Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation.

Cuproptosis, a new type of programmed cell death (PCD), is closely related to cellular tricarboxylic acid cycle and cellular respiration, while hypoxia can modulate PCD. However, their combined contribution to tumor subtyping remains unexplored. Here, we applied a multi-omics approach to classify TCGA_COADREAD based on cuproptosis and hypoxia. The classification was validated in three colorectal cancer (CRC) cohorts and extended to a pan-cancer analysis. The results demonstrated that pan-cancers, including CRC, could be divided into three distinct subgroups (cuproptosis-hypoxia subtypes, CHSs): CHS1 had active metabolism and poor immune infiltration but low fibrosis; CHS3 had contrasting characteristics with CHS1; CHS2 was intermediate. CHS1 may respond well to cuproptosis inducers, and CHS3 may benefit from a combination of immunotherapy and anti-fibrosis/anti-hypoxia therapies. In CRC, the CHSs also showed a significant difference in prognosis and sensitivity to classic drugs. Organoid-based drug sensitivity assays validated the results of transcriptomics. Cell-based assays indicated that masitinib and simvastatin had specific effects on CHS1 and CHS3, respectively. A user-friendly website based on the classifier was developed (https://fan-app.shinyapps.io/chs_classifier/) for accessibility. Overall, the classifier based on cuproptosis and hypoxia was applicable to most pan-cancers and could aid in personalized cancer therapy.

Laparoscopic resection is not superior to endoscopic resection for relative small gastric gastrointestinal stromal tumors: A propensity score-matched study.

Background and Aim: Endoscopic resection (ER) and laparoscopic resection (LAP) have been recommended for the treatment of gastric gastrointestinal stromal tumors (GISTs) less than 2 cm. However, the therapeutic approach for gastric GISTs between 2 and 5 cm in diameter is still under debate. In this retrospective study, we aimed to evaluate the feasibility, efficacy, and safety of ER for gastric GISTs (2-5 cm) compared with LAP. Methods: From January, 2011 to January, 2018, 197 patients with GISTs at our institution with tumor diameter between 2 and 5 cm were included in our study. Clinical baseline characteristics, histopathological results, and perioperative outcomes were collected and compared in all the patients. Propensity score matching (PSM) methods were used to balance baseline characteristics. Results: There was no significant difference in age (p = 0.246), gender (p = 0.572), tumor location (p = 0.333), pathological risk classification (p = 0.543), Ki-67 index (p = 0.212), and follow-up time (p = 0.831) in the ER and LAP groups. However, significance difference was found in times to liquid diet intake (4.45 ± 1.2 vs. 5.40 ± 1.5 days, p = 0.013) and hospital stays (7.72 ± 1.1 vs. 10.01 ± 1.3 days, p < 0.001). During the follow-up period, there was one recurrence in the ER group vs. two recurrences in the LAP group. After PSM, the tumor size was balanced between the two groups with 49 patients in each group. The times to liquid diet intake (4.18 ± 1.3 vs. 5.16 ± 1.6 days, p = 0.042) and hospital stay days (7.12 ± 1.1 vs. 9.94 ± 1.3, p < 0.0001) were still short in the ER group. Conclusions: ER is more associated with a quick postoperative recovery than LAP. ER could be an alternative approach for gastric GISTs (2-5 cm). However, the long-term follow-up outcomes are still unclear and random control trials are needed.

Personalized four-category staging for predicting prognosis in patients with small bowel Adenocarcinoma: an international development and validation study.

BACKGROUND: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. METHODS: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988-2010, 437 patients from SEER database between 2011-2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. FINDINGS: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P < 0.001), validation cohort (0.682 vs. 0.654, P = 0.022), and test cohort (0.659 vs. 0.611, P = 0.023), respectively. TLM staging continued to show its higher predictive efficacy than the 8th TNM in TNM stage II/III patients or in patients with lymph node yield less than 8. INTERPRETATION: TLM staging showed a better prognostic performance than the 8th TNM staging especially TNM stage II/III or patients with lymph node yield less than 8 and therefore, could serve to complement the TNM staging in patients with SBA. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Inverse Association of Age with Risk of Lymph Node Metastasis in Superficial Colorectal Cancer: A Large Population-Based Study.

BACKGROUND: Superficial colorectal cancer (SCRC) is defined as colorectal cancer (CRC) confined to the mucosa or submucosa. Endoscopic resection (ER) is widely used to resect differentiated SCRC from patients without lymph node metastasis (LNM). However, it is unclear whether ER is suitable for use with patients with differentiated early-onset SCRC because early-onset CRC is more aggressive. Therefore, we aimed to investigate the association between age of CRC onset and LNM. MATERIALS AND METHODS: We retrieved data for patients with surgically resected differentiated-type SCRCs from the Surveillance, Epidemiology, and End Results (SEER) database. Rate of LNM was compared among patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years. The association between age and LNM was further examined using multivariate logistic regression. RESULTS: We retrieved 34,506 records of differentiated SCRCs from the SEER database, including 667 patients aged 18-39 years, 2,385 aged 40-49, 8,075 aged 50-59 years, 9,577 aged 60-69 years, and 13,802 aged ≥70 years. Rates of LNM were 15.74%, 14.13%, 10.67%, 8.07%, and 6.76% for patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years, respectively. We found an inverse correlation between age at diagnosis and risk of LNM from the univariate analysis (p < .001). Compared with patients aged 18-39, the odds ratios with 95% confidence interval (CI) for patients aged 40-49, 50-59, 60-69, and ≥70 years were 0.90 (0.71-1.15, p = .376), 0.69 (0.56-0.87, p = .001), 0.54 (0.43-0.68, p < .001), and 0.47 (0.38-0.60, p < .001), respectively. CONCLUSION: In differentiated SCRCs, younger age at diagnosis was associated with higher risk of LNM. IMPLICATIONS FOR PRACTICE: Endoscopic resection (ER) is widely used to resect differentiated superficial colorectal cancer (SCRC) without lymph node metastasis (LNM). However, no study has ever investigated risk of LNM of early-onset SCRC compared with average onset SCRC to explore whether ER is suitable for early-onset SCRC. To the authors' knowledge, this population-based study is the first study to find inverse correlation between age at diagnosis and risk of LNM in differentiated SCRCs. This finding indicates that ER may not be suitable for young patients with differentiated SCRC. Because the 30-day operative mortality after surgery is higher but the risk of LNM is lower in older patients compared with younger patients, ER for differentiated SCRCs may be advantageous over surgery for older patients.

Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer.

BACKGROUND: The hunt for the molecular markers with specificity and sensitivity has been a hot area for the tumor treatment. Due to the poor diagnosis and prognosis of pancreatic cancer (PC), the excision rate is often low, which makes it more urgent to find the ideal tumor markers. METHODS: Robust Rank Aggreg (RRA) methods was firstly applied to identify the differentially expressed genes (DEGs) between PC tissues and normal tissues from GSE28735, GSE15471, GSE16515, and GSE101448. Among these DEGs, the highly correlated genes were clustered using WGCNA analysis. The co-expression networks and molecular complex detection (MCODE) Cytoscape app were then performed to find the sub-clusters and confirm 35 candidate genes. For these genes, least absolute shrinkage and selection operator (lasso) regression model was applied and validated to build a diagnostic risk score model. Cox proportional hazard regression analysis was used and validated to build a prognostic model. RESULTS: Based on integrated transcriptomic analysis, we identified a 19 gene module (SYCN, PNLIPRP1, CAP2, GNMT, MAT1A, ABAT, GPT2, ADHFE1, PHGDH, PSAT1, ERP27, PDIA2, MT1H, COMP, COL5A2, FN1, COL1A2, FAP and POSTN) as a specific predictive signature for the diagnosis of PC. Based on the two consideration, accuracy and feasibility, we simplified the diagnostic risk model as a four-gene model: 0.3034*log2(MAT1A)-0.1526*log2(MT1H) + 0.4645*log2(FN1) -0.2244*log2(FAP), log2(gene count). Besides, a four-hub gene module was also identified as prognostic model = - 1.400*log2(CEL) + 1.321*log2(CPA1) + 0.454*log2(POSTN) + 1.011*log2(PM20D1), log2(gene count). CONCLUSION: Integrated transcriptomic analysis identifies two four-hub gene modules as specific predictive signatures for the diagnosis and prognosis of PC, which may bring new sight for the clinical practice of PC.

Comparison of three lymph node staging schemes for predicting the outcome in patients with small bowel adenocarcinoma: A population-based cohort and international multicentre cohort study.

BACKGROUND: The prognostic roles of three common lymph node staging schemes, number of positive lymph nodes (pN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in small bowel adenocarcinoma (SBA) are unclear. We assessed their prognostic ability in SBA. METHODS: A total of 2128 patients diagnosed with SBA between 1988 and 2010 from the Surveillance, Epidemiology, and End Results (SEER) database and 186 patients from 15 hospitals in France and China were identified. We evaluated the prognostic ability of the schemes in both continuous and stratified patterns using R2, Harrell's C, and time-dependent receiver operating characteristic curve analyses. FINDINGS: For continuous pattern, the LODDS had a better capacity of discrimination and higher accuracy of prognosis than pN and LNR. Similarly, the stratified LODDS classification had a better performance of discrimination and higher accuracy of prognosis than the pN and LNR classification. The multivariable model using the LODDS classification also showed superiorly predictive accuracy and discriminatory capacity to those of the 7th and, 8th TNM node and LNR classification. These results were fully validated in an independent international multicentre cohort. INTERPRETATION: The LODDS scheme showed a better prognostic performance than the LNR or pN schemes in patients with SBA regardless of continuous or stratified pattern. The LODDS scheme could serve as an auxiliary to lymph node staging systems in future revisions of the American Joint Committee on Cancer (AJCC) manual. FUND: This work was funded by the Zhejiang Province Natural Science Fund of China.

Robust analysis of novel mRNA-lncRNA cross talk based on ceRNA hypothesis uncovers carcinogenic mechanism and promotes diagnostic accuracy in esophageal cancer.

BACKGROUND: ceRNAs have emerged as pivotal players in the regulation of gene expression and play a crucial role in the physiology and development of various cancers. Nevertheless, the function and underlying mechanisms of ceRNAs in esophageal cancer (EC) are still largely unknown. METHODS: In this study, profiles of DEmRNAs, DElncRNAs, and DEmiRNAs between normal and EC tumor tissue samples were obtained from the Cancer Genome Atlas database using the DESeq package in R by setting the adjusted P<0.05 and |log2(fold change)|>2 as the cutoff. The ceRNA network (ceRNet) was initially constructed to reveal the interaction of these ceRNAs during carcinogenesis based on the bioinformatics of miRcode, miRDB, miRTarBase, and TargetScan. Then, independent microarray data of GSE6188, GSE89102, and GSE92396 and correlation analysis were used to validate molecular biomarkers in the initial ceRNet. Finally, a least absolute shrinkage and selection operator logistic regression model was built using an oncogenic ceRNet to diagnose EC more accurately. RESULTS: We successfully constructed an oncogenic ceRNet of EC, crosstalk of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1. In addition, the risk-score model -0.0053*log2(CADM2)+0.0168*log2(SERPINE1)-0.0073*log2(ADAMTS9-AS2)+0.0905*log2(PVT1)+0.0047*log2(hsa-miR372)-0.0193*log2(hsa-miR145), (log2[gene count]) could improve diagnosis of EC with an AUC of 0.988. CONCLUSION: We identified two novel pairs of ceRNAs in EC and its role of diagnosis. The pairs of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1 were likely potential carcinogenic mechanisms of EC, and their joint detection could improve diagnostic accuracy.

Additional lymphadenectomy might not improve survival of patients with resectable metastatic colorectal adenocarcinoma of T4 stage, proximal location, poor/undifferentiation, or N3/N4 stages: a large population-based study.

This study was performed to evaluate the prognostic effect of lymphadenectomy on outcomes in patients with resectable metastatic colorectal adenocarcinoma (mCRC). We selected patients with mCRC from 2004 to 2013 from Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan-Meier analysis, univariate Cox regression and multivariate Cox regression analysis were performed to assess the clinical value of lymphadenectomy on overall survival (OS) and cause-specific survival (CSS) of patients with resectable mCRC. A total 24178 eligible patients were included, 23056 (95.36%) of which received lymphadenectomy. Results showed that lymphadenectomy was an independent protective factor for survival of patients with mCRC overall [OS (HR: 0.86, 95%CI: 0.79-0.93, P=0.002) and CSS (HR: 0.85, 95%CI: 0.78-0.93, P<0.001)]. Further analysis showed that lymphadenectomy improved survival of patients with T1 stage [OS (HR: 0.51, 95%CI: 0.39-0.66, P<0.001); CSS (HR: 0.48, 95%CI: 0.36-0.65, P<0.001)], distal [OS (HR: 0.65, 95%CI: 0.56-0.75, P<0.001); CSS (HR: 0.65, 95%CI: 0.65-0.75, P<0.001)], rectal [OS (HR: 0.60, 95%CI: 0.52-0.70, P<0.001); CSS (HR: 0.59, 95%CI: 0.51-0.69, P<0.001)] , well/moderately differentiated [OS (HR: 0.62, 95%CI: 0.56-0.70, P<0.001); CSS (HR: 0.62, 95%CI: 0.55-0.69, P<0.001)], N1 stage [OS (HR: 0.76, 95%CI: 0.67-0.85, P<0.001); CSS (HR: 0.74, 95%CI: 0.65-0.84, P<0.001)] and N2 stage [OS (HR: 0.63, 95%CI: 0.54-0.74, P<0.001; CSS (HR: 0.65, 95%CI: 0.55-0.77, P<0.001)) mCRC. While lymphadenectomy might not improve survival of patients with T4 stage, proximal, poor or undifferentiated, N3 and N4 stage mCRC. In general, Additional lymphadenectomy was suggested for patients with mCRC overall. However, lymphadenectomy might not improve survival of patients with mCRC of higher malignancy tendency, such as T4 stage, proximal location, poor or undifferentiation, N3 and N4 stages.

Role of differentially expressed genes and long non-coding RNAs in papillary thyroid carcinoma diagnosis, progression, and prognosis.

Currently, the combination of ultrasonography and fine-needle aspiration biopsy (FNAB) can not discriminate between benign and malignant tumor of thyroid in some cases. The main issue in assessing the patients with thyroid nodules is to distinguish thyroid cancer from benign nodules, and reduce diagnostic surgery. To identify potential molecular biomarkers for patients with indeterminate FNAB, we explored the differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs) in TCGA database between 318 papillary thyroid carcinoma (PTC) tissues and 35 normal thyroid gland tissues by DESeq R. Furthermore, DEGs were verified by gene expression profile GSE33630. Ten top DEGs and DElncRNAs were identified as candidate biomarkers for diagnosis and Lasso (Least Absolute Shrinkage and Selection Operator) logistic regression analysis were performed to improve the diagnostic accuracy of them. Besides, partial molecular biomarkers of top DEGs and DElncRNAs were closely related to the tumor stage (T), lymph node metastasis (N), metastasis (M) and pathological stage of PTC, which could reflect behavior of tumor progression. According to multivariate Cox analysis, the combination of two DEGs (METTL7B and KCTD16) and two DElncRNAs (LINC02454 and LINC02471) could predict the outcome in a more exact way. In conclusion, top DEGs and DElncRNAs could raise diagnosis of PTC in indeterminate FNAB specimens, and some could function as molecule biomarkers for tumor progression and prognosis.

Combination of TNM staging and pathway based risk score models in patients with gastric cancer.

Due to the complexity and heterogeneity of gastric cancer (GC) in individual patient, current staging system is inadequate for predicting outcome of GC. Comprehensive computational and bioinformatics approach may triumph for the prediction. In this study, GC patients were devided according to stage and treatment: curative surgery plus chemoradiotherapy in stage II, curative surgery plus chemoradiotherapy in stages III, and IV, unresectable metastatic gastric cancer. The training sets were downloaded from GEO datasets (GSE26253 and GSE14208). Gene set enrichment analysis (GSEA) was performed to explore enriched difference between recurrence and nonrecurrence. The core enrichment genes of enriched pathways significantly associated with recurrence or progression were identified using Cox proportional hazards analysis. Thereafter, the risk score models were externally validated in independent datasets-GSE15081 and The Cancer Genome Atlas (TCGA). We generated respective risk score models of patients in different stages and treatment. A five-gene signature comprising FARP1, SGCE, SGCA, LAMA4, and COL9A2 was strongly associated with recurrence of patients with curative surgery plus chemoradiotherapy in stage II. A six-gene signature consisting of SHH, NF1, AP4B1, COMP, MATN3, and CCL8 was correlated with recurrence of patients with curative surgery plus chemoradiotherapy in stages III and IV. And a four-gene signature composing of ABCC2, AHNAK2, RNF43, and GSPT2 was highly related to progression of patients with unresectable metastatic GC. Taking into consideration TNM stage and gene signature reflecting recurrence or progression, the risk score models significantly improved the accuracy in predicting outcome of GC.

CD44 promotes the migration of bone marrow-derived mesenchymal stem cells toward glioma.

Previous in vivo and in vitro studies have shown that human mesenchymal stem cells (MSCs) exhibit tropism for gliomas. However, the mechanism underlying this directed migration remains unclear. The aim of the present study was to investigate the possible mechanism underlying platelet-derived growth factor-BB (PDGF-BB)-induced chemotactic migration of bone marrow-derived MSCs (BMSCs) toward glioma. Rat glioma C6 cell-conditioned medium was utilized to evaluate the chemotactic response of BMSCs toward glioma using an in vitro migration assay. Recombinant rat PDGF-BB was added to C6 cell-conditioned medium to assess its effect on the tropism of BMSCs. The effect of PDGF-BB on the expression levels of cluster of differentiation (CD)44 in BMSCs was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence assays. The results revealed that chemotactic migration was induced in BMSCs by rat glioma C6 cell-conditioned medium, which was enhanced by PDGF-BB treatment in a dose-dependent manner. Furthermore, RT-PCR and immunofluorescence assays showed that CD44 expression was upregulated in BMSCs following treatment with 40 ng/ml PDGF-BB for 12 h. Additionally, 3-h pretreatment with the anti-CD44 neutralizing antibody OX-50 was observed to attenuate the tropism of BMSCs toward glioma in the presence or absence of PDGF-BB. The results of the present study indicate that CD44 mediates the tropism of BMSCs toward glioma, and PDGF-BB promotes the migration of BMSCs toward glioma via the upregulation of CD44 expression in BMSCs. These findings suggest CD44 inhibition may be a potential therapeutic target for the treatment of glioma.

Fish consumption and lung cancer risk: systematic review and meta-analysis.

There is evidence pointing to a possible role of diet on cancer etiology. Prior studies evaluating the relationship between fish consumption and lung cancer risk reported inconclusive results. The aim of this study was to achieve a comprehensive assessment of the relationship between fish consumption and lung cancer risk through systematic review and meta-analysis. Case control and cohort studies up to September 1, 2012 about fish consumption and lung cancer risk were confirmed by an online search. Separate relative risk (RR) or odds ratio (OR) estimates with 95% confidence interval (CI) of the relationship between lung cancer risk and fish consumption level from the included articles were combined by Stata11.0 software. Publication bias was evaluated by Egger's linear regression test and funnel plot. Twenty articles (17 case-control and 3 cohort studies) comprising 8799 cases of lung cancer and 17,072 noncases were included in the final analysis. The pooled results from all studies indicated that high fish consumption was significantly associated with a decreased risk of lung cancer (pooled RR: 0.79; 95% CI: 0.69-0.92). There was heterogeneity among the studies (I(2) = 73%, P < 0.05). Pooled RR in case control and cohort studies were 0.76 (95% CI: 0.63-0.91) and 0.95 (95% CI: 0.73-1.24), respectively. Omission of any single study had little effect on the combined risk estimates. This article had no publication bias. This study identifies a significant association between fish consumption and lung cancer, confirming a protective role of fish in lung cancer. More well-designed prospective studies are required to further verify the effect of fish consumption on lung cancer.

Cyclooxygenase-2 expression is associated with poor overall survival of patients with gastric cancer: a meta-analysis.

BACKGROUND: Cyclooxygenase-2 (COX-2) is believed to be involved in gastric carcinogenesis. However, it is still controversial whether COX-2 expression can be regarded as a prognostic factor for gastric cancer patients. AIM: To obtain a more accurate relationship between COX-2 overexpression and prognosis in gastric cancer by meta-analysis. METHOD: Relevant articles published up to May 2013 were searched by use of several keywords in electronic databases. Separate hazard ratio (HR) estimates and 95 % confidence intervals (95 % CI) for COX-2 overexpression and overall survival (OS) and disease-free survival (DFS) with gastric cancer were extracted. Combined HR with 95 % CI was calculated by use of Stata11.0 software to estimate the size of the effect. Publication bias testing and sensitivity analysis were also performed. RESULTS: A total of 27 studies which included 3,891 gastric cancer patients were combined in the final analysis. Combined results suggested that COX-2 overexpression was associated with an unfavorable OS (HR 1.58, 95 % CI 1.36-1.84) but not DFS (HR 1.15, 95 % CI 0.93-1.43) among patients with gastric cancer. Publication bias was absent. Sensitivity analysis suggested that the results of this meta-analysis were robust. CONCLUSIONS: The results of this meta-analysis suggest that high COX-2 expression may be an independent risk factor for poor OS of patients with gastric cancer. More large prospective studies are now needed to further clarify the prognostic value of COX-2 expression for DFS in gastric cancer.

Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: a meta-analysis.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) is related to tumor invasion and metastasis. However, the role of MMP-9 expression in breast cancer survival remains controversial. The purpose of this study was to accomplish a more accurate estimation of the association between MMP-9 expression and survival results in breast cancer patients through meta-analysis. METHODS: A meta-analysis of published studies investigating the effects of positive MMP-9 expression on both relapse free survival (RFS) and overall survival (OS) was performed. Relevant literature was confirmed by searching electronic databases including PubMed, Ovid, EMBASE and China National Knowledge Infrastructure (CNKI) before November 1, 2012. Individual hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95% CIs were used to evaluate the strength of the association between positive MMP-9 expression and survival results of breast cancer patients. Funnel plot and Egger's regression tests were used to evaluate publication bias. Heterogeneity and sensitivity analysis was also conducted. All the work was completed using STATA. RESULTS: A total of 2,344 patients from 15 evaluative studies were finally included. Pooled HRs and 95% CIs suggested that MMP-9 overexpression had an unfavorable impact on both OS (HR: 1.70, 95% CI: 1.41-2.04) and RFS (HR: 1.54, 95% CI: 1.17-2.01) in breast cancer patients. There was no significant heterogeneity observed in the studies reported for OS (P=0.360, I2=8.8%), but not RFS (P=0.002, I2=67%). Publication bias was absent among the studies both in OS and RFS cases (t=-0.54, P=0.605 and t=1.71, P=0.131, respectively). Omission of any single study had little effect on the combined risk estimates on sensitivity analysis. CONCLUSION: The results of this meta-analysis suggest that positive MMP-9 expression confers a higher risk of relapse and a worse survival in patients with breast cancer. Larger prospective studies are now needed to evaluate the clinical utility of MMP-9 expression.

Prognostic value of survivin expression in breast cancer patients: a meta-analysis.

The prognostic role of survivin expression in breast cancer patients has been widely reported. However, controversy still remains. Thus, a meta-analysis was conducted to obtain a more precise estimation of the relationship between survivin expression and overall survival (OS) in breast cancer patients. Relevant articles were selected for further assessment by online search in PubMed, EMBASE, and China National Knowledge Infrastructure. Pooled hazard ratios (HR) with 95 % confidence interval (95 % CI) were used to estimate the strength of the association between survivin expression and OS in breast cancer patients. Funnel plots of Begger's and Egger's linear regression test were used to evaluate the publication bias. Heterogeneity and sensitivity analysis were also assessed. Fifteen studies were included in the final analysis with the total number of 2,202 patients. There was a significant association between positive survivin expression and a poor OS consequence in patients with breast cancer (pooled HR 1.80, 95 % CI 1.55-2.09). No significant heterogeneity was observed among all the eligible studies (x (2) = 21.87, p = 0.081, I (2) = 36.0 %). Publication bias was absent. Sensitivity analysis revealed that the results of this meta-analysis were robust. Our results suggested that high survivin expression had an unfavorable prognostic role for patients with breast cancer.