The present systematic review and meta-analysis of case-control studies examines the associations between rs7903146 and rs12255372 polymorphisms of the TCF7L2 gene and PCOS. A search of the literature published until August 2014 was carried out in PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and LILACS. There were no other limits except for the end date. We included observational studies with women of any age diagnosed with PCOS and healthy controls that analyzed polymorphisms rs7903146 and rs12255372. We included case-control or cross-sectional studies analyzing polymorphism rs7903146 or rs12255372 in women with PCOS and healthy controls. Eighteen studies were identified after the primary literature search and seven articles were included in the meta-analysis. All employed Rotterdam criteria for the diagnosis of PCOS. The genotypic distributions in the control groups were in agreement with Hardy-Weinberg equilibrium in all studies. The pooled population included Asian descendents (Chinese, Korean), Caucasians from southern Brazil, Tunisian, and European populations (British/Irish, Northern Finns, Greeks, Czechs), including 1,892 women with PCOS and 2,695 controls. There were no significant associations between PCOS and TCF7L2 rs7903146 or rs12255372 polymorphisms, irrespective of whether allele contrast, additive, dominant, or recessive models of inheritance were used. Furthermore, no significant associations were found after stratification for ethnicity (Asian or non-Asian). There was no significant heterogeneity between studies and no publication bias. The present results suggest that rs7903146 T allele or rs12255372 is not associated with risk for PCOS in non-Asian or Asian women. This systematic review and meta-analysis are registered in PROSPERO under number CRD42013005930.

The aim of this study was to systematically review the articles investigating the prognostic value of different microRNAs (miRs) in human head and neck squamous cell carcinoma (HNSCC). Following the guidelines of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE), we performed a broad and sensitive search on online databases to identify the studies that examined associations between different miRs expression and HNSCC prognosis. In this study, we considered clinical endpoints such as overall survival (OS) and disease specific survival (DFS) as acceptable outcomes. The prognostic value was demonstrated using hazard ratio (HR) with 95% confidence interval (CI). A total of 21 studies involving 1685 subjects analyzed the relationship between miRNA and prognosis of HNSCC. Our findings showed that significant elevated expressions of miR-21, miR-18a, miR-134a, miR-210, miR-181a, miR-19a, and miR-155 were associated with poor survival in human HNSCC. Conversely, decreased expressions of miR-153, miR-200c, miR-363, miR-203, miR-17, miR-205, miR-Let-7d, Let-7g, miR-34a, miR-126a, miR-375, miR-491-p5, miR 218, miR-451 and miR-125b were associated with poor prognosis. Alteration in miR-193b expression level does not show any significant association with cancer survival. We performed meta-analysis on the articles choosing miR-21 as prognostic marker. After excluding the study causing heterogeneity, a fixed model was applied, which showed an association between increased expression of miR-21 and poor survival (Pooled HR=1.57-95% CI: 1.22-2.02, P<0.05). Based on the results, it can be concluded that miRs specifically miR-21 may be promising markers for prognosis prediction in HNSCC.

Despite improvements in both diagnostic and therapeutic strategies, the prognosis of oral squamous cell carcinoma (OSCC) has not changed significantly over the last decades. Prognosis of OSCC particularly depends on the presence of nodal metastasis in the neck. Therefore, proper determination of the nodal status is pivotal for appropriate treatment. Unfortunately, current available imaging techniques (magnetic resonance imaging or ultrasound even with fine needle aspiration of suspected lymph nodes (LNs)) fail to detect occult nodal disease accurately. Clinicians in head and neck oncology urgently need new diagnostic tools to reliably determine the presence of nodal metastasis of the neck. Gain of the chromosomal region 11q13 is one of the most prominent genetic alterations in head and neck cancer and is associated with poor prognosis and metastasis. The aim of this systematic review and meta-analysis was to determine the diagnostic value of either 11q13 amplification or amplification/protein overexpression of individual genes located on 11q13 to detect nodal metastasis in OSCC. A search was conducted in Pubmed, EMBASE, and Cochrane, and 947 unique citations were retrieved. Two researchers independently screened all articles and only 18 were found to meet our inclusion criteria and were considered of sufficient quality for meta-analysis. Pooled results of those show that both amplification of CCND1 and protein overexpression of cyclin D1 significantly correlate with lymph node metastasis (LNM) in OSCC. In addition, amplification of CCND1 shows a negative predictive value of 80 % in the detection of LNM in early stage OSCCs which are clinically lymph node negative although this evidence is sparse and should be validated in a larger homogeneous cohort of T1-2 OSCC.

Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict. To clarify the characteristics and course of paediatric mastocytosis, we performed a literature review of 1747 cases published between 1950 and April 2014. Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1·4. KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2·9% of patients.

