Jian Hua Fu

An Evaluation of the Number of Lymph Nodes Examined and Survival for Node-Negative Esophageal Carcinoma: Data from China

BackgroundThe current American Joint Committee on Cancer (AJCC) staging system for esophageal cancer does not define the minimum number of lymph nodes (LNs) necessary for accurate nodal staging. This study aimed to seek the minimum number of LNs examined for adequate nodal staging of patients with node-negative esophageal cancer.MethodsWe conducted a retrospective review of 592 patients undergoing R0 resection with node-negative esophageal carcinoma between December 1996 and December 2004. The relationship between the total number of examined LNs and death from esophageal cancer was investigated by means of a scatterplot of this variable versus Martingale residuals from a Cox proportional hazard regression model without the variable of interest. A smoothed line fit of the scatterplot was applied to detect the reasonable cutoff point.ResultsThe patients were classified into four categories according to the number of examined LNs: ≤5, 6 to 9, 10 to 17, and ≥18. A reduced hazard ratio of death was observed with an increasing number of LNs examined. The 5-year cancer-specific survival rate was 42.8% among patients with ≤5 LNs examined, compared with 52.6, 56.8, and 75% for those with 6–9 LNs, 10–17 LNs, and ≥18 LNs, respectively. Multivariate Cox regression analysis suggested that female sex, lower grade of cell differentiation, lower T category and increasing number of examined LNs were independent factors favoring cancer-specific survival.ConclusionsAt least 18 LNs should be resected for accurate staging of operable esophageal carcinoma. However, a validation from other institute is warranted.

Tumor location does not impact long-term survival in patients with operable thoracic esophageal squamous cell carcinoma in China.

BACKGROUND The seventh edition of the American Joint Committee on Cancer staging system considers tumor location as a factor in staging esophageal squamous cell carcinoma (ESCC). However, more data are essential to test its efficacy. The purpose of this study is to assess whether tumor location should be included as a factor in staging of thoracic ESCC in Chinese patients. METHODS A retrospective review of 1,220 patients with ESCC who underwent complete resection between December 1996 and December 2008 was conducted. Survival was calculated by the Kaplan-Meier method, and the log-rank test was used to assess survival differences between groups. Subgroup analysis and the Cox proportional hazards model were used to further determine the impact of tumor location on overall survival. RESULTS The median survival times for patients with ESCC in the upper third, middle third, and lower third of the esophagus were 45.1 months, 62.9 months, and 39.2 months, respectively, with corresponding 5-year survival rates of 44.8%, 50.5%, and 45.6%, respectively (p=0.191). Subgroup analysis also demonstrated that tumor location did not determine survival prognosis. Multivariate Cox regression analysis suggested that being female (p=0.001), being young (p<0.001), having a lower grade of cell differentiation (p=0.030), T category (p<0.001), and N category (p<0.001) were independent factors favoring overall survival, whereas tumor location (p=0.295) and surgical approaches (p=0.521) were not independent factors impacting prognosis. CONCLUSIONS Staging of ESCC in the Chinese population should be simplified by omitting tumor location as a variable. More data from Asian populations are warranted to verify these results.

Prognostic role of neutrophil-lymphocyte ratio in operable esophageal squamous cell carcinoma

