Insufficient Milk Supply and Breast Cancer Risk: A Systematic Review

Background

An association between insufficient milk supply, the inability of a mother''s breast milk to provide sufficiently for her infant, and breast cancer has been suggested by observations in animal models. To determine if an association has been reported in epidemiological studies of human breast cancer, a systematic review of the literature has been conducted. We also sought to identify the methodological limitations of existing studies to guide the design of any future prospective studies in this field.

Methodology/Principal Findings

PubMed, EMBASE, Web of Science, BIOSIS, and CAB abstracts were searched. We selected any study that (1) assessed breast cancer in association with breastfeeding history and (2) examined the relationship between insufficient milk supply with breast cancer. Seven relevant studies were identified that met both criteria. There was statistically significant heterogeneity among the results which likely reflects clinically significant differences in definitions of insufficient milk supply and reference groups that were used. Among premenopausal women who had experienced insufficient milk supply, odds ratios (ORs) for breast cancer risk ranged from 0.9 to 16.3. Among postmenopausal women, ORs ranged from 0.6 to 6.7. Based on the range of odds ratios obtained in the studies reported in this review, it remains unclear if there is a true association between insufficient milk supply and breast cancer.

Conclusions/Significance

Although some studies have shown a strong positive association, there is no consistent evidence for an effect of insufficient milk supply on breast cancer risk. Exposure definitions are in need of improvement in order to focus on primary insufficient milk supply. Reference groups consisting of women who have successfully breastfed may also introduce positive bias (inflation of the odds ratio) into study results because of the protective effect of prolonged breastfeeding in the control group.     

The Association of RAS Association Domain Family Protein1A (RASSF1A) Methylation States and Bladder Cancer Risk: A Systematic Review and Meta-Analysis

RAS association domain family protein 1a (RASSF1A) is a putative tumor suppressor gene located on 3p21, has been regarded playing important roles in the regulation of different types of human tumors. Previous reports demonstrated that the frequency of RASSF1A methylation was significantly higher in patients group compared with controls, but the relationship between RASSF1A promoter methylation and pathological features or the tumor grade of bladder cancer remains controversial. Therefore, A meta-analysis of published studies investigating the effects of RASSF1A methylation status in bladder cancer occurrence and association with both pTNM (p, pathologic stage; T, tumor size; N, node status; M, metastatic status) and tumor grade in bladder cancer was performed in the study. A total of 10 eligible studies involving 543 cases and 217 controls were included in the pooled analyses. Under the fixed-effects model, the OR of RASSF1A methylation in bladder cancer patients, compared to non-cancer controls, was 8. 40 with 95%CI = 4. 96–14. 23. The pooled OR with the random-effects model of pTNM and tumor grade in RASSF1A methylated patients, compared to unmethylated patients, was 0. 75 (95%CI = 0. 28–1. 99) and 0. 39 (95%CI = 0. 14–1. 09). This study showed that RASSF1A methylation appears to be an independent prognostic factor for bladder cancer. The present findings also require confirmation through adequately designed prospective studies.     

Obesity and Risk of Colorectal Cancer: A Systematic Review of Prospective Studies

Background

Mounting evidence indicates that obesity may be associated with the risk of colorectal cancer (CRC). To conduct a systematic review of prospective studies assessing the association of obesity with the risk of CRC using meta-analysis.

Methodology/Principal Findings

Relevant studies were identified by a search of MEDLINE and EMBASE databases before January 2012, with no restrictions. We also reviewed reference lists from retrieved articles. We included prospective studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between general obesity [measured using body mass index (BMI)] or central obesity [measured using waist circumference (WC)] and the risk of colorectal, colon, or rectal cancer. Approximately 9, 000, 000 participants from several countries were included in this analysis. 41 studies on general obesity and 13 studies on central obesity were included in the meta-analysis. The pooled RRs of CRC for the obese vs. normal category of BMI were 1.334 (95% CI, 1.253–1.420), and the highest vs. lowest category of WC were 1.455 (95% CI, 1.327–1.596). There was heterogeneity among studies of BMI (P<0.001) but not among studies of WC (P = 0.323).

Conclusions

Both of general and central obesity were positively associated with the risk of CRC in this meta-analysis.     

Association between 3801T>C Polymorphism of CYP1A1 and Idiopathic Male Infertility Risk: A Systematic Review and Meta-Analysis

Background

Epidemiological studies have evaluated the association between 3801T>C polymorphism of CYP1A1 gene and the risk for idiopathic male infertility, but the results are inconclusive. We aimed to derive a more precise estimation of the relationship by conducting a meta-analysis of case-control studies.

Methods

This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase and CNKI databases were searched through November 2013 to identify relevant studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Q-test was performed to evaluate between-study heterogeneity and publication bias was appraised using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis findings.

