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A closer association has been found between the microRNA-146a rs2910164 polymorphism and the risk of head and neck carcinoma in some molecular epidemiological studies. Recently two meta-analyses were performed to explore the relationship between miRNA-146a polymorphisms and the susceptibility of squamous cell carcinoma of the head and neck (SCCHN); however, they yielded conflicting results in susceptibility regarding ethnic variations. Hence, the present study was performed to explain the relationship between the miRNA-146a rs2910164 polymorphism and the risk of SCCHN development of Chinese patients. We retrieved databases and screened eligible papers up to March 10, 2017 and then we extracted the essential data. The subgroup analyses were also performed based on the tumor site, region, and genotyping means. Crude odds ratios (OR) at 95% confidence intervals (CI) were chosen to describe the strength of the association. As a result, 6 publications were included in our study which involved 8 independent case-control studies. A significant association was found between miR-146a rs2910164 polymorphisms and the risk of SCCHN in Chinese patients according to the overall data [CC+CG vs. GG: OR = 1.13; 95%CI = 1.00–1.29; CC vs. GG: OR = 1.19; 95%CI = 1.03–1.38]. According to the subgroup analysis based on tumor site, the risk of cancer was significantly increased among laryngeal cancer (dominant model: OR = 1.76, 95%CI = 1.26~2.46, P = 0.001; homozygote model: OR = 1.83, 95%CI = 1.25~2.67, P = 0.002) and nasopharyngeal carcinoma (homozygote model: OR = 1.41, 95%CI = 1.05~1.90, P = 0.022). In summary, variant alleles of miR-146a rs2910164 alleles may have an association with the increased risk of SCCHN in Chinese patients, and these associations differed based on tumor site. Further studies including a larger sample size will be necessary to clarify these results. [ABSTRACT FROM AUTHOR]

Robustly predicting outcome for cancer patients from gene expression is an important challenge on the road to better personalized treatment. Network-based outcome predictors (NOPs), which considers the cellular wiring diagram in the classification, hold much promise to improve performance, stability and interpretability of identified marker genes. Problematically, reports on the efficacy of NOPs are conflicting and for instance suggest that utilizing random networks performs on par to networks that describe biologically relevant interactions. In this paper we turn the prediction problem around: instead of using a given biological network in the NOP, we aim to identify the network of genes that truly improves outcome prediction. To this end, we propose SyNet, a gene network constructed ab initio from synergistic gene pairs derived from survival-labelled gene expression data. To obtain SyNet, we evaluate synergy for all 69 million pairwise combinations of genes resulting in a network that is specific to the dataset and phenotype under study and can be used to in a NOP model. We evaluated SyNet and 11 other networks on a compendium dataset of >4000 survival-labelled breast cancer samples. For this purpose, we used cross-study validation which more closely emulates real world application of these outcome predictors. We find that SyNet is the only network that truly improves performance, stability and interpretability in several existing NOPs. We show that SyNet overlaps significantly with existing gene networks, and can be confidently predicted (~85% AUC) from graph-topological descriptions of these networks, in particular the breast tissue-specific network. Due to its data-driven nature, SyNet is not biased to well-studied genes and thus facilitates post-hoc interpretation. We find that SyNet is highly enriched for known breast cancer genes and genes related to e.g. histological grade and tamoxifen resistance, suggestive of a role in determining breast cancer outcome. [ABSTRACT FROM AUTHOR]

How can we predict the occurrence of acute kidney injury (AKI) in cancer patients based on machine learning with serum creatinine data? Given irregular and heterogeneous clinical data, how can we make the most of it for accurate AKI prediction? AKI is a common and significant complication in cancer patients, and correlates with substantial morbidity and mortality. Since no effective treatment for AKI still exists, it is important to take timely preventive measures. While several approaches have been proposed for predicting AKI, their scope and applicability are limited as they either assume regular data measured over a short hospital stay, or do not fully utilize heterogeneous data. In this paper, we provide an AKI prediction model with a greater applicability, which relaxes the constraints of existing approaches, and fully utilizes irregular and heterogeneous data for learning the model. In a cohort of 21,022 cancer patients who were registered into Korea Central Cancer Registry (KCCR) in Seoul National University Hospital between January 1, 2004 and December 31, 2013, our method achieves 0.7892 precision, 0.7506 recall, and 0.7576 F-measure in predicting whether a patient will develop AKI during the next 14 days. [ABSTRACT FROM AUTHOR]

