Overexpression of MMP Family Members Functions as Prognostic Biomarker for Breast Cancer Patients: A Systematic Review and Meta-Analysis

Background

Matrix metalloproteinases (MMPs) are regarded to be relevant to the prognosis of breast cancer. Numerous studies have confirmed the association between MMPs and tumor growth, invasion and metastasis in breast cancer. However, their prognostic values for survival in patients with breast cancer remain controversial. Hence, a meta-analysis was performed to clarify a more accurate estimation of the role of MMPs on prognosis of breast cancer patients.

Method

A systemic electronic search was conducted in PubMed, Embase and Web of science databases to identify eligible studies, which were associated with the relationship between MMPs and prognosis of breast cancer. The correlation in random-effect model was evaluated by using the hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

A total of 28 studies covering 4944 patients were included for meta-analysis. A summary hazard ratio (HR) of all studies was calculated, as well as the sub-group HRs. The combined HRs calculated by either univariate or multivariate analysis both suggested that overexpression of MMPs had an unfavorable impact on overall survival (OS) (HR = 1.694, 95%CI: 1.347–2.129, P < 0.001; HR = 1.611, 95%CI: 1.419–1.830, P < 0.001, respectively). And the univariate analysis showed that patients with overexpression of MMPs had worse relapse-free survival (RFS) (HR = 1.969, 95%CI: 1.460–2.655, P < 0.001) in all eligible studies. In the sub-group analyses, HRs of MMP-9 positivity with poor OS were 1.794 (95%CI: 1.330–2.420, P < 0.001) and 1.709 (95%CI: 1.157–2.526, P = 0.007) which were separately evaluated by univariate and multivariate analysis. A small number of articles demonstrated that MMP-2 overexpression was not related with shorter OS (HR = 1.400, 95%CI: 0.610–3.029, P = 0.427). Four studies included in the OS analysis of MMPs expression in serum suggested that positive expression of serum MMPs may be an unfavorable factor (HR = 1.630, 95%CI: 1.065–2.494) for breast cancer patients. No publication bias was observed in the current meta-analysis.

Conclusions

Our findings suggested that MMPs overexpression (especially MMP-9, MMP-2, MMPs overexpression in serum) might indicate a higher risk of poor prognosis in breast cancer. Larger prospective studies are further needed to estimate the prognostic values of MMPs overexpression.     

PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC

IntroductionImmune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC.MethodsA tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression.ResultsOf 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36–0.94, p = 0.031; HR 0.46, 95%CI 0.26–0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50–0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%).ConclusionPD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.     

The Prognostic Significance of Wnt-5a Expression in Primary Breast Cancer Is Extended to Premenopausal Women

Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33–0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51–5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.     

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

Objective

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

Methods

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

Results

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

Conclusions

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

Astrocyte Elevated Gene-1 as a Novel Clinicopathological and Prognostic Biomarker for Gastrointestinal Cancers: A Meta-Analysis with 2999 Patients

Background

There have been numerous articles as to whether the staining index (SI) of astrocyte elevated gene-1 (AEG-1) adversely affects clinical progression and prognosis of gastrointestinal cancers. Nevertheless, controversy still exists in terms of correlations between AEG-1 SI and clinicopathological parameters including survival data. Consequently, we conducted a comprehensive meta-analysis to confirm the role of AEG-1 in clinical outcomes of gastrointestinal carcinoma patients.

Methods

We performed a comprehensive search in PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, EMBASE, Science Direct, Wiley Online Library, China National Knowledge Infrastructure (CNKI), WanFang and Chinese VIP databases. STATA 12.0 (STATA Corp., College, TX) was used to analyze the data extracted from suitable studies and Newcastle-Ottawa Scale was applied to assess the quality of included articles.

Results

The current meta-analysis included 2999 patients and our results suggested that strong associations emerged between AEG-1 SI and histological differentiation (OR = 2.129, 95%CI: 1.377–3.290, P = 0.001), tumor (T) classification (OR = 2.272, 95%CI: 1.147–4.502, P = 0.019), lymph node (N) classification (OR = 2.696, 95%CI: 2.178–3.337, P<0.001) and metastasis (M) classification (OR = 3.731, 95%CI: 2.167–6.426, P<0.001). Furthermore, high AEG-1 SI was significantly associated with poor overall survival (OS) (HR = 2.369, 95%CI: 2.005–2.800, P<0.001) and deteriorated disease-free survival (DFS) (HR = 1.538, 95%CI: 1.171–2.020, P = 0.002). For disease-specific survival (DSS) and relapse-free survival (RFS), no statistically significant results were observed (HR = 1.573, 95%CI: 0.761–3.250, P = 0.222; HR = 1.432, 95%CI: 0.108–19.085, P = 0.786). Subgroup analysis demonstrated that high AEG-1 SI was significantly related to poor prognosis in esophageal squamous cell carcinoma (ESCC) (HR = 1.715, 95%CI: 1.211–2.410, P = 0.002), gastric carcinoma (GC) (HR = 2.255, 95%CI: 1.547–3.288, P<0.001), colorectal carcinoma (CRC) (HR = 2.922, 95%CI: 1.921–4.444, P<0.001), gallbladder carcinoma (GBC) (HR = 3.047, 95%CI: 1.685–5.509, P<0.001), hepatocellular carcinoma (HCC) (HR = 2.245, 95%CI: 1.620–3.113, P<0.001), pancreatic adenocarcinoma (PAC) (HR = 2.408, 95%CI: 1.625–3.568, P<0.001).

Conclusions

The current meta-analysis indicated that high AEG-1 SI might be associated with tumor progression and poor survival status in patients with gastrointestinal cancer. AEG-1 might play a vital role in promoting tumor aggression and could serve as a potential target for molecular treatments. Further clinical trials are needed to validate whether AEG-1 SI provides valuable insights into improving treatment decisions.     

Prognostic Value of Basic Fibroblast Growth Factor (bFGF) in Lung Cancer: A Systematic Review with Meta-Analysis

Background

Basic fibroblast growth factor (bFGF) is known to stimulate angiogenesis and thus to influence the proliferation, migration and survival of tumor cells. Many studies examined the relationship between human bFGF overexpression and survival in lung cancer patients, but the results have been mixed. To systematically summarize the clinical prognostic function of bFGF in lung cancer, we performed this systematic review with meta-analysis.

Method

Studies were identified by an electronic search of PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang databases, including publications prior toAugust 2014. Pooled hazard ratios (HR) for overall survival (OS) were aggregated and quantitatively analyzed by meta-analysis.

Results

Twenty-two studies (n = 2154) were evaluated in the meta-analysis. Combined HR suggested that bFGF overexpression had an adverse impact on survival of patients with lung cancer(HR = 1.202,95%CI, 1.022–1.382). Our subgroup analysis revealed that the combined HR evaluating bFGF expression on OS in operable non-small cell lung cancer (NSCLC) was 1.553 (95%CI, 1.120–1.986); the combined HR in small cell lung cancer (SCLC) was 1.667 (95%CI, 1.035–2.299). There was no significant impact of bFGF expression on survival in advanced NSCLC.

Conclusion

This meta-analysis showed that bFGF overexpression is a potential indicator of worse prognosis for patients with operable NSCLC and SCLC, but is not associated with outcome in advanced NSCLC. The data suggests that high bFGF expression is highly related to poor prognosis. Nevertheless,more high-quality studies should be performed in order to provide additional evidence for the prognostic value of bFGF in lung cancer.     

Prognostic Value,Clinicopathologic Features and Diagnostic Accuracy of Interleukin-8 in Colorectal Cancer: A Meta-Analysis

Background

The prognostic value and diagnostic accuracy of Interleukin-8 (IL-8) in colorectal cancer have been assessed with several studies, but the conclusions were inconclusive. Thus we performed a meta-analysis to evaluate the impact of IL-8 expression on colorectal cancer prognosis, clinicopathologic features and diagnostic accuracy.

Methods

Comprehensive search strategies were used to search relevant literature in the PubMed, EBSCO and the ISI Web of Science databases. The correlation between IL-8 expression and prognosis, clinicopathologic features and diagnostic accuracy was analyzed.

Results

A total of 18 articles met the inclusion criteria, including 1509 patients for clinicopathologic features or prognosis evaluation and 725 participants for diagnostic evaluation. The results suggested that overexpression of IL-8 was significantly associated with poor prognosis in colorectal cancer (HR = 1.54, 95%CI 1.03–2.32), especially in Union for International Cancer Control (UICC) stage IV patients (HR = 2.28, 95%CI 1.60–3.25). With further subgroup analysis, we found that high IL-8 level in serum was significantly correlated with poor prognosis (HR = 2.13, 95%CI 1.49–3.05). In addition, significant correlations were observed between high IL-8 expression and advanced stage (OR = 3.01, 95%CI 1.98–4.56), lymphatic metastasis (OR = 2.24, 95%CI 1.39–3.63), and liver metastasis (OR = 3.47, 95%CI 1.74–6.89). Moreover, IL-8 had high diagnostic accuracy, with pooled sensitivity 0.70(95%CI 0.66–0.74), specificity 0.91(95%CI 0.86–0.94), positive likelihood ratio (LR) 7.00(95%CI 2.48–19.73), negative LR 0.24(95%CI 0.09–0.64), diagnostic OR 24.00(95%CI 5.52–104.38).

Conclusions

This study showed that IL-8 could be a potential indicator for detecting colorectal cancer and predicting prognosis. In addition, high IL-8 level was significantly correlated with advanced stage, lymphatic metastasis, liver metastasis.     

The Prognostic Value of Decreased LKB1 in Solid Tumors: A Meta-Analysis

BackgroundLiver kinase B1 (LKB1) is a protein kinase that regulates the growth, integrity and polarity of mammalian cells. Recent studies have reported the prognostic value of decreased LKB1 expression in different tumors. However, the results of these studies remain controversial. Therefore, this meta-analysis was performed to more accurately estimate the role of decreased LKB1 in the prognostication of human solid tumors.MethodsA systematic literature search in the electronic databases PubMed, Embase, Web of Science and CNKI (updated to October 15, 2015) was performed to identify eligible studies. The overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and clinicopathological features data were collected from these studies. The hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and pooled with a random-effects models using Stata12.0 software.ResultsA total of 14 studies covering 1915 patients with solid tumors were included in this meta-analysis. Decreased LKB1 was associated with poorer OS in both the univariate (HR: 1.86, 95%CI: 1.42–2.42, P<0.001) and multivariate (HR: 1.55, 95%CI: 1.09–2.21, P = 0.015) analyses. A subgroup analysis revealed that the associations between decreased LKB1 and poor OS were significant within the Asian region (HR 2.18, 95%CI: 1.66–2.86, P<0.001) and obvious for lung cancer (HR: 2.16, 95%CI: 1.47–3.18, P<0.001). However, the articles that involved analyses of both RFS and DFS numbered only 3, and no statistically significant correlations of decreased LKB1 with RFS or DFS were observed in this study. Additionally, the pooled odds ratios (ORs) indicated that decreased LKB1 was associated with larger tumor size (OR: 1.60, 95%CI: 1.09–2.36, P = 0.017), lymph node metastasis (OR: 2.41, 95%CI: 1.53–3.78, P<0.001) and a higher TNM stage (OR: 3.35, 95%CI: 2.20–5.09, P<0.001).ConclusionThese results suggest that decreased LKB1 expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognostic factors. Additional studies are required to verify the clinical utility of decreased LKB1 in solid tumors.     

The impact of chemokine receptor CXCR4 on breast cancer prognosis: A meta-analysis

