across studies and estimated summary effect sizes. Overall, patients who received curative treatments had improved three-year survival (hazard ratio (HR), 2.19 [95% CI, 1.83 to 2.62]) and five-year survival (HR, 2.22 [95% CI, 1.83 to 2.69]) compared with those who received palliative treatments. Patients who received curative treatments had an increased risk of treatment-related morbidity (odds ratio (OR), 2.90 [95% CI, 2.02 to 4.17]), but there was no significant difference in treatment-related mortality between patients who received curative treatments and those who received palliative treatments (OR, 1.46 [CI, 0.62 to 3.47]). Curative treatments improved overall survival in colorectal cancer patients with peritoneal metastasis and did not increase the risk of treatment-related mortality. Curative treatments were associated with a higher risk of treatment-related morbidity. These data highlight the importance for further investigation aimed at prevention of treatment-associated morbidity.