Background: LncRNA CCAT1 is significantly overexpressed in various types of cancers, suggesting that it might be associated with prognosis and clinicopathological features in patients with cancer. Methods: A comprehensive search was performed in Pubmed, Web of Science, OVID and CNKI databases. We also retrieved articles from other sources, such as retrieving from the reference lists of relevant articles. Eligible studies were included based on defined exclusion and inclusion criteria to perform a meta-analysis. STATA 14.0 was used to estimate pooled hazard ratios (HRs) with 95% confidence interval (95% CI), the heterogeneity among studies and publication bias to judge the prognostic value. Results: A total of 1587 patients from 11 eligible studies were included in the meta-analysis. The results showed that high expression level of CCAT1 was significantly associated with shorter overall survival in cancer patients (HR 2.335, 95% CI:1.551–3.517); in the subgroup analysis, region (China or UK), sample size (more or less than 100), type of cancer (digestive or non-digestive disease) and paper quality (score more or less than 7) did not alter the association between CCAT1 expression and cancer prognosis but preoperative treatment did. And CCAT1 expression was an independent prognostic marker for overall survival in patients with cancer (pooled HR 2.195, 95%CI:1.316–3.664) using Cox multivariate analyses. The clinicopathological parameters analysis further showed that increased expression level of CCAT1 was correlated with tumor size, lymph node metastasis, TNM stage, distant metastasis, microvascular invasion and capsular formation in relevant cancers. Conclusions: The meta-analysis results from present study suggested that increased expression level of CCAT1 was associated with poor prognosis and can serve as an independent biomarker. And the expression level of CCAT1 was associated with clinicopathological features in relevant cancers. [ABSTRACT FROM AUTHOR]

Background: Recent literature has suggested that tumor sidedness in colorectal cancer (CRC) is an independent prognostic and potentially predictive marker of survival. The aims of the study were to determine the prognostic significance of tumor sidedness in colorectal cancer patients undergoing primary tumor resection and to assess associated tumor biology. Methods: A total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012 were analyzed for association with tumor biologic factors and with overall survival. Metastatic patients were excluded from analysis. Results: Left sided CRCs were associated with a number of additional key prognostic markers including BRAFV600E wildtype status (P<0.001), mismatch repair proficiency (p<0.001), absence of peritumoral lymphocytic response (p = 0.001), high lymphocyte-to-monocyte ratio (p<0.001) and low neutrophil-to-lymphocyte ratio (p<0.001). In primary analysis with 3067 patients, there was no statistical difference in sidedness in the univariate analysis (p = 0.291). Three further subgroup analyses were performed. In the first subgroup, only stage III patients were analyzed. In the second, patients with mismatch repair deficiency were removed. In the third, additional clinicopathologic variables known to be independently prognostic were added into analysis. In all three subgroup analyses tumor sidedness was not an independent prognostic marker. Conclusions: Tumor sidedness was not an independent prognostic marker of CRC. However, right sided CRCs were associated with several key independent prognostic markers supporting a hypothesis that tumor sidedness is a surrogate for other biomarkers. [ABSTRACT FROM AUTHOR]

Drug screening studies typically involve assaying the sensitivity of a range of cancer cell lines across an array of anti-cancer therapeutics. Alongside these sensitivity measurements high dimensional molecular characterizations of the cell lines are typically available, including gene expression, copy number variation and genomic mutations. We propose a sparse multitask regression model which learns discriminative latent characteristics that predict drug sensitivity and are associated with specific molecular features. We use ideas from Bayesian nonparametrics to automatically infer the appropriate number of these latent characteristics. The resulting analysis couples high predictive performance with interpretability since each latent characteristic involves a typically small set of drugs, cell lines and genomic features. Our model uncovers a number of drug-gene sensitivity associations missed by single gene analyses. We functionally validate one such novel association: that increased expression of the cell-cycle regulator C/EBPδ decreases sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat. [ABSTRACT FROM AUTHOR]

Tumour heterogeneity plays a large role in the response of tumour tissues to radiation therapy. Inherent biological, physical, and even dose deposition heterogeneity all play a role in the resultant observed response. We here implement the use of Haralick textural analysis to quantify the observed glycogen production response, as observed via Raman spectroscopic mapping, of tumours irradiated within a murine model. While an array of over 20 Haralick features have been proposed, we here concentrate on five of the most prominent features: homogeneity, local homogeneity, contrast, entropy, and correlation. We show that these Haralick features can be used to quantify the inherent heterogeneity of the Raman spectroscopic maps of tumour response to radiation. Furthermore, our results indicate that Haralick-calculated textural features show a statistically significant dose dependent variation in response heterogeneity, specifically, in glycogen production in tumours irradiated with clinically relevant doses of ionizing radiation. These results indicate that Haralick textural analysis provides a quantitative methodology for understanding the response of murine tumours to radiation therapy. Future work in this area can, for example, utilize the Haralick textural features for understanding the heterogeneity of radiation response as measured by biopsied patient tumour samples, which remains the standard of patient tumour investigation. [ABSTRACT FROM AUTHOR]

Despite canine B-cell Lymphoma (BCL) representing the most common haematological tumour, epigenetic events driving development and progression are scarcely known. Recently, canine Diffuse Large BCL (DLBCL) DNA methylome by genome-wide CpG microarray has identified genes and pathways associated to pathogenesis. To validate data previously obtained by array analysis, the CLBL-1 cell line was used and the HOXD10, FGFR2, ITIH5 and RASAL3 genes were selected. CLBL-1 cells were treated with two hypomethylating drugs (HDs; IC50, 50% inhibitory concentration), i.e. azacytidine and decitabine (DEC), either alone or in combination with three histone deacetylase inhibitors (HDACis; IC20), i.e. valproic acid, trichostatin and vorinostat. Following the incubation with both HDs, an overall decrease of promoter methylation was highlighted, thus confirming target genes hypermethylation. The highest mRNA restoration was observed following the exposure to HDs combined with HDACis, and mostly with valproic acid. Contrasting results were only obtained for RASAL3. An in vivo confirmation was finally attempted treating Nod-Scid mice engrafted with CLBL-1 cells with DEC. Although DEC did not arrest tumour growth, target genes promoter methylation was significantly reduced in DEC-treated mice vs controls. Overall, this work demonstrates that CLBL-1 cell line represents a reliable in vitro model to validate the methylation-dependent silencing of key genes for BCL; moreover, it may be useful for xenograft models in mice, despite its aggressive behaviour. In future, functional studies will be performed to deepen the role of selected genes on BCL pathogenesis and progression, and their methylation-dependent mechanism of regulation. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the leading cause of death by gynecologic cancers in the Western world. The aim of the study was to identify microRNAs (miRNAs) associated with prognosis and/or resistance to chemotherapy among patients with epithelial ovarian cancer. Methods: Using information from the Pelvic Mass Study we identified a cohort of women with epithelial ovarian cancer. Tumor tissues were then collected and analyzed by global miRNA microarrays. MiRNA profiling was then linked to survival and time to progression using Cox proportional-hazards regression models. Logistic regression models were used for the analysis of resistance to chemotherapy. Our results were validated using external datasets retrieved from the NCBI Gene Expression Omnibus database. Results: A total of 197 patients with epithelial ovarian cancer were included for miRNA microarray analysis. In multivariate analyses we identified a number of miRNAs significantly correlated with overall survival (miR-1183 (HR: 1.42, 95% CI:1.17–1.74, p = 0.0005), miR-126-3p (HR: 1.38, 95% CI:1.11–1.71, p = 0.0036), time to progression (miR-139-3p (HR: 1.48, 95% CI: 1.13–1.94, p = 0.0047), miR-802 (HR: 0.48, 95% CI: 0.29–0.78, p = 0.0035)), progression free survival (miR-23a-5p (HR:1.32, 95% CI:1.09–1.61, p = 0.004), miR-23a-3p (HR:1.70, 95% CI:1.15–2.51, p = 0.0074), miR-802 (HR: 0.48, 95% CI: 0.29–0.80, p = 0.0048)), and resistance to chemotherapy (miR-1234 (HR: 0.26, 95% CI: 0.11–0.64, p = 0.003)). A few miRNAs identified in our training cohort, were validated in external cohorts with similar results. Conclusion: Eight miRNAs were identified as significant predictors of overall survival, progression free survival, time to progression, and chemotherapy resistance. A number of these miRNAs were significantly validated using external datasets. Inter-platform and inter-laboratory variations may have influence on the ability to compare and reproduce miRNA results. The use of miRNAs as potential markers of relapse and survival in ovarian cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: In our clinical practice we have observed that despite a high hepatic metastatic tumor burden, serum alkaline phosphatase (AP) levels are frequently normal in cases of metastatic neuroendocrine tumor (NET). Patients and methods: We retrospectively reviewed the records of patients with grade 1 and 2 NETs with liver metastases but without bone metastases seen at our institution in 2013. In total, 49 patients were included (22 female), with a median age of 60 years (range: 28 to 84 years). The primary tumors were located in the duodenum/pancreas (n = 29), small bowel (n = 17) or colon/rectum (n = 3); 10 cases were grade 1 and 39 grade 2. Hepatic involvement was bulky, with more than 10 lesions in 23 patients and a tumor burden above 10% of the liver volume in 26 patients. Results: Serum AP levels were elevated (≥ upper limit of normal (ULN)) in 16 patients. In multiparametric analysis, elevated serum AP levels were not associated with the primary site, grade, or number or volume of metastases. In multiparametric analysis, progression-free survival was only correlated with grade (p = 0.010) and AP level (p = 0.017). Conclusions: Serum AP levels are frequently normal in liver metastases from NET, even in the event of a major tumor burden, and the serum AP level can be of prognostic value. [ABSTRACT FROM AUTHOR]