Background: C-X-C chemokine receptor type 4 (CXCR4) has been implicated in the invasiveness and metastasis of diverse cancers. However, the published data remain controversial on the correlation between CXCR4 expression level, as well as its subcellular distribution in tumor cells, and the clinical outcome of patients with breast cancer. Methods: To identify the precise role of CXCR4 in the clinical outcome of breast cancer, we performed a meta-analysis including 15 published studies. Original data included the hazard ratios (HRs) of overall survival (OS) and disease-free survival (DFS) in breast cancer with high CXCR4 expression versus low expression. We pooled hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the hazard. Results: A total of 15 published studies (including 3104 patients) were eligible. Overall survival (OS) and disease-free survival (DFS) of breast cancer were found to be significantly related to CXCR4 expression level, with the HR being 1.65 (95%CI: 1.34–2.03; P < 0.00001) and 1.94 (95%CI: 1.42–2.65; P < 0.00001) respectively. Stratified analysis according to subcellular distribution of CXCR4 showed that high expression in whole cells, cytoplasm and nucleus could predict unfavorable OS, with the HR of 2.02 (95%CI: 1.43–2.85; P < 0.0001), 1.57 (95%CI: 1.13–2.18; P = 0.007), and 1.47 (95%CI: 1.19–1.81; P = 0.0004) respectively. As for DFS, elevated expression level of CXCR4 both in whole cells and cytoplasm predicted a poor outcome, with the HR being 2.23 (95%CI: 1.48–3.37; P = 0.0001) and 1.76 (95%CI: 1.11–2.80; P = 0.02), while high expression in the nucleus had no statistical significance, with HR 1.15 (95%CI: 0.52–2.55; P = 0.73). Conclusions: Increased CXCR4 expression, especially in whole cells and cytoplasm, may serve as a poor prognostic indicator in patients with breast cancer. Future studies are warranted to investigate the relationship between CXCR4 expression and survival of patients with breast carcinoma, which could help predict the clinical outcome and guide clinical decision-making for therapy.     

High Expression of KIF26B in Breast Cancer Associates with Poor Prognosis

To date, a great number of studies have demonstrated that altered expression of kinesins is associated with development and progression of various human cancers. Kinesin family member 26B (KIF26B), a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. However, the role of KIF26B during tumorigenesis and progression is limited. Here, we demonstrate that both KIF26B mRNA and protein are overexpression in breast cancer tissues by RT-qPCR and western blot. Immunohistochemistry revealed that KIF26B expression significantly correlated with clinicopathological factors, including tumor size (P = 0.011), grade (P = 0.017), lymph node status (P = 0.009) and ER status (P = 0.012). Moreover, the Kaplan-Meier analysis indicated that breast cancer patients with high KIF26B expression had a shorter survival than those with low KIF26B expression. In addition, multivariate analysis indicated that KIF26B is an independent prognostic for outcome in breast cancer (HR, 2.356; 95%CI, 1.268–4.378; P = 0.007). Collectively, our study demonstrated that KIF26B was overexpression in breast cancer and could be served as a potential prognostic marker.     

Metabolic Syndrome and Breast Cancer Risk: A Case-Cohort Study Nested in a Multicentre Italian Cohort

Background

Metabolic syndrome (defined as at least three among abdominal obesity, high blood triglycerides, low high-density lipoprotein cholesterol, high blood glucose, and high blood pressure) is emerging as a risk factor for breast cancer; however few studies – most confined to postmenopausal women – have investigated associations between breast cancer risk and metabolic syndrome. The purpose of this study was to examine the association between metabolic syndrome and its components, and risk of breast cancer in postmenopausal and premenopausal women.

Methods

We performed a case-cohort study on 22,494 women recruited in 1993-1998 to four Italian centres (Turin, Varese, Naples, Ragusa) of the European Prospective Investigation into Cancer and Nutrition (EPIC) and followed-up for up to 15 years. A random subcohort of 565 women was obtained and 593 breast cancer cases were diagnosed. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Prentice-weighted Cox proportional hazards models.

Results

Presence of metabolic syndrome was associated with significantly increased breast cancer risk in all women (HR 1.52, 95%CI 1.14-2.02). When the analyses were repeated separately for menopausal status, the association was limited to postmenopausal women (HR 1.80, 95%CI 1.22-2.65) and absent in premenopausal women (HR 0.71, 95%CI 0.43-1.16); P for interaction between metabolic syndrome and menopausal status was 0.001. Of metabolic syndrome components, only high blood glucose was significantly associated with increased breast cancer risk in all women (HR 1.47, 95%CI 1.13-1.91) and postmenopausal women (HR 1.89, 95%CI 1.29-2.77), but not premenopausal women (HR 0.80, 95%CI 0.52-1.22; P interaction=0.004).

Conclusions

These findings support previous data indicating that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women, but not in premenopausal women, and suggest that prevention of metabolic syndrome through lifestyle changes could confer protection against breast cancer.     

Molecular Marker Identification for Relapse Prediction in 5-FU-Based Adjuvant Chemotherapy in Gastric and Colorectal Cancers

To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(−) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2–43.4; JNK(−), p = 0.0302, HR4.4, 95%CI 1.2–16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2–426.0; JNK(−), p = 0.0098, HR3.2, 95%CI 1.3–7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.     

Incidence of Cancer in ANCA-Associated Vasculitis: A Meta-Analysis of Observational Studies

ObjectiveThe purpose of this paper is to examine cancer incidence in patients with ANCA-associated vasculitis (AASV) derived from population-based cohort studies by means of meta-analysis.MethodsRelevant electronic databases were searched for studies characterizing the associated risk of overall malignancy in patients with AASV. Standardized incidence rates (SIRs) with 95% confidence intervals (CIs) were used to evaluate the strength of association. We tested for publication bias and heterogeneity and stratified for site-specific cancers.ResultsSix studies (n = 2,578) were eventually identified, of which six provided the SIR for overall malignancy, five reported the SIR for non-melanoma skin cancer (NMSC), four for leukemia, five for bladder cancer, three for lymphoma, three for liver cancer, four for lung cancer, three for kidney cancer, four for prostate cancer, four for colon cancer and four for breast cancer. Overall, the pooled SIR of cancer in AASV patients was 1.74 (95%CI = 1.37–2.21), with moderate heterogeneity among these studies (I² = 65.8%, P = 0.012). In sub-analyses for site-specific cancers, NMSC, leukemia and bladder cancer were more frequently observed in patients with AASV with SIR of 5.18 (95%CI = 3.47–7.73), 4.89 (95%CI = 2.93–8.16) and 3.84 (95%CI = 2.72–5.42) respectively. There was no significant increase in the risk of kidney cancer (SIR = 2.12, 95%CI = 0.66–6.85), prostate cancer (SIR = 1.45, 95%CI = 0.87–2.42), colon cancer (SIR = 1.26, 95%CI = 0.70–2.27), and breast cancer (SIR = 0.95, 95%CI = 0.50–1.79). Among these site-specific cancers, only NMSC showed moderate heterogeneity (I² = 55.8%, P = 0.06). No publication bias was found by using the Begg’s test and Egger''s test.ConclusionsThis meta-analysis shows that AASV patients treatment with cyclophosphamide (CYC) are at increased risk of late-occurring malignancies, particularly of the NMSC, leukemia and bladder cancer. However, there is no significant association between AASV and kidney cancer, prostate cancer, colon cancer and breast cancer. These findings emphasize monitoring and preventative management in AASV patients after cessation of CYC therapy is momentous.     

LncRNA AWPPH as a prognostic predictor in human cancers in Chinese population: evidence from meta-analysis

Background: Long non-coding RNA associated with poor prognosis of hepatocellular carcinoma (AWPPH) is dysregulated in a variety of human cancers. However, the prognostic value of AWPPH in various cancers remains unclear.Methods: Comprehensive literature search was performed in PubMed, Web of Science, CNKI and Wangfang databases, and eligible studies were obtained according to the inclusion and exclusion criteria. The pooled hazard ratios (HRs) and odds ratios (ORs) were applied to assess the clinical value of AWPPH expression for overall survival (OS) and clinicopathological features.Results: A total of 19 articles including 1699 cancer patients were included in the study. The pooled results demonstrated that evaluated AWPPH expression was positively related to a poorer overall survival of patients with cancers (HR = 1.79, 95%CI: 1.44–2.14, P<0.001). Subgroup analysis revealed that tumor type and sample size affect the predictive value of AWPPH on OS, whereas cut-off value and HR estimation method have no impact on it. In addition, the pooled data also showed that AWPPH was positively linked to advanced TNM stage (OR = 2.50, 95%CI: 1.94–3.22, P<0.001), bigger tumor size (OR = 2.64, 95%CI: 1.47–4.73, P=0.001), macro-vascular invasion (OR = 2.08, 95%CI: 1.04–4.16, P=0.04) and lymph node metastasis (OR = 2.68, 95%CI: 1.82–3.96, P<0.001). Moreover, the results of the trim and fill analysis confirmed the reliability of our finding.Conclusions: Up-regulation of AWPPH was associated with advanced TNM stage, bigger tumor size, worse lymph node metastasis, macro-vascular invasion and shorter overall survival, suggesting that AWPPH may serve as a biomarker for prognosis and clinicopathological characteristics in human cancers among the Chinese population.     

The Prognostic Value of Forkhead Box P3 Expression in Operable Breast Cancer: A Large-Scale Meta-Analysis

Background

Recent studies have shown that the forkhead box P3 (FOXP3) protein has a prognostic role in breast cancer. However, these results are controversial. Therefore, the aim of this meta-analysis was to clarify the prognostic role of FOXP3 expression in operable breast cancer cases.

Methods

Eligible studies describing the use of FOXP3 as a prognostic factor for operable breast cancer cases were identified. Clinicopathological features, disease-free survival (DFS), and overall survival (OS) data were collected from these studies and were analyzed using Stata software.

Results

A total of 16 articles containing data from 13,217 breast cancer patients met the inclusion criteria established for this study. The subsequent meta-analysis that was performed showed that high levels of FOXP3 are not significantly associated with DFS and OS with significant heterogeneity. An additional subgroup analysis demonstrated that intratumoral FOXP3+ regulatory T cells (Tregs) were positively correlated with adverse clinicopathological parameters, yet they did not show an association with DFS or OS. For tumor cells, the pooled results revealed that FOXP3 is significantly associated with DFS (HR: 2.55, 95% CI: 1.23–5.30) but is not associated with clinicopathological parameters or OS. We also observed a significant correlation between FOXP3 expression and survival in the estrogen receptor-positive (ER)+ subgroup (HR: 1.83, 95% CI: 1.36–2.47 for DFS, HR: 1.87, 95% CI 1.28–2.73 for OS), in the Asian region (HR: 1.98, 95% CI: 1.56–2.50 for DFS, HR: 1.93, 95% CI: 1.12–3.35 for OS) and using the median as the FOXP3-positive cut-off value (HR: 1.94, 95% CI: 1.57–2.39 for DFS, HR: 2.06; 95% CI: 1.36–3.11 for OS).

Conclusion

This meta-analysis indicates that a prognostic role for FOXP3 expression in operable breast cancer cases depends on the FOXP3-positive region, ER status, geographic region and the FOXP3-positive cut-off value.     

PD-L1 expression in anogenital and oropharyngeal squamous cell carcinomas associated with different clinicopathological features,HPV status and prognosis: a meta-analysis

Background: Little research has been done on clinicopathological characteristics and human papillomavirus (HPV) status of anogenital and oropharyngeal squamous cell carcinomas (SCC) with a strong expression of programmed death ligand 1 (PD-L1) in tumor cells. Therefore, we conducted this meta-analysis. Methods: We performed a comprehensive research in PubMed, Embase and Cochrane databases up to 30 September 2020. The effect size was hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS). The pooled odds ratio (OR) with 95% CI were used to assess the association between PD-L1 expression and clinicopathological features along with HPV status. Results: A total of 2003 cases (944 anogenital and 1059 oropharynx SCC patients) were included. High PD-L1 expression in anogenital SCC cases were associated with advanced age (OR = 1.63, 95% CI: 1.04–2.58) and HPV negativity (OR = 0.47, 95% CI: 0.31–0.71). Besides, PD-L1 positive anogenital SCC cases held a significantly declined OS (HR = 2.18, 95% CI: 1.37–3.47) and CSS (HR = 2.45, 95% CI: 1.30–4.65). For oropharynx SCC, PD-L1 was more frequent in younger and HPV positive patients (OR = 0.60, 95% CI: 0.37–0.98; OR = 3.01, 95% CI: 1.78–5.09) and PD-L1 expression was relevant to better OS and DFS (HR = 0.76, 95% CI: 0.60–0.97; HR = 0.50, 95% CI: 0.33–0.75). Conclusions: The meta-analysis demonstrated that in anogenital SCC, PD-L1 positivity had to do with a worse outcome, which might attribute to advanced age, higher tumor grade, lymph node metastasis and HPV negativity, while in oropharynx cancer, PD-L1 expression was related to better prognosis for the reason that PD-L1 was less frequent in the aged and negative HPV status.     

Expression and Prognostic Value of miR-486-5p in Patients with Gastric Adenocarcinoma

MicroRNA (miR)-486-5p expression is often reduced in human cancers. However, its expression in gastric carcinoma and its relation to clinicopathological features and prognosis are unclear. Tissue microarrays were constructed from 84 patients with gastric adenocarcinoma (GC) who were undergoing radical resection. miR-486-5p expression was detected by miRNA-locked nucleic acid in situ hybridization, and its correlations with clinicopathological features and overall survival were analyzed. Bioinformatic studies predict that fibroblast growth factor 9 (FGF9) is a potential target gene of miR-486-5p. miR-486-5p was mainly located in the cytoplasm of GC cells and neighboring normal tissues. Compared with paracancerous normal tissue, miR-486-5p expression was decreased in 63.1% (53/84) of the GC samples, increased in 32.1% (27/84) and unchanged in 4.8% (4/84). FGF9 expression was decreased in 69.0% (58/84) of GC samples and increased in 31.0% (26/84) compared with normal paracancerous tissues using immunohistochemical analysis. Low or unchanged miR-486-5p expression (P = 0.002), tumor stage (P = 0.001), tumor status (P = 0.001), node status (P = 0.001), tumor size (P = 0.004), and depth of tumor invasion (P = 0.013) were significant negative prognostic predictors for overall survival in patients with GC. After stratification according to American Joint Committee on Cancer (AJCC) stage, low/unchanged miR-486-5p expression remained a significant predictor of poor survival in stage II (P = 0.024) and stage III (P = 0.003). Cox regression analysis identified the following predictors of poor prognosis: tumor status (hazard ratio [HR], 7.19; 95% confidence interval [CI], 1.75–29.6; P = 0.006), stage (HR, 2.62; 95%CI, 1.50–4.59; P = 0.001), lymph node metastasis (HR, 2.52; 95% CI, 1.27–4.99; P = 0.008), low/unchanged miR-486-5p (HR, 2.47; 95% CI, 1.35–4.52; P = 0.003), high level of FGF9 (HR, 2.41; 95% CI, 1.42–4.09; P = 0.001) and tumor size (HR, 2.50; 95% CI, 1.30–4.82; P = 0.006). Low or unchanged expression of miR-486-5p compared with neighboring normal tissues was associated with a poor prognosis, while high expression was associated with a good prognosis in GC. miR-486-5p may thus be useful for evaluating prognosis and may provide a novel target treatment in patients with GC.     

Aberrant Keap1 methylation in breast cancer and association with clinicopathological features

Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. We determined methylation status of the KEAP1 promoter in 102 primary breast cancers, 14 pre-invasive lesions, 38 paired normal breast tissues and 6 normal breast from reductive mammoplasty by quantitative methylation specific PCR (QMSP). Aberrant promoter methylation was detected in 52 out of the 102 primary breast cancer cases (51%) and 10 out of 14 pre-invasive lesions (71%). No mutations of the KEAP1 gene were identified in the 20 breast cancer cases analyzed by fluorescence based direct sequencing. Methylation was more frequent in the subgroup of patients identified as ER positive-HER2 negative tumors (66.7%) as compared with triple-negative breast cancers (35%) (p = 0.05, Chi-square test). The impact of the interactions between Er, PgR, Her2 expression and KEAP1 methylation on mortality was investigated by RECPAM multivariable statistical analysis, identifying four prognostic classes at different mortality risks. Triple-negative breast cancer patients with KEAP1 methylation had higher mortality risk than patients without triple-negative breast cancer (HR = 14.73, 95%CI: 3.65–59.37). Both univariable and multivariable COX regressions analyses showed that KEAP1 methylation was associated with a better progression free survival in patients treated with epirubicin/cyclophosfamide and docetaxel as sequential chemotherapy (HR = 0.082; 95%CI: 0.007–0.934). These results indicate that aberrant promoter methylation of the KEAP1 gene is involved in breast cancerogenesis. In addition, identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.