Current data on the concordance of KRAS, BRAF, PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer (CRC) are conflicting. We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients. The biomarker status in primary tumors was used as the reference standard. Concordance data for KRAS, BRAF, PIK3CA and PTEN were provided by 43, 16, 9 and 7 studies, respectively. The pooled concordance rate was 92.0% (95% CI: 89.7%-93.9%) for KRAS, 96.8% (95% CI: 94.8%-98.0%) for BRAF, 93.9% (95% CI: 89.7%-96.5%) for PIK3CA and 71.7% (95% CI: 57.6%-82.5%) for PTEN. The pooled false positive and false negative rates for KRAS were 9.0% (95% CI: 6.5%-12.4%) and 11.3% (95% CI: 8.0%-15.8%), respectively. KRAS, BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC, but PTEN loss is not. Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases, while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases. These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment.

OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27(Kip1), CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.

Recent studies have shown that c-Met is an important signal in the development of colorectal cancer, but the prognostic value of c-Met remains unclear. We aimed to analyze the prognostic effect of c-Met in colorectal cancer through a systematic review and meta-analysis. Through database searches, we identified six articles describing how c-Met status affects colorectal cancer prognosis. A meta-analysis was performed to investigate the relationship between the hazard ratio and survival. The available outcome data from six articles were examined. A meta-analysis of the HR and the 95% confidence interval (CI) indicated a significantly poor overall survival and disease-free survival in patients with high expression levels of c-Met. The subgroup analysis showed that the prognostic effect of the c-Met level was similar in different methods and was not associated with disease stages. High c-Met expression levels could predict a poor prognosis in colorectal cancer patients. The c-Met status could be used to evaluate the prognosis in clinical patients.

Aberrant microRNA expression has the potential to be used for early diagnosis of gastric cancer or to predict survival and treatment response. This study performed a systematic review and meta-analysis of altered miRNAs in gastric cancer in order to assess the use of miRNAs as novel biomarkers for early detection and prognosis prediction of gastric cancer.

The objective of this study was to perform a systematic review of correlations between the single-nucleotide polymorphism at nucleotide 309 (single-nucleotide polymorphism, SNP309) in the murine double-minute 2 (MDM2) gene promoter and susceptibility to leukemia.

Family history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks.

The oxyguanine glycosylase 1 (OGG1) gene has an important role in DNA repair, and the polymorphism of the gene may alter cancer susceptibility. This study aims to examine the association between the OGG1 Ser326Cys polymorphism and cancer risk based on meta-analysis. Relevant studies were identified through a search of PubMed and Weipu databases, and a total of 109 studies including 111 comparisons containing 34,041 cases and 42,730 controls were enrolled. Overall, significant association was observed between OGG1 Ser326Cys polymorphism and cancer risk in all genetic models except for heterozygote model (Cys/Cys + Cys/Ser vs Ser/Ser: OR 1.071, 95 % CI 1.019-1.125; Cys/Cys vs Cys/Ser + Ser/Ser: OR 1.159, 95 % CI 1.076-1.248; Cys/Cys vs Ser/Ser: OR 1.202, 95 % CI 1.105-1.308). In stratified analysis by cancer type, significantly increased cancer risk was observed in digestive system cancer, head and neck cancer and lung cancer. For gynecologic cancer, significantly increased cancer risk was also observed in homozygote model (OR 1.974, 95 % CI 1.254-3.107). In addition, in stratified analysis by ethnicities, increased cancer risk was found in Asians (Cys/Cys vs Cys/Ser + Ser/Ser: OR 1.195, 95 % CI 1.088-1.313; Cys/Cys + Cys/Ser vs Ser/Ser: OR 1.115, 95 % CI 1.045-1.190; Cys/Cys vs Ser/Ser: OR 1.273, 95 % CI 1.149-1.410). The OGG1 Ser326Cys polymorphism may be a risk factor for cancers of lung, digestive system and head and neck.

The aim of this systematic review was to determine the prognostic value of Bcl-2 immunostaining in patients affected by laryngeal squamous cell carcinoma. An appropriate search was conducted on PubMed to retrieve articles dealing with this topic. A double cross-check was performed on citations and full-text articles by 2 investigators independently to review all manuscripts and perform a comprehensive quality assessment. Of 115 abstracts identified, 15 articles were included. These studies reported on 1,150 patients with histologically confirmed diagnosis of laryngeal squamous cell carcinoma. Only a few studies showed a statistical correlation between Bcl-2 immunohistochemical expression and at least 1 of the clinical and histopathological parameters considered by the authors. Moreover, these findings were also discordant between them. Overall the studies analyzed suggested that Bcl-2 expression was statistically connected with N stage (2/14), grading (2/14), disease-free survival (3/14) and overall survival (5/14). Interestingly, all of the 3 studies investigating the relation between Bcl-2 and radioresistance showed significant results in terms of recurrence-free survival and overall survival. Our review strongly suggests that the immunohistochemical staining of Bcl-2 does not correlate with tumoral aggressiveness and prognosis of patients affected by laryngeal squamous cell carcinoma and treated with primary surgery. However, an interesting connection of this protein could be demonstrated with tumoral radioresistance. Further, high-quality prospective studies should be carried out to confirm this hypothesis.