Purpose: miRNAs are stable and can be extracted from tissues, blood and other body fluid without degradation. miRNAs are abnormally expressed in the presence of a pathological status, including cancer. Therefore, miRNAs are ideal biomarkers for cancer diagnosis and prognosis. Patients with triple negative breast cancer (TNBC) suffer the worst prognosis, although great efforts have been made. Many studies have investigated the role of miRNAs in predicting the outcomes of TNBC patients for better adjustment of treatment. However, results were inconsistent. Thus, we performed a meta-analysis to summarize the published studies for conclusive results. Methods: Eligible studies from different database were retrieved from the online databases, and we used STSTA 12.0 to analysis the prognostic role of miRNAs in triple negative breast cancer. Results: Overall high miRNA expression indicated a worse survival with HR value of 1.78 (95% CI: 0.97–3.25). However, subtotal HRs of oncogenic miRNAs and tumor suppressive miRNAs were 2.73 (95% CI: 2.08–3.57; P<0.001) and 0.44 (95% CI: 0.21–0.90; P = 0.024), respectively, and no heterogeneity was observed within the subgroups. Conclusions: The miRNAs showed a slightly stronger prognostic value for disease-free survival, relapse-free survival and distant metastasis-free survival compared to the overall survival of TNBC patients. Circulating miRNAs could serve as potential biomarkers for the prognosis of TNBC patients and need further investigation. [ABSTRACT FROM AUTHOR]

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing, phenotypic screening, and side effect prediction. The software and benchmark are available at . [ABSTRACT FROM AUTHOR]

Background: Estimation of the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC) currently relies on tumour-related factors such as resection margins and on lymph-node ratio (LNR) both inconveniently available only postoperatively. Our aim was to assess the accuracy of preoperative laboratory data in predicting PDAC prognosis. Methods: Collection of laboratory and clinical data was retrospective from 265 consecutive patients undergoing surgery for PDAC at Helsinki University Hospital. Cancer-specific survival assessment utilized Kaplan-Meier analysis, and independent associations between factors were by the Cox regression model. Results: During follow-up, 76% of the patients died of PDAC, with a median survival time of 19.6 months. In univariate analysis, CRP, albumin, CEA, and CA19-9 were significantly associated with postoperative cancer-specific survival. In multivariate analysis, taking into account age, gender, LNR, resection margins, tumour status, and adjuvant chemotherapy, the preoperative biomarkers independently associated with adverse prognosis were hypoalbuminemia (< 36 g/L, hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.10–2.19, p = 0.011), elevated CRP (> 5 mg/L, HR 1.44, 95% CI 1.03–2.02, p = 0.036), CEA (> 5 μg/L, HR 1.60, 95% CI 1.07–2.53, p = 0.047), and CA19-9 (≥555 kU/L, HR 1.91, 95% CI 1.18–3.08, p = 0.008). Conclusion: For patients with resectable PDAC, preoperative CRP, along with albumin and tumour markers, is useful for predicting prognosis. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that carcinoembryonic antigen (CEA) and cancer antigen 15–3 (CA15-3) levels are both independent prognostic factors in breast cancer. However, the utility of CEA and CA15-3 levels as conventional cancer biomarkers in patients with triple-negative breast cancer (TNBC) remains controversial. The current study was performed to explore the predictive value of pre-therapeutic serum CEA and CA15-3 levels, and nomograms were developed including these serum cancer biomarkers to improve the prognostic evaluation of TNBC patients. Pre-therapeutic CA15-3 and CEA concentrations were measured in 247 patients with stage I–IV TNBC. Kaplan-Meier analysis showed that TNBC patients with high levels of both CEA and CA15-3 had shorter overall survival (OS) and disease-free survival (DFS) rates than those in the low-level groups (p<0.05). Multivariate analysis suggested that pre-therapeutic CA15-3 and CEA levels are independent predictive elements for OS (p = 0.022 and p = 0.040, respectively) and DFS (p = 0.023 and p = 0.028, respectively). In addition, novel nomograms were established and validated to provide personal forecasts of OS and DFS for patients with TNBC. These novel nomograms may help physicians to select the optimal treatment plans to ensure the best outcomes for TNBC patients. [ABSTRACT FROM AUTHOR]

Objective: There is a heated debate on whether the prognostic value of NME1 is favorable or unfavorable. Thus, we carried out a meta-analysis to evaluate the relationship between NME1 expression and the prognosis of patients with digestive system neoplasms. Methods: We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled odd ratios (ORs) and corresponding 95%CI were calculated to evaluate the prognostic value of NME1 expression in patients with digestive system neoplasms, and the association between NME1 expression and clinicopathological factors. We also performed subgroup analyses to find out the source of heterogeneity. Results: 2904 patients were pooled from 28 available studies in total. Neither the incorporative OR combined by 17 studies with overall survival (OR = 0.65, 95%CI:0.41–1.03, P = 0.07) nor the pooled OR with disease-free survival (OR = 0.75, 95%CI:0.17–3.36, P = 0.71) in statistics showed any significance. Although we couldn’t find any significance in TNM stage (OR = 0.78, 95%CI:0.44–1.36, P = 0.38), elevated NME1 expression was related to well tumor differentiation (OR = 0.59, 95%CI:0.47–0.73, P<0.00001), negative N status (OR = 0.54, 95%CI:0.36–0.82, P = 0.003) and Dukes’ stage (OR = 0.43, 95%CI:0.24–0.77, P = 0.004). And in the subgroup analyses, we only find the “years” which might be the source of heterogeneity of overall survival in gastric cancer. Conclusions: The results showed that statistically significant association was found between NME1 expression and the tumor differentiation, N status and Dukes’ stage of patients with digestive system cancers, while no significance was found in overall survival, disease-free survival and TNM stage. More and further researches should be conducted to reveal the prognostic value of NME1. [ABSTRACT FROM AUTHOR]

Background: Image texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment. Methods and Findings: Patients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan–Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10−3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan–Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger population will be needed to validate the results. Conclusions: Heterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment. Therefore, texture analysis shows potential to be a clinically useful imaging biomarker providing additional prognostic information for patient selection. [ABSTRACT FROM AUTHOR]

Antibodies targeting programmed death 1 (PD-1) help prevent tumor cells from escaping immune-mediated destruction. We conducted this systematic review and meta-analysis to gain insight into the efficacy of PD-1 antibodies for the treatment of melanoma. Five trials involving 2,828 adult patients were included in this meta-analysis. In patients with previously untreated or refractory melanoma, treatment with PD-1 antibodies significantly improved the six-month progression-free survival (PFS) (HR 0.55, 95% CI 0.50–0.60, P<0.00001) and the overall response rate (OR 3.89, 95% CI 3.12–4.83, P<0.00001). This meta-analysis indicated that anti-PD-1 treatment might provide a significant survival benefit in patients with melanoma. In addition, we found that patients treated with nivolumab reported significantly fewer treatment-related adverse events (OR 0.74, 95% CI 0.57–0.97, P = 0.03) than those treated with other agents, but there was a dose-dependent increase in the frequency of adverse events in patients treated with pembrolizumab. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer. Methods: We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias. Results: We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%). Median survival was prolonged by a factor of 1.45 (1.30–1.62). Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias. Conclusion: We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research. [ABSTRACT FROM AUTHOR]

Background: Recently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL. Methods: We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity. Results: Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22–0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24–0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01–1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22–1.05; p = 0.07). Conclusion: Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET. Methods: Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling. Results: Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72–1.27], PFS (RR 0.95; CI 0.81–1.13), or OS (RR 1.03; CI 0.77–1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04–1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27–0.82) and lower overall renal toxicity (RR 3.61; CI 1.24–10.51). Conclusion: Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the prognostic significance of pretreatment plasma fibrinigen in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). Methods: A cohort of 183 patients with locally advanced OOSCC receiving preoperative chemoradiotherapy was retrospectively examined. Using ROC curve analysis, a pretreatment plasma fibrinogen cutoff value of 447mg/dL was determined. The primary endpoints were overall survival and recurrence-free survival. A secondary endpoint was to determine whether pretreatment plasma fibrinogen could predict treatment response to neoadjuvant chemoradiotherapy. Cox regression models and Kaplan–Meier curves were used for survival analyses. Results: Seventy-one patients had an elevated pretreatment plasma fibrinogen (fibrinogen >447mg/dL). Patients with high fibrinogen showed significantly higher pathologic stages after neoadjuvant treatment than those with low fibrinogen (p = 0.037). In univariate analysis, elevated fibrinogen was associated with poor overall survival (p = 0.005) and recurrence-free survival (p = 0.008) Multivariate analysis revealed that elevated fibrinogen remained an independent risk factor for death (hazard ratio 1.78, 95% CI 1.09–2.90, p = 0.021) and relapse (hazard ratio 1.78, 95% CI 1.11–2.86, p = 0.016). Conclusion: Elevated pretreatment plasma fibrinogen is associated with lack of response to neoadjuvant chemoradiotherapy and reduced OS and RFS in patients with OOSCC. Thus, plasma fibrinogen may emerge as a novel prognostic indicator and a potential therapeutic target in OOSCC. [ABSTRACT FROM AUTHOR]

Objective: Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results: The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue. Conclusion: The combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients. [ABSTRACT FROM AUTHOR]

Background and Objective: Surgery carries the best hope for cure in the treatment of cholangiocarcinoma (CC), whereas surgical outcome is not fully satisfactory. Bio-molecular markers have been used to improve tumor staging and prognosis prediction. Mucin antigen MUC4 (MUC4) has been implicated as a marker for poor survival in various tumors. However, prognostic significance of MUC4 for patients with CC remains undefined. The aim of the present meta-analysis was to investigate the association between MUC4 expression and overall survival (OS) of patients with resected CC. Methods: The meta-analysis was conducted in adherence to the MOOSE guidelines. PubMed, Embase databases, Cochrane Library and the Chinese SinoMed were systematically searched to identify eligible studies from the initiation of the databases to April, 2016. OSs were pooled by using hazard ratio (HR) with corresponding 95% confidence interval (CI). Random effect models were utilized because of the between-study heterogeneities. Results: Five studies reporting on 249 patients were analyzed: 94 (37.75%) were in positive or high expression group and 155 (62.25%) in negative or low expression group. The pooled HR for positive or high expression group was found to be 3.04 (95% CI 2.25–4.12) when compared with negative or low expression group with slight between-study heterogeneities (I2 3.10%, P = 0.39). The result indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. A commensurate result was identified by sensitivity analysis. The main limitations of the present meta-analysis were the rather small size of the studies included and relatively narrow geographical distribution of population. Conclusion: The result of this meta-analysis indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I–IV) and sgrade II–IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD. [ABSTRACT FROM AUTHOR]

Background: Awake craniotomy (AC) renders an expanded role in functional neurosurgery. Yet, evidence for optimal anaesthesia management remains limited. We aimed to summarise the latest clinical evidence of AC anaesthesia management and explore the relationship of AC failures on the used anaesthesia techniques. Methods: Two authors performed independently a systematic search of English articles in PubMed and EMBASE database 1/2007-12/2015. Search included randomised controlled trials (RCTs), observational trials, and case reports (n>4 cases), which reported anaesthetic approach for AC and at least one of our pre-specified outcomes: intraoperative seizures, hypoxia, arterial hypertension, nausea and vomiting, neurological dysfunction, conversion into general anaesthesia and failure of AC. Random effects meta-analysis was used to estimate event rates for four outcomes. Relationship with anaesthesia technique was explored using logistic meta-regression, calculating the odds ratios (OR) and 95% confidence intervals [95%CI]. Results: We have included forty-seven studies. Eighteen reported asleep-awake-asleep technique (SAS), twenty-seven monitored anaesthesia care (MAC), one reported both and one used the awake-awake-awake technique (AAA). Proportions of AC failures, intraoperative seizures, new neurological dysfunction and conversion into general anaesthesia (GA) were 2% [95%CI:1–3], 8% [95%CI:6–11], 17% [95%CI:12–23] and 2% [95%CI:2–3], respectively. Meta-regression of SAS and MAC technique did not reveal any relevant differences between outcomes explained by the technique, except for conversion into GA. Estimated OR comparing SAS to MAC for AC failures was 0.98 [95%CI:0.36–2.69], 1.01 [95%CI:0.52–1.88] for seizures, 1.66 [95%CI:1.35–3.70] for new neurological dysfunction and 2.17 [95%CI:1.22–3.85] for conversion into GA. The latter result has to be interpreted cautiously. It is based on one retrospective high-risk of bias study and significance was abolished in a sensitivity analysis of only prospectively conducted studies. Conclusion: SAS and MAC techniques were feasible and safe, whereas data for AAA technique are limited. Large RCTs are required to prove superiority of one anaesthetic regime for AC. [ABSTRACT FROM AUTHOR]

Background: Germline mutations in the BRCA1 and BRCA2 genes are the most frequent known hereditary causes of familial breast cancer. Little is known about the interaction of age at diagnosis, estrogen receptor (ER) and progesterone receptor (PgR) expression and outcomes in patients with BRCA1 or BRCA2 mutations. Methods: A PubMed search identified publications exploring the association between BRCA mutations and clinical outcome. Hazard ratios (HR) for overall survival were extracted from multivariable analyses. Hazard ratios were weighted and pooled using generic inverse-variance and random-effect modeling. Meta-regression weighted by total study sample size was conducted to explore the influence of age, ER and PgR expression on the association between BRCA mutations and overall survival. Results: A total of 16 studies comprising 10,180 patients were included in the analyses. BRCA mutations were not associated with worse overall survival (HR 1.06, 95% CI 0.84–1.34, p = 0.61). A similar finding was observed when evaluating the influence of BRCA1 and BRCA2 mutations on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89–1.61, p = 0.24; BRCA2: HR 1.01, 95% CI 0.80–1.27, p = 0.95). Meta-regression identified an inverse association between ER expression and overall survival (β = -0.75, p = 0.02) in BRCA1 mutation carriers but no association with age or PgR expression (β = -0.45, p = 0.23 and β = 0.02, p = 0.97, respectively). No association was found for BRCA2 mutation status and age, ER, or PgR expression. Conclusion: ER-expression appears to be an effect modifier in patients with BRCA1 mutations, but not among those with BRCA2 mutations. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to prospectively evaluate various quantitative metrics on FDG PET/CT for monitoring sunitinib therapy and predicting prognosis in patients with metastatic renal cell cancer (mRCC). Methods: Seventeen patients (mean age: 59.0 ± 11.6) prospectively underwent a baseline FDG PET/CT and interim PET/CT after 2 cycles (12 weeks) of sunitinib therapy. We measured the highest maximum standardized uptake value (SUVmax) of all identified lesions (highest SUVmax), sum of SUVmax with maximum six lesions (sum of SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) from baseline PET/CT and interim PET/CT, and the % decrease in highest SUVmax of lesion (%Δ highest SUVmax), the % decrease in sum of SUVmax, the % decrease in TLG (%ΔTLG) and the % decrease in MTV (%ΔMTV) between baseline and interim PET/CT, and the imaging results were validated by clinical follow-up at 12 months after completion of therapy for progression free survival (PFS). Results: At 12 month follow-up, 6/17 (35.3%) patients achieved PFS, while 11/17 (64.7%) patients were deemed to have progression of disease or recurrence within the previous 12 months. At baseline, PET/CT demonstrated metabolically active cancer in all cases. Using baseline PET/CT alone, all of the quantitative imaging metrics were predictive of PFS. Using interim PET/CT, the %Δ highest SUVmax, %Δ sum of SUVmax, and %ΔTLG were also predictive of PFS. Otherwise, interim PET/CT showed no significant difference between the two survival groups regardless of the quantitative metric utilized including MTV and TLG. Conclusions: Quantitative metabolic measurements on baseline PET/CT appears to be predictive of PFS at 12 months post-therapy in patients scheduled to undergo sunitinib therapy for mRCC. Change between baseline and interim PET/CT also appeared to have prognostic value but otherwise interim PET/CT after 12 weeks of sunitinib did not appear to be predictive of PFS. [ABSTRACT FROM AUTHOR]

EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox-proportional hazards models were utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome. [ABSTRACT FROM AUTHOR]

Objectives: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods: Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. Results: The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. Conclusions: Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background: Standardly collected clinical and pathological patient information has demonstrated only moderate ability to predict risk of biochemical recurrence (BCR) of prostate cancer in men undergoing salvage radiation therapy (SRT) for a rising PSA after radical prostatectomy (RP). Although elevated FOXA1 staining has been associated with poor patient outcomes following RP, it has not been studied in the specific setting of SRT after RP. The aim of this study was to evaluate the association between FOXA1 staining level and BCR after SRT for recurrent prostate cancer. Methods: A total of 141 men who underwent SRT at our institution were included. FOXA1 staining levels in primary tumor samples were detected using immunohistochemistry. FOXA1 staining percentage and intensity were measured and multiplied together to obtain a FOXA1 H-score (range 0–12) which was our primary staining measure. P-values ≤ 0.0056 were considered as statistically significant after applying a Bonferroni correction for multiple comparisons. Results: There was not a significant association between FOXA1 H-score and risk of BCR when considering H-score as an ordinal variable or as a categorical variable (all P≥0.090). Similarly, no significant associations with BCR were observed for FOXA1 staining percentage or staining intensity (all P≥0.14). Conclusions: FOXA1 staining level does not appear to have a major impact on risk of BCR after SRT. [ABSTRACT FROM AUTHOR]

Background: Prognostic factors and prognostic models play a key role in medical research and patient management. The Nottingham Prognostic Index (NPI) is a well-established prognostic classification scheme for patients with breast cancer. In a very simple way, it combines the information from tumor size, lymph node stage and tumor grade. For the resulting index cutpoints are proposed to classify it into three to six groups with different prognosis. As not all prognostic information from the three and other standard factors is used, we will consider improvement of the prognostic ability using suitable analysis approaches. Methods and Findings: Reanalyzing overall survival data of 1560 patients from a clinical database by using multivariable fractional polynomials and further modern statistical methods we illustrate suitable multivariable modelling and methods to derive and assess the prognostic ability of an index. Using a REMARK type profile we summarize relevant steps of the analysis. Adding the information from hormonal receptor status and using the full information from the three NPI components, specifically concerning the number of positive lymph nodes, an extended NPI with improved prognostic ability is derived. Conclusions: The prognostic ability of even one of the best established prognostic index in medicine can be improved by using suitable statistical methodology to extract the full information from standard clinical data. This extended version of the NPI can serve as a benchmark to assess the added value of new information, ranging from a new single clinical marker to a derived index from omics data. An established benchmark would also help to harmonize the statistical analyses of such studies and protect against the propagation of many false promises concerning the prognostic value of new measurements. Statistical methods used are generally available and can be used for similar analyses in other diseases. [ABSTRACT FROM AUTHOR]

Purpose: To discover novel prognostic biomarkers in ovarian serous carcinomas. Methods: A meta-analysis of all single genes probes in the TCGA and HAS ovarian cohorts was performed to identify possible biomarkers using Cox regression as a continuous variable for overall survival. Genes were ranked by p-value using Stouffer’s method and selected for statistical significance with a false discovery rate (FDR) <.05 using the Benjamini-Hochberg method. Results: Twelve genes with high mRNA expression were prognostic of poor outcome with an FDR <.05 (AXL, APC, RAB11FIP5, C19orf2, CYBRD1, PINK1, LRRN3, AQP1, DES, XRCC4, BCHE, and ASAP3). Twenty genes with low mRNA expression were prognostic of poor outcome with an FDR <.05 (LRIG1, SLC33A1, NUCB2, POLD3, ESR2, GOLPH3, XBP1, PAXIP1, CYB561, POLA2, CDH1, GMNN, SLC37A4, FAM174B, AGR2, SDR39U1, MAGT1, GJB1, SDF2L1, and C9orf82). Conclusion: A meta-analysis of all single genes identified thirty-two candidate biomarkers for their possible role in ovarian serous carcinoma. These genes can provide insight into the drivers or regulators of ovarian cancer and should be evaluated in future studies. Genes with high expression indicating poor outcome are possible therapeutic targets with known antagonists or inhibitors. Additionally, the genes could be combined into a prognostic multi-gene signature and tested in future ovarian cohorts. [ABSTRACT FROM AUTHOR]

Background: miRNAs might be potentially useful biomarkers for prediction of response to chemotherapeutic agents, radiotherapy and survival. The aim of this retrospective study was to validate miRNA response predictors in a cohort of patients with gastrooesophageal cancer in order to predict overall survival (OS) and disease-specific survival (DSS). Material and Methods: The study population encompassed 53 patients treated with curative intend for loco-regional gastrooesophageal cancer. miRNA expression was quantified from pre-therapeutic and diagnostic, formalin-fixed, paraffin embedded tumour specimens using Affymetrix GeneChip miRNA 1.0 Array. Based on growth inhibition of the NCI60 panel in the presence of cisplatin, epirubicine and capecitabine, a miRNA based response predictor was developed. The Cox proportional hazards model was applied to assess the correlations of the response predictor with OS and DSS. Results: A univariate analysis demonstrated a statistical significant improvement of OS for patients who had undergone surgical resection with prediction scores above the median prediction score (HR: 0.41 (95% CI: 0.17–0.96). Adjusting for surgery and stage, this predictor was identified to be independently associated with both OS (HR: 0.37 (95% CI: 0.16–0.87)) and DSS (HR: 0.32 (0.12–0.87)). Conclusion: The miRNA profile predictive for sensitivity to cisplatin, epirubicine and capecitabine was shown to be independently associated with OS and DSS in patients with gastrooesophageal cancer. [ABSTRACT FROM AUTHOR]

The head and neck squamous cell carcinoma (HNSCC) transcriptome has been profiled extensively, nevertheless, identifying biomarkers that are clinically relevant and thereby with translational benefit, has been a major challenge. The objective of this study was to use a meta-analysis based approach to catalog candidate biomarkers with high potential for clinical application in HNSCC. Data from publically available microarray series (N = 20) profiled using Agilent (4X44K G4112F) and Affymetrix (HGU133A, U133A_2, U133Plus 2) platforms was downloaded and analyzed in a platform/chip-specific manner (GeneSpring software v12.5, Agilent, USA). Principal Component Analysis (PCA) and clustering analysis was carried out iteratively for segregating outliers; 140 normal and 277 tumor samples from 15 series were included in the final analysis. The analyses identified 181 differentially expressed, concordant and statistically significant genes; STRING analysis revealed interactions between 122 of them, with two major gene clusters connected by multiple nodes (MYC, FOS and HSPA4). Validation in the HNSCC-specific database (N = 528) in The Cancer Genome Atlas (TCGA) identified a panel (ECT2, ANO1, TP63, FADD, EXT1, NCBP2) that was altered in 30% of the samples. Validation in treatment naïve (Group I; N = 12) and post treatment (Group II; N = 12) patients identified 8 genes significantly associated with the disease (Area under curve>0.6). Correlation with recurrence/re-recurrence showed ANO1 had highest efficacy (sensitivity: 0.8, specificity: 0.6) to predict failure in Group I. UBE2V2, PLAC8, FADD and TTK showed high sensitivity (1.00) in Group I while UBE2V2 and CRYM were highly sensitive (>0.8) in predicting re-recurrence in Group II. Further, TCGA analysis showed that ANO1 and FADD, located at 11q13, were co-expressed at transcript level and significantly associated with overall and disease-free survival (p<0.05). The meta-analysis approach adopted in this study has identified candidate markers correlated with disease outcome in HNSCC; further validation in a larger cohort of patients will establish their clinical relevance. [ABSTRACT FROM AUTHOR]

Background: Previous studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with gastric cancer. We therefore performed a meta-analysis to expound the relationship between p53 status and response to chemotherapy. Methods/Findings: Thirteen previously published eligible studies, including 564 cases, were identified and included in this meta-analysis. p53 positive status (high expression of p53 protein and/or a mutant p53 gene) was associated with improved response in gastric cancer patients who received chemotherapy (good response: risk ratio [RR]  = 0.704; 95% confidence intervals [CI]  = 0.550–0.903; P = 0.006). In further stratified analyses, association with a good response remained in the East Asian population (RR = 0.657; 95% CI = 0.488–0.884; P = 0.005), while in the European subgroup, patients with p53 positive status tended to have a good response to chemotherapy, although this did not reach statistical significance (RR = 0.828, 95% CI = 0.525–1.305; P = 0.417). As five studies used neoadjuvant chemotherapy (NCT) and one used neoadjuvant chemoradiotherapy (NCRT), we also analyzed these data, and found that p53 positive status was associated with a good response in gastric cancer patients who received chemotherapy-based neoadjuvant treatment (RR = 0.675, 95% CI = 0.463–0.985; P = 0.042). Conclusion: This meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in gastric cancer. Further prospective studies with larger sample sizes and better study designs are required to confirm our findings. [ABSTRACT FROM AUTHOR]