Jing Wen

Overexpression of cyclooxygenase-2 is associated with chemoradiotherapy resistance and prognosis in esophageal squamous cell carcinoma patients

Our objective was to investigate whether cyclooxygenase-2 (COX-2) expression can predict the patients response to chemoradiotherapy (CRT) and ensuing prognosis in esophageal squamous cell carcinoma (ESCC). The clinicopathological and follow-up data of 112 patients with ESCC who underwent CRT from January 2001 to June 2006 were analyzed retrospectively. The immunohistochemical expression level of COX-2 was examined for all biopsy specimens of primary tumors, and the correlation of COX-2 expression with the patients response to CRT and prognosis was examined. COX-2 positive immunostaining was detected in 111 (99.1%) of the patients, including overexpression in 54 (48.2%) patients and low expression in 58 (51.8%) of the patients. The response of tumors with a low level expression of COX-2 (70.7%, 41/58) was significantly higher than that of tumors with COX-2 overexpression (42.6%, 23/54; P = 0.003). Patients with a low level of COX-2 expression had a higher downstaged rate than those with a high level of COX-2 expression (9/13 vs 2/8), but the difference was not statistically significant (P = 0.08). In the definitive CRT group (91 cases), COX-2 overexpression was significantly associated with poor 3-year overall survival (P = 0.028). Multivariate analysis showed that only metastatic stage (nonregional node metastasis) was an independent prognosis factor. The assessment of COX-2 status may provide additional information to identify ESCC patients with poor chances of response to CRT and potential candidates for more individualized treatment.

MMP1 promotes tumor growth and metastasis in esophageal squamous cell carcinoma

Matrix metalloproteinases play an essential role in the progression of esophageal squamous cell carcinoma (ESCC). Here, we show that MMP1 expression was markedly increased in a majority of ESCC compared with nontumorous tissue. High expressions of MMP1 were closely associated with lymph node metastasis, microvessel density and advanced TNM stage. Kaplan-Meier and multivariate analyses indicated MMP1 as an independent factor for overall survival in two independent cohorts of 613 patients with ESCC. In vitro studies demonstrated that MMP1 overexpression resulted in enhanced cell viability, abilities of colony formation and cell migration. The knockdown of MMP1 in ESCC cells resulted in the opposite phenomenon. Consistently, in vivo data showed that ectopic expression of MMP1 promoted tumor growth and metastasis. Further study revealed that MMP1 facilitated ESCC through the activation of the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway by LY294002 significantly attenuated MMP1-mediated cell proliferation and migration. Taken together, our data suggest that MMP1 functions as an oncogene and serves as a prognostic biomarker and a potential therapeutic target in ESCC.

CyclinD1, p53, E-cadherin, and VEGF discordant expression in paired regional metastatic lymph nodes of esophageal squamous cell carcinoma: a tissue array analysis.

The correlation of biomarker expression between primary tumors and corresponding metastases has not yet been well reported in esophageal squamous cell carcinoma (ESCC). This study was to confirm whether primary ESCC tumors differ from their regional metastatic lymph nodes (RMLN) in CyclinD1, p53, E‐cadherin, and vascular endothelial growth factor (VEGF) expression and determine prognostic value of their alteration.

A novel blood tool of cancer prognosis in esophageal squamous cell carcinoma: The Fibrinogen/Albumin ratio

Background: Coagulation and nutrition play important roles in cancer progression. We aim to investigate the impact of the fibrinogen/albumin ratio(FAR) in esophageal squamous cell carcinoma (ESCC) patients. Methods: We retrospectively analyzed 1135 patients with radical esophagectomy for ESCC from January 2008 to December 2010 in our center. X-tile software was used to determine the optimal cutoff levels for these biomarkers. Results: The optimal cutoff value was 0.08 for the FAR by the X-tile software. The FAR was statistically significantly associated with age(p=0.003), sex(p=0.030), tumor length (p=0.043), pT status(p<0.001) and pN status(p<0.001). Pearsons correlation indicated that the FAR were positively associated with the serum C-reactive protein (CRP) ( r=0.583, p<0.001), and the NLR ( r=0.316, p<0.001). Multivariate analysis indicated that age, tumor grade, pT status, pN status and preoperative FAR were independent prognostic factors in patients with ESCC. Conclusions: Preoperative FAR was an independent prognostic factor in ESCC patients. Lower FAR may improve OS of ESCC patients.

Identification and Validation of Lymphovascular Invasion as a Prognostic and Staging Factor in Node-Negative Esophageal Squamous Cell Carcinoma

Introduction: Lymphovascular invasion (LVI) is a histopathological feature that is associated with an increased risk for micrometastasis. The aim of this study was to determine the prognostic and staging value of LVI among patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy. Methods: A prospective database of patients with ESCC was used to retrospectively analyze 666 cases to identify the relationship between LVI and survival, and to evaluate predictive accuracy of prognosis after combining LVI and the tumor, node, and metastasis (TNM) system. Pathological slides were reassessed by gastrointestinal pathologists according to the strict criteria; 1000‐bootstrap resampling was used for internal validation, and 222 cases from an independent multicenter database were used for external validation. Results: LVI was present in 33.8% of patients, and the proportion increased with advancing T and N classification. LVI was an independent predictor of unfavorable disease‐specific survival (DSS) (hazard ratio = 1.59, 95% confidence interval: 1.30–1.94) and disease‐free survival (DFS) (hazard ratio = 1.62, 95% confidence interval: 1.32–1.98) after T classification. Among node‐negative patients, LVI and T classification were two independent predictors of DSS and DFS (p < 0.001). The risk score model combing LVI and T classification improved the predictive accuracy of the TNM system for DSS and DFS by 3.5% and 4.8%, respectively (p < 0.001). The external validation showed congruent results. The DSS of TxN0MO disease with LVI was similar to the DSS of TxN1M0 (both p > 0.05). In contrast, LVI was not associated with DSS or DFS among node‐positive patients. Conclusions: The independent prognostic significance of LVI existed only in node‐negative patients with ESCC, and the combination of LVI and the TNM system enhanced the predictive accuracy of prognosis. After confirmation, node‐negative patients with LVI might be considered for upstaging in pathological staging.

Expression profiles of early esophageal squamous cell carcinoma by cDNA microarray

An effective way to decrease the mortality rate in esophageal cancer (EC) is to provide diagnosis and treatment for early EC patients. Identification of molecular markers would be helpful for early diagnosis. In this study, we obtained the gene expression profile of early esophageal squamous cell carcinoma (ESCC) and further screened molecular markers that might be useful in early diagnosis and treatment. RNA extracted from EC cancer tissues and matched normal esophageal epithelium of four EC patients were analyzed using whole-genome microarrays. Welchs t-test was applied to normalized data to identify genes expressed differently between cancer and normal tissues. Significantly differentially expressed genes were classified according to gene ontology. Gene mapping software was used to identify pathways involving the genes that were significantly changed. Among the 54,613 gene transcripts and variants analyzed, 367 were differentially expressed between early ESCC and normal esophageal epithelium (Welchs t-test, P<0.01). Specifically, 104 genes were significantly upregulated and 263 were downregulated in early ESCC, compared with normal esophageal epithelium. Functional gene sets expressed differentially between ESCC cancer and normal tissues included those involved in gene transcription, cell proliferation, motility, apoptosis, and metabolism (specifically, pathways of cell apoptosis, the cell cycle, G protein, and TGF-beta signal transduction). We conclude that a large number of genes are involved in the occurrence and development of early ESCC and take part in various cell processes and pathways. The present findings contribute theoretical information for further screening of genes related to early ESCC.

MiRNA Expression Analysis of Pretreatment Biopsies Predicts the Pathological Response of Esophageal Squamous Cell Carcinomas to Neoadjuvant Chemoradiotherapy.

Objective:To identify miRNA markers useful for esophageal squamous cell carcinoma (ESCC) neoadjuvant chemoradiotherapy (neo-CRT) response prediction. Summary:Neo-CRT followed by surgery improves ESCC patients’ survival compared with surgery alone. However, CRT outcomes are heterogeneous, and no current methods can predict CRT responses. Methods:Differentially expressed miRNAs between ESCC pathological responders and nonresponders after neo-CRT were identified by miRNA profiling and verified by real-time quantitative polymerase chain reaction (qPCR) of 27 ESCCs in the training set. Several class prediction algorithms were used to build the response-classifying models with the qPCR data. Predictive powers of the models were further assessed with a second set of 79 ESCCs. Results:Ten miRNAs with greater than a 1.5-fold change between pathological responders and nonresponders were identified and verified, respectively. A support vector machine (SVM) prediction model, composed of 4 miRNAs (miR-145-5p, miR-152, miR-193b-3p, and miR-376a-3p), were developed. It provided overall accuracies of 100% and 87.3% for discriminating pathological responders and nonresponders in the training and external validation sets, respectively. In multivariate analysis, the subgroup determined by the SVM model was the only independent factor significantly associated with neo-CRT response in the external validation sets. Conclusions:Combined qPCR of the 4 miRNAs provides the possibility of ESCC neo-CRT response prediction, which may facilitate individualized ESCC treatment. Further prospective validation in larger independent cohorts is necessary to fully assess its predictive power.

Prognostic value of HOXB7 mRNA expression in human oesophageal squamous cell cancer

Abstract Objective: This study was to determine the role of HOXB7 in predicting outcomes of patients with oesophageal squamous cell cancer (OSCC). Methods: Samples were collected from 179 OSCC patients. HOXB7 mRNA expression was measured by quantitative real-time polymerase chain reaction. Results: HOXB7 mRNA expression was up-regulated in 85.1% of OSCC tumorous tissues, and correlated with age, pathological T and N category, as well as cancer-specific survival (CSS). However, subgroup analysis revealed its discernibility on CSS was only pronounced in early stage. Conclusions: HOXB7 mRNA expression might serve as a novel prognostic biomarker for resected OSCC patients in early stage.

Localization of peripheral pulmonary lesions to aid surgical resection: a novel approach for electromagnetic navigation bronchoscopic dye marking

OBJECTIVES Video‐assisted thoracoscopic sublobar resection of ultra‐small, non‐visible and non‐palpable pulmonary lesions is challenging. The purpose of this study was to explore an alternative and efficient method for the localization of pulmonary lesions using electromagnetic navigation bronchoscopy (ENB). METHODS Between May 2015 and April 2016, 24 consecutive patients with 30 pulmonary peripheral lesions underwent video‐assisted thoracoscopic surgery for sublobar resection in our hospital. ENB was performed before surgery to guide a catheter adjacent to the target lesion, and fibrin sealant mixed with methylene blue was injected. RESULTS All patients underwent ENB with pleural dye marking followed immediately by surgery. No surgical complications occurred. The median size of the nodules was 11.0 mm (range, 6‐19 mm). The median navigation time was 18.0 min (range, 13 to 120 min), and the average interval between dye marking and thoracic surgery was 22.1 min (range, 15‐40 min). In all cases, the target pulmonary parenchyma was stained and had tactile sense with few complications. All lesions were fully excised, and pathological examination confirmed the accuracy of the dye staining. CONCLUSIONS Fibrin sealant mixed with methylene blue injection with ENB guidance is a new effective approach to localize even ultra‐small and non‐palpable pulmonary lesions. The visible staining and tactile sensation of this method may allow more rapid intraoperative identification of lesions.

Prognostic Relevance of Id-1 Expression in Patients With Resectable Esophageal Squamous Cell Carcinoma

BACKGROUND Inhibitor of differentiation or DNA binding 1 (Id-1) is a transcriptional regulator that is associated with enhanced malignant potential and unfavorable survival in many cancers. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) has not been elucidated adequately. The purpose of this study was to explore the pattern of Id-1 expression and analyze its correlation with clinical outcomes of patients with resectable ESCC. METHODS Primary tumors from 407 surgically resected ESCC specimens assembled on tissue microarrays were evaluated with immunohistochemical analysis for Id-1. The effect of Id-1 expression on survival outcome was analyzed by the Kaplan-Meier method. RESULTS The expression of Id-1 correlated closely with pT category (p<0.001), pathologic staging (p<0.001), and pN category (p<0.001). The sensitivity, specificity, and accuracy of predicting lymph node metastasis by Id-1 expression were 93.3%, 94.7%, and 94.1%, respectively. Disease-specific survival was significantly favorable in patients with low-level Id-1 expression (p<0.001). Overexpression of Id-1 was also effective to predict unfavorable survival in subgroups of patients with poor differentiation (p<0.001) or with advanced T staging (p<0.001). Multivariate analysis showed that the level of Id-1 expression was an independent prognostic factor in ESCC (p<0.001; relative risk, 1.578). CONCLUSIONS Expression of Id-1 can be used as a complement for predicting lymph node metastasis in pretreatment workup. High level of Id-1 expression suggested unfavorable prognosis for patients with resectable ESCC.