EGFR TKIs alone have demonstrated activity against intracranial disease in EGFR mutant non-small cell lung cancer (NSCLC). This study aimed to determine if upfront cranial radiotherapy improves intracranial disease control and survival outcomes in EGFR mutant NSCLC with brain metastases relative to TKIs alone.

A number of studies have been carried out to investigate the association of X-ray repair complementing defective repair in Chinese hamster cells 6 (XRCC6) polymorphisms and cancer risks, and the results remained inconsistent and inconclusive.To assess the effect of XRCC6 polymorphisms on cancer susceptibility, we conducted a meta-analysis, up to May 23rd 2014, 6267 cases with different types of tumor and 7536 controls from 20 published case-control studies. Summary odds ratios and corresponding 95% confidence intervals for XRCC6 polymorphism and cancer risk were estimated using fixed- or random-effects models when appropriate. Heterogeneity was assessed by chi-squared-based Q-statistic test, and the sources of heterogeneity were explored by subgroup analyses, logistic meta-regression analyses and Galbraith plot. Publication bias was evaluated by Begg funnel plot and Egger test. Sensitivity analyses were also performed.The rs2267437 polymorphism was associated with a significant increase in risks of overall cancers, breast cancer, renal cell carcinoma and hepatocellular carcinoma, and it could increase the cancer risk in Asian population; the rs5751129 polymorphism could increase the cancer risk in overall cancers; the rs132770 polymorphism was associated with the increased renal cell carcinoma risk; furthermore, the rs132793 polymorphism could decrease breast cancer risk and increase risks in "other cancers".Overall, the results provided evidences that the single nucleotide polymorphisms in XRCC6 promoter region might play different roles in various cancers, indicating different cancers have different tumorigenesis mechanisms. Our studies may perhaps supplement for the disease monitoring of cancers in the future, and additional studies to determine the exact molecular mechanism might provide us with interventions to protect the susceptible subgroups.

To obtain precise estimates of endometrial cancer risk associated with a family history of endometrial cancer or cancers at other sites.

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.

Genetic polymorphisms of xeroderma pigmentosum group D (XPD) in the nucleotide excision repair pathway may influence cancer susceptibility by affecting the capacity for DNA repair. Studies investigating the association between XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma (HCC) risk reported inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association. Eligible studies were identified by searching electronic databases including PubMed, Embase, Cochrane library, and CBM, Chinese Biomedical Literature Database, for the period up to October 2014. The association of XPD Lys751Gln and Asp312Asn polymorphisms and HCC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Finally, a total of 11 studies with 4322 cases and 4970 controls were included for XPD Lys751Gln polymorphism and 6 studies with 2223 cases and 2441 controls were available for XPD Asp312Asn polymorphism. With respect to XPD Lys751Gln polymorphism, statistically significant increased HCC risk was found when all studies were pooled into the meta-analysis (Gln/Gln vs Lys/Lys: OR = 1.363, 95% CI 1.065-1.744, P = 0.014; Lys/Gln vs Lys/Lys: OR = 1.205, 95% CI 1.099-1.321, P = 0.000; Gln/Gln+Lys/Gln vs Lys/Lys: OR = 1.300, 95% CI 1.141-1.480, P = 0.000). In subgroup analyses by ethnicity, source of control, Hardy-Weinberg equilibrium (HWE) in controls, hepatitis B virus (HBV) infection, and statistically significant increase of HCC risk was found in East Asians, population-based studies, studies consistent with HWE, and HBV-positive subjects, but not in mixed/other populations, hospital-based studies, studies deviating from HWE, and HBV-negative subjects. With respect to XPD Asp312Asn polymorphism, no significant association with HCC risk was found in the overall and subgroup analyses. The results suggest that the XPD Lys751Gln polymorphism contributes to increased HCC susceptibility, especially in East Asian populations. Further, large and well-designed studies are required to validate this association.

Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.

Previous reports indicate that RUNX3 is a tumor suppressor in several types of human tumors, including breast cancer (BC). However, the correlation between RUNX3 hypermethylation and the incidence of BC remains unclear. In this study, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of BC.

Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities.