Prognostic impact of lymph node harvest for patients with node-negative esophageal squamous cell carcinoma: a large-scale multicenter study.

BACKGROUND: We examined the association between the number of resected lymph nodes and survival to determine the optimal lymphadenectomy for thoracic esophageal squamous cell carcinoma (ESCC) patients with negative lymph node. METHODS: We included 1,836 patients from Chinese three high-volumed hospitals with corresponding clinicopathological characters such as gender, age, tumor location, tumor grade and TNM stage of patients. The median follow-up of included patients was 45.7 months (range, 1.03-117.3 months). X-Tile plot was used to identify the lowest number of lymphadenectomy. The multivariate model's construction was in use of parameters with clinical significance for survival and a nomogram based on clinical variable with P<0.05 in Cox regression analysis. Both two models were validated using a cohort extracted from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database between 1975 and 2016 (n=951). RESULTS: More lymphadenectomy numbers were significantly associated with better survival in patients both in training cohort [hazard ratio (HR) =0.980; 95% confidence interval (CI): 0.971-0.988; P<0.001] and validation cohort (HR =0.980; 95% CI: 0.968-0.991; P=0.001). Cut-off point analysis determined the lowest number of 9 for thoracic ESCC patients in N0 stage through training cohort (C-index: 0.623; sensitivity: 80.7%; 1 - specificity: 72.5%) when compared with 10 in validation cohort (C-index: 0.643; sensitivity: 78.2%; 1 - specificity: 63.0%). The cut-off points of 9 were examined in training cohort and validated in the divided cohort from validation cohort (all P<0.05). Meanwhile, nomograms for both cohorts were constructed and the calibration curves for both cohorts agreed well with the actual observations in terms of predicting 3- and 5-year survival, respectively. CONCLUSIONS: Larger number for lymphadenectomy was associated with better survival in thoracic ESCC patients in N0 stage. Nine was what we got as the lowest number for lymphadenectomy in pN0 ESCC patients through this study, and our result should be confirmed further.

Prognostic Role of Nodal Skip Metastasis in Thoracic Esophageal Squamous Cell Carcinoma: A Large-Scale Multicenter Study.

BACKGROUND: Nodal-skip metastasis (NSM) is found in esophageal squamous cell carcinoma (ESCC), but its prognostic role is controversial. This study aimed to investigate the prognostic value of NSM for thoracic ESCC patients. METHODS: Categorization of NSM was according to the N groupings of Japan Esophagus Society (JES) staging system, which is dependent on tumor location. Using the Kaplan-Meier method and Cox-regression analysis, this study retrospectively analyzed the overall survival (OS) for 2325 ESCC patients after radical esophagectomy at three high-volume esophageal cancer centers. Predictive models also were constructed. RESULTS: The overall NSM rate was 20% (229/1141): 37.4% in the in upper, 12.9% in the middle, and 22.2% in the lower thoracic ESCC. The patients with NSM always had a better prognosis than those without NSM. Furthermore, NSM was an independent prognostic factor for thoracic ESCC patients (hazard ratio [HR], 0.633; 95% confidence interval [CI], 0.499-0.803; P < 0.001). By integrating the prognostic values of NSM and N stage, the authors proposed the new N staging system. The categories defined by the new N staging system were more homogeneous in terms of OS than those defined by the current N system. Moreover, the new N system was shown to be an independent prognostic factor also for thoracic ESCC patients (HR, 1.607; 95% CI, 1.520-1.700; P < 0.001). Overall, the new N system had slightly better homogeneity, discriminatory ability, and monotonicity of gradient than the current N system. CONCLUSIONS: This study emphasized the prognostic power of NSM and developed a modified node-staging system to improve the efficiency of the current International Union for Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) N staging system.

Lymph Node Station-Based Nodal Staging System for Esophageal Squamous Cell Carcinoma: A Large-Scale Multicenter Study.

BACKGROUND: The American Joint Committee on Cancer (AJCC) nodal staging for esophageal squamous cell carcinoma (ESCC) has been defined by the number of metastatic lymph nodes (N system). However, the precise counting of individual positive lymph nodes is difficult and unreliable in some clinical settings, which calls for a more available and reliable system. This study examined the performance of a newly proposed nodal staging category, termed the S system, based on the number of metastatic lymph node stations. METHODS: Using the Kaplan-Meier method and Cox-regression analysis, this study retrospectively analyzed the overall survival (OS) of 2285 ESCC patients who underwent esophagectomy in three major China hospitals. Predictive models were constructed, and C-indices were computed to evaluate the discriminatory power of the S system, and to compare it with the N system. RESULTS: The categories defined by the S system were more homogeneous in terms of OS than those defined by the N system. Overall, the S system had a slightly better C-index (p = 0.659) than the N system ((p = 0.658). Subgroup analyses also showed that the C-index of the S system was slightly better than that of the N system for each subgroup of sex and age, but the two were comparable for each subgroup defined by the tumor location. CONCLUSION: The S system demonstrated a competing prognostic performance compared with the current AJCC N system. Due to the relatively easy accessibility of the number of metastatic lymph node stations, the S system may offer an easier option for cancer staging without a loss of discriminative power.

Curcumin Inhibits Proliferation of Synovial Cells by Downregulating Expression of Matrix Metalloproteinase-3 in Osteoarthritis.

OBJECTIVE: To investigate the association between curcumin and the differentially expressed genes (DEG) in synovial tissues of osteoarthritis. METHODS: Microarray analysis was used to screen for the DEG in osteoarthritis synovial cells. Curcumin-related genes were identified through the drug-gene interaction network STITCH (http://stitch.embl.de/cgi/input.pl). Expression levels of fibronectin 1 (FN1) and collagen III protein were measured by western blot. MTT assay was used to examine the effects of different concentrations of curcumin on cell viability. Western blot and quantitative real-time polymerase chain reaction were used to validate the different expression levels of matrix metalloproteinase-3 (MMP3). Clone formation assay, flow cytometry, and the TUNEL method were conducted for detecting the cell proliferation and apoptosis rate. RESULTS: In the two chips of GSE1919 and GSE55235, the average expression of MMP3 in the osteoarthritis group was 63.7% and 12.9% higher than that of the healthy control, respectively. The results of western blot also showed that the average expression of MMP3 in 30 osteoarthritis patients was 132% higher than that of the healthy group, which confirmed that MMP3 was highly expressed in osteoarthritis group. The results of MTT showed that at 72 h, the cell viability of 40 µmol/L curcumin was the lowest and 79.6% lower than for the 0 µmol/L group, so the final curcumin concentration of 40 µmol/L was selected for subsequent experiments. Western blot results further showed that the expression of MMP3 was 44% lower in the untreated groups compared with the curcumin group, and the expressions of FN1 and collagen III were increased by 112% and 84%, respectively, which indicated that curcumin inhibited MMP3 expression and decreased osteoarthritis synovial cell activity. Cloning formation experiments showed that cell numbers increased by 75% and 20.5% in untreated and curcumin groups, and compared with the untreated group, the cells in the curcumin group decreased by 30.8%. Flow cytometry showed that the apoptotic rate in the curcumin group increased by 85.1% compared with the untreated group, but for a single group, MMP3 decreased the apoptotic rate by 53.9% and 46.7%, respectively. CONCLUSIONS: MMP3 was highly expressed in osteoarthritis synovial cells. Curcumin could reduce cell viability, inhibit cell proliferation, increase cell apoptosis, and eventually alleviate inflammation of osteoarthritis by inhibiting the expression of MMP3.

Single-stage posterior vertebral column resection and internal fixation for old fracture-dislocations of thoracolumbar spine: a case series and systematic review.

PURPOSE: To evaluate the efficacy of single-stage posterior vertebral column resection for old thoracolumbar fracture-dislocations with spinal cord injury. METHODS: From January 2007 to June 2013, twelve male patients (average age, 32.6 years; range 19-57 years) with old fracture-dislocations of the thoracolumbar spine and spinal cord injury underwent single-stage posterior vertebral column resection and internal fixation. All patients were assessed for relief of the pain and restoration of neurologic function. Postoperative Cobb angle was measured and bone graft fusion was evaluated by X-ray. A systematic review of 25 studies evaluating surgical management of thoracolumbar fractures with spinal cord injuries was also performed. RESULTS: From our case series, six of the nine patients with Frankel grade A had significant improvement in urination and defecation after surgery. The three patients with Frankel grades B and C had progression of 1-2 grades after surgery. Bony fusion was achieved and local back pain was relieved in all patients after surgery. From our systematic review of 25 studies, the majority of patients had improved back pain, the postoperative kyphotic angle was significantly reduced compared with pre-operative kyphotic angle. CONCLUSION: Single-stage posterior vertebral column resection and internal fixation for old thoracolumbar fracture-dislocations is an ideal treatment allowing for thorough decompression, relief of pain, correction of deformities, and restoration of spinal stability. LEVEL OF EVIDENCE: IV.

Effects of TGF-ß1 and alginate on the differentiation of rabbit bone marrow-derived mesenchymal stem cells into a chondrocyte cell lineage.

The aim of the present study was to investigate the effect of a three-dimensional (3D) culture system of sodium alginate gel on the directional differentiation induction of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes, as well as the in vitro gene transfection technique. The biological characteristics of the passage and proliferation of rabbit BMSCs were investigated under conditions of in vitro monolayer and 3D culture of sodium alginate gel. Transforming growth factor (TGF)-ß1 gene recombinant adenoviral cosmid vectors and the recombinant adenoviral vector Ad.TGF-ß1 were constructed, and the effect of Ad.TGF-ß1 transfection on the differentiation of BMSCs into chondrocytes was investigated. The whole bone marrow rinsing method was used to obtain, separate and purify the rabbit BMSCs, and the in vitro monolayer and 3D culture of sodium alginate gel were thus successfully and stably established. A safe, stable and efficient method of constructing Ad.TGF-ß1 TGF-ß1 gene recombinant adenoviral vectors was established. Following TGF-ß1 transfection, BMSCs were able to continuously secrete significantly increased amounts of specific extracellular matrix components of chondrocytes, such as collagen II and proteoglycans. Furthermore, the effects in the post-gene transfection 3D culture group were found to be enhanced compared with those in the monolayer culture group. In conclusion, the 3D culture system of sodium alginate gel and in vitro gene transfection exhibited significant inductive effects on differentiation, which could be used to promote BMSCs to differentiate into chondrocytes.

Low EphA7 Expression Correlated with Lymph Node Metastasis and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma.

As a member of the Eph family of receptor tyrosine kinases, EphA7 plays an important role in cancer. However, the expression and significance of Eph receptors in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we detected the expression of EphA7 by immunohistochemistry in a sample of 352 patients with ESCC, and aimed to investigate the expression status of EphA7 in ESCC and its impact on prognosis. The results showed that low EphA7 expression significantly correlated with lymph node metastases (N0: 29%; N1: 64%. p<0.001), poor degree of tumor differentiation (G1: 31%; G2: 49%; G3: 58%. p=0.009) and pTNM staging (I+II: 33%; III+IV: 58%. p<0.001). Furthermore, in a combined analysis, patients with low EphA7-expressing tumors showed a shorter overall survival than those with high expression, resulting in a five-year overall survival rate of 47.4% vs. 52.6%, respectively (p=0.016). Consequently, patients with a low EphA7 expression have poorer prognosis in ESCC compared with those manifesting high expression.

The prognostic implications of microvascular density and lymphatic vessel density in esophageal squamous cell carcinoma: Comparative analysis between the traditional whole sections and the tissue microarray.

Focal distribution of microvascular and lymphatic vessels is a critical issue in cancer, and is measured by tissue microarray (TMA) construction from paraffin-embedded surgically obtained tissues, a process that may not accurately reflect true focal distribution. The aim of this study was to assess the concordance of microvascular density (MVD) and lymphatic vessel density (LVD) in TMAs with corresponding whole sections, and to correlate the MVD or LVD with clinicopathological parameters in 124 cases of esophageal squamous cell carcinoma (ESCC). MVD, determined by CD105 immunohistochemistry of whole sections, was strongly associated with lymph node metastasis (p=0.000) and pTNM stage (p=0.001). Kaplan-Meier survival analysis showed that increasing CD105 microvessel count correlated with decreasing survival (p<0.001). The same result was acquired when MVD was calculated from tissue microarrays. Analysis of continuous data showed a highly significant correlation between whole sections and TMA data (Pearson r=0.522, p<0.001). Increasing LVD, as determined by D2-40 immunohistochemistry of whole sections, correlated with decreasing survival, but this relationship was undetectable using TMAs. In conclusion, we demonstrate that for the selected endothelial markers, TMAs can provide a realistic and reliable estimate of the extent of MVD, but not LVD in ESCC samples.