AIM To determine the prognostic significance of preoperative serum neutrophil-lymphocyte ratio (NLR) in esophageal squamous cell carcinoma (ESCC). METHODS Data from 371 eligible patients with ESCC who had undergone surgery with curative intent at our institution between October 2000 and May 2007 were retrospectively recruited for analysis. The cutoff value of NLR was 3.0 as determined by the receiver operating characteristic curve, which discriminated between survival and death; the area under the curve was 0.709, and the sensitivity and specificity were 66.1% and 69.1%, respectively, at the cutoff point. The correlation between the NLR and clinicopathological characteristics was analyzed using a χ(2) test. The prognostic influence of the NLR and other clinicopathological factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) was studied using the Kaplan-Meier method. To evaluate the independent prognostic value of NLR, multivariate Cox regression models were applied. RESULTS The median age of the patients was 57.0 years, and 276/371 (74.4%) patients were male. The NLR was ≤ 3.0 in 80.1% (297/371) of the patients, and the remaining 19.9% (74/371) had an NLR > 3.0. Median postoperative follow-up was 66.0 mo [interquartile range (IQR): 49.0-76.0 mo], with a follow-up rate of 94%. Follow-up was not significantly different between patients with an NLR ≤ and > 3.0 (63.13 ± 1.64 vs 61.52 ± 3.66, P = 0.711). However, higher preoperative serum NLR was associated with significantly increased risks of higher pathological tumor status (P = 0.007). A significant, independent association between high preoperative serum NLR and poor clinical outcome was identified in a multivariate analysis for CSS (HR = 1.591; P = 0.007) and RFS (HR = 1.525; P = 0.013). Moreover, when patients were stratified by pathological tumor-node-metastasis (TNM) staging, the adverse effects of preoperative serum NLR on CSS (HR = 2.294; P = 0.008) and RFS (HR = 2.273; P = 0.008) were greatest in those patients with stage IIIA disease. CONCLUSION Preoperative serum NLR is a useful prognostic marker to complement TNM staging for operable ESCC patients, particularly in patients with stage IIIA disease.

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.

MULTIDISCIPLINARY MODALITIES ACHIEVE ENCOURAGING LONG-TERM SURVIVAL IN RESECTABLE LIMITED-DISEASE ESOPHAGEAL SMALL CELL CARCINOMA

Background The management of limited-disease esophageal small cell carcinoma is not well defined, and the role of surgery is still controversial. We aim to determine the optimal treatment strategy in limited-disease of esophageal small cell carcinoma. Methods and Findings We conducted a retrospective review of 141 patients with limited-disease esophageal small cell carcinoma from 3 institutions in China who underwent treatment between July 1994 and September 2008, July 1994 and July 2011, and June 2004 and December 2010, respectively. The survival rate was calculated by the Kaplan-Meier method, and the log-rank test was used to assess the survival differences between the groups. Cox proportional hazards model were used to further determine the independent factors impacting overall survival. The median survival time was 16.1 months for the entire cohort of patients, with a 5-year survival rate of 6.7%. The median survival times for surgery alone, surgery combined with chemotherapy, surgery combined with radiotherapy, surgery combined with chemotherapy and radiotherapy, chemotherapy plus radiotherapy, and chemotherapy alone were 18.0 months, 15.0 months, 23.0 months, 25.0 months, 17.1 months, and 6.1 months, respectively; the corresponding 5-year survival rates were 0%, 15.4%, 0%, 38.9%, 0%, and 0%, respectively. For the 105 patients who underwent R0 resection, the median disease-free survival time was 12.0 months, with a 95% confidence interval of 9.5 months to 14.5 months. The multivariate Cox regression analysis demonstrated that advanced pathological staging (p = 0.003), and pure esophageal small cell carcinoma (p = 0.035) were independent factors decreasing overall survival. Conclusions Our data suggested that multidisciplinary modalities achieved encouraging long-term survival in patients with resectable limited-disease of esophageal small cell carcinoma.

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.

Expression and prognostic relevance of p21Waf1 in stage Iii esophageal squamous cell carcinoma

The prognostic effect of p21(WAF1) expression on esophageal squamous cell carcinoma patients is controversial. Further clarifying the effect of this protein is beneficial for optimizing the patient outcomes. In the current study, we investigated the expression of p21(WAF1) protein in 189 specimens of stage III ESCC by immunohistochemistry. As shown by the Kaplan-Meier curve, the overall survival rate of the positive-expression group was significantly higher than that of the negative-expression group (P < 0.05). No significant correlation was observed between p21(WAF1) expression and clinicopathological parameters in terms of gender, age, tumor location, tumor grade, pathological stage, and number of regional lymph node metastases (P > 0.05). We concluded that p21(WAF1) played an intricate role in the tumorigenesis and development of ESCC. p21(WAF1) could serve as a positive prognostic predictor for stage III ESCC patients.

Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma

BackgroundThe correlation of S-phase kinase–associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival.MethodsTissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro.ResultsSkp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs.ConclusionsNegative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells.

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.

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.