Results

Six studies involving 1,060 cases and 1,225 controls were included in this meta-analysis. Overall, significant associations between 3801T>C polymorphism and idiopathic male infertility risk were observed in allelic comparison (OR = 1.36, 95% CI: 1.01–1.83), homozygous model (OR = 2.18, 95% CI: 1.15–4.12), and recessive model (OR = 1.86, 95% CI: 1.09–3.20), with robust findings according to sensitivity analyses. However, subgroup analyses did not further identify the susceptibility to idiopathic male infertility in all comparisons. Funnel plot inspections did not reveal evidence of publication bias.

Conclusions

The current meta-analysis provides evidence of a significant association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Considering the limitation inherited from the eligible studies, further confirmation in large-scale and well-designed studies is needed.     

Tea and Coffee Consumption and Risk of Laryngeal Cancer: A Systematic Review Meta-Analysis

Background

Tea and coffee are the most commonly consumed beverages in the worldwide. The relationship between tea and coffee consumption on the risk of laryngeal cancer was still unclear.

Methods

Relevant studies were identified by searching electronic database (Medline and EMBASE) and reviewing the reference lists of relevant articles until Oct. 2013. Observational studies that reported RRs and 95% CIs for the link of tea and coffee consumption on the risk of laryngeal cancer were eligible. A meta-analysis was obtained to combine study-specific RRs with a random-effects model.

Results

A total of 2,803 cases and 503,234 controls in 10 independent studies were identified. The overall analysis of all 10 studies, including the case-control and cohort studies, found that tea drinking was not associated with laryngeal carcinoma (RR = 1.03; 95% CI: 0.66–1.61). However, coffee consumption was significantly associated with the laryngeal carcinoma (RR = 1.47; 95% CI: 1.03–2.11). A dose-response relationship between coffee intake and laryngeal carcinoma was detected; however, no evidence of dose-response link between tea consumption and laryngeal carcinoma risk was detected.

Conclusions

The results from this meta-analysis of observational studies demonstrate that coffee consumption would increase the laryngeal cancer risk, while tea intake was not associated with risk of laryngeal carcinoma.     

Risk of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis

Background

People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.

Methods and Findings

We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.

Conclusions

VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times. Please see later in the article for the Editors'' Summary.     

A Systematic Review of Meta-Analyses on Gene Polymorphisms and Gastric Cancer Risk

Background

Individual variations in gastric cancer risk have been associated in the last decade with specific variant alleles of different genes that are present in a significant proportion of the population. Polymorphisms may modify the effects of environmental exposures, and these gene-environment interactions could partly explain the high variation of gastric cancer incidence around the world. The aim of this report is to carry out a systematic review of the published meta-analyses of studies investigating the association between gene polymorphisms and gastric cancer risk, and describe their impact at population level. Priorities on the design of further primary studies are then provided.

Methods

A structured bibliographic search on Medline and EMBASE databases has been performed to identify meta-analyses on genetic susceptibility to gastric cancer, without restriction criteria. We report the main results of the meta-analyses and we describe the subgroup analyses performed, focusing on the detection of statistical heterogeneity. We investigated publication bias by pooling the primary studies included in the meta-analyses, and we computed the population attributable risk (PAR) for each polymorphism.

Results

Twelve meta-analyses and one pooled-analysis of community based genetic association studies were included, focusing on nine genes involved in inflammation (IL-1β, IL-1RN, IL-8), detoxification of carcinogens (GSTs, CYP2E1), folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53). According to their random-Odds Ratios, individuals carrying one of the IL-1RN *2, IL-1β -511T variant alleles or homozygotes for MTHFR 677T are significantly at higher risk of gastric cancer than those with the wild type homozygote genotypes, showing high PARs. The main sources of heterogeneity in the meta-analyses were ethnicity, quality of the primary study, and selected environmental co-exposures. Effect modification by Helicobacter pylori infection for subjects carrying the unfavourable variant of IL-1 polymorphisms and by low folate intake for individuals homozygotes for MTHFR 677T allele has been reported, while genes involved in the detoxification of carcinogens show synergistic interactions. Publication bias was observed (Egger test, p = 0.03).

Discussion

The published meta-analyses included in our systematic review focused on polymorphisms having a small effect in increasing gastric cancer risk per se. Nevertheless, the risk increase by interacting with environmental exposures and in combination with additional unfavourable polymorphisms. Unfortunately meta-analyses are underpowered for many subgroup analyses, so additional primary studies performed on larger population and collecting data on environmental and genetic co-exposures are demanded.Key Words: Gastric cancer, meta-analysis, heterogeneity, polymorphism, population attributable risk.     

Four Genetic Polymorphisms of Lymphotoxin-Alpha Gene and Cancer Risk: A Systematic Review and Meta-Analysis

Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I² = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I² = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I² = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I² = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01–1.20, P = 0.023, I² = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I² = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.     

Association of VEGF Genetic Polymorphisms with Recurrent Spontaneous Abortion Risk: A Systematic Review and Meta-Analysis

Background

Studies of the associations between the genetic polymorphisms of the vascular endothelial growth factor (VEGF) gene and recurrent spontaneous abortion (RSA) have revealed conflicting results. The present meta-analysis was performed to provide a more precise estimation of these relationships and to explore potential sources of heterogeneity that may have influenced the reported disparities.

Methods

An extensive literature search for relevant studies was conducted on PubMed, Embase, and The Cochrane Library through June 6, 2014. Crude odds ratio (OR) with 95% confidence intervals were calculated.

Results

10 case-control studies including 1,832 RSA patients and 2,271 healthy controls were identified. Meta-analysis indicated that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms in the VEGF gene correlated with elevated RSA risk. The rs1570360 variant was statistically significantly relevant to RSA risk among non-Asian populations. Interestingly, the rs3025039 variant was statistically significantly relevant to RSA risk among Asian populations.

Conclusions

The current meta-analysis indicates that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms increase RSA susceptibility. Moreover, rs1570360 and rs3025039 polymorphisms may play various roles in RSA susceptibility in various geographic groups.     

Association Studies of ERCC1 Polymorphisms with Lung Cancer Susceptibility: A Systematic Review and Meta-Analysis

Background

Excision repair cross-complimentary group 1 (ERCC1) is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial.

Objectives

An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C), rs3212986 (C>A), rs3212961 (A>C), rs3212948 (G>C), rs2298881 (C>A).

Methods

Several major databases (MEDLINE, EMBASE and Scopus) and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations.

Results

Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls) suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04–1.48, P = 0.02). However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67–0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69–0.91, P = 0.001).

Conclusion

Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are needed to validate these findings.     

Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis

Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31–2.21), (ii) 5.65; (A-S+, 3.38–9.42), (iii) 8.70 (A+S+, 5.8–13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26–1.77) and the multiplicative index = 0.91 (95% CI = 0.63–1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00–1.28) and 0.51 (95% CI = 0.31–0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.     

Significantly Increased Risk of Cancer in Patients with Diabetes Mellitus: A Systematic Review and Meta-Analysis

ObjectiveTo conduct a review and meta-analysis of the effect of diabetes mellitus on the incidence of and mortality attributable to cancer at any anatomic site.MethodsWe performed a search of MEDLINE and the Cochrane Library for pertinent articles published from the origin of these databases to July 5, 2010, and included them in a qualitative review and meta-analysis of the risk of all-cancer incidence and mortality in patients with diabetes.ResultsAmong patients with diabetes (n = 257,222) in 12 cohort studies, the cancer incidence was about 7%. The cancer mortality was approximately 3% among patients with diabetes (n = 152,091) in 19 cohort studies. The pooled adjusted risk ratio (RR) of all-cancer incidence was significantly elevated—RR, 1.10 (95% confidence interval [CI], 1.04 to 1.17) overall; RR, 1.14 (CI, 1.06 to 23) for men; and RR, 1.18 (CI, 1.08 to 1.28) for women. Diabetes was also associated with an increased RR of mortality across all cancer types—RR, 1.16 (CI, 1.03 to 1.30) overall; RR, 1.10 (CI, 0.98 to 1.23) for men; and RR, 1.24 (CI, 1.11 to 1.40) for women.ConclusionCancer prevention and early detection by appropriate screening methods in patients with diabetes should be important components of clinical management and investigation, inasmuch as the exponentially increasing prevalence of diabetes will translate into substantial clinical and public health consequences on a global scale. (Endocr Pract. 2011;17:616-628)     

The Association between the Use of Proton Pump Inhibitors and the Risk of Hypomagnesemia: A Systematic Review and Meta-Analysis

Background

Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis.

Methods

We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords “proton pump,” “dexlansoprazole,” “esomeprazole,” “ilaprazole,” “lansoprazole,” “omeprazole,” “pantoprazole,” “rabeprazole,” “hypomagnesemia,” “hypomagnesaemia,” and “magnesium.” Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran’s Q test and I ² statistics.

Results

Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6–9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3–55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3–52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077–2.924). Significant heterogeneity was identified using Cochran’s Q test (df = 7, P<0.001, I ² = 98.0%).

Conclusions

PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion.     

Use of Fibrates and Cancer Risk: A Systematic Review and Meta-Analysis of 17 Long-Term Randomized Placebo-Controlled Trials

Background

Fibrates comprise a class of well-established antilipidemic agents that significantly reduce cardiovascular events. Given the concerns of cancer with fibrate therapy, we undertook a systematic review and meta-analysis to investigate the effects of fibrates on cancer outcomes.

Methods

We systematically searched Medline, Scopus, SCI Expanded, and the Cochrane Library for studies published up to 2012. We included randomized controlled trials (RCTs) that evaluated a fibrate therapy compared with placebo, had a minimum duration of two years, and reported data on the incidence of and/or deaths from cancer during the trial. Reviews of each study were performed and the relative data were abstracted. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the inverse variance weighted approach. Subgroup, sensitivity and meta-regression analyses were also conducted.

Results

Seventeen RCTs, involving 44,929 participants with an average follow-up of 5.2 years, contributed to the analysis. The degree of variability between trials was consistent with what would be expected to occur by chance alone. The quantitative synthesis of data retrieved from the RCTs was not indicative of a fibrate effect on cancer incidence (780 [fibrate] vs 814 [control]; RR = 1.02, 95% CI 0.92–1.12) or cancer death (385 [fibrate] vs 377 [control]; RR = 1.06, 95% CI: 0.92–1.22). When the analysis was restricted to major RCTs, the results did not substantially change. Similarly, we found no evidence of differential effects by length of follow-up or type of fibrate. Insignificant results were also obtained for the role of fibrates in cancers of the respiratory tract, breast, colon, gastrointestinal tract, prostate, genitourinary tract, or in melanoma.

Conclusion

Our findings demonstrate that fibrates have a neutral effect on cancer outcomes. However, it is important to continue monitoring their long-term safety profiles.     

The Impact of TRPV1 on Cancer Pathogenesis and Therapy: A Systematic Review

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is a transmembrane protein that can be activated by various physical and chemical stimuli and is associated with pain transduction. In recent years, TRPV1 was discovered to play essential roles in cancer tumorigenesis and development, as TRPV1 expression levels are altered in numerous cancer cell types. Several investigations have discovered direct associations between TRPV1 and cancer cell proliferation, cell death, and metastasis. Furthermore, about two dozen TRPV1 agonists/antagonists are under clinical trial, as TRPV1 is a potential drug target for treating various diseases. Hence, more researchers are focusing on the effects of TRPV1 agonists or antagonists on cancer tumorigenesis and development. However, both agonists and antagonists may reveal anti-cancer effects, and the effect may function via or be independent of TRPV1. In this review, we provide an overview of the impact of TRPV1 on cancer cell proliferation, cell death, and metastasis, as well as on cancer therapy and the tumor microenvironment, and consider the implications of using TRPV1 agonists and antagonists for future research and potential therapeutic approaches.     

DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis

Objective

The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk.

Methods

A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source.

Results

A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14–40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83–36.78). The association was also confirmed in all the subgroups analyses.

Conclusions

A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus.     

The Relationship Between Selenium Levels and Breast Cancer: A Systematic Review and Meta-Analysis

Breast cancer is the most common cancer type. In several studies, hints have been provided that there is a correlation between selenium deficiency and the incidence of breast cancer. Findings of these published reports are, however, inconsistent. This study serves as a pioneering study aiming at combining the results of studies using a meta-analytic method. A total of 16 articles published between 1980 and 2012 worldwide were selected through searching PubMed, Scopus, and Google scholar databases, and the information were analyzed using a meta-analytic method [random effects model]. I ² statistics were used to examine heterogeneity. The information was then analyzed by STATA version 12. In this study, due to the non-uniform methods used to measure selenium concentrations, selenium levels were measured in the various subgroups in both case and control groups. There were significant correlations between selenium concentration and breast cancer [P?<?0.05]. Hence, the mean risk differentiating criteria were estimated to be 0.63 [95 % confidence interval [95% CI] 0.93 to 0.32] in serum and toenails. Subgroup analysis showed that the value in toenails was ?0.07 [95% CI ?0.16 to 0.03] and in serum ?1.04 [95% CI 1.71 to ?0.38]. In studies in which selenium concentrations were measured in serum, a significant correlation was observed between selenium concentration and breast cancer. In contrast, in studies in which selenium concentration was measured in toenails, the correlation was not significant. Therefore, the selenium concentration can be used as one predictor for breast cancer.     

Metformin Therapy and Risk of Cancer in Patients with Type 2 Diabetes: Systematic Review

Aims/Hypothesis

Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes.

Methods

Data source: MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers.

Results

Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death [6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80], all malignancies [18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88], liver [8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60] colorectal [12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74–0.92], pancreas [9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36–0.86], stomach [2 studies, 100701 patients, OR:0.83, 95%CI: 0.76–0.91], and esophagus cancer [2 studies, 100694 patients, OR:0.90, 95%CI: 0.83–0.98]. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma.

Conclusions/Interpretation

Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted.