Tie Hua Rong

Fibroblast Growth Factor Receptor 2–Positive Fibroblasts Provide a Suitable Microenvironment for Tumor Development and Progression in Esophageal Carcinoma

Purpose: Tumor fibroblasts (TF) have been suggested to play an essential role in the complex process of tumor-stroma interactions and tumorigenesis. The aim of the present study was to investigate the specific role of TF in the esophageal cancer microenvironment. Experimental Design: An Affymetrix expression microarray was used to compare gene expression profiles between six pairs of TFs and normal fibroblasts from esophageal squamous cell carcinoma (ESCC). Differentially expressed genes were identified, and a subset was evaluated by quantitative real-time PCR and immunohistochemistry. Results: About 43% (126 of 292) of known deregulated genes in TFs were associated with cell proliferation, extracellular matrix remodeling, and immune response. Up-regulation of fibroblast growth factor receptor 2 (FGFR2), which showed the most significant change, was detected in all six tested TFs compared with their paired normal fibroblasts. A further study found that FGFR2-positive fibroblasts were only observed inside the tumor tissues and not in tumor-surrounding stromal tissues, suggesting that FGFR2 could be used as a TF-specific marker in ESCC. Moreover, the conditioned medium from TFs was found to be able to promote ESCC tumor cell growth, migration, and invasion in vitro. Conclusions: Our study provides new candidate genes for the esophageal cancer microenvironment. Based on our results, we hypothesize that FGFR2(+)-TFs might provide cancer cells with a suitable microenvironment via secretion of proteins that could promote cancer development and progression through stimulation of cancer cell proliferation, induction of angiogenesis, inhibition of cell adhesion, enhancement of cell mobility, and promotion of the epithelial-mesenchymal transition.

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.

Survival and Risk Factors of Surgically Treated Mediastinal Invasion T4 Non-Small Cell Lung Cancer

BACKGROUND Surgical treatment of T4 non-small cell lung cancer (NSCLC) patients with mediastinal involvement is controversial. This study was conducted to propose subgroups of patients with T4 NSCLC with mediastinal involvement who are more likely to benefit from resection. METHODS Consecutive patients with T4 NSCLC with mediastinal involvement who underwent thoracotomy (n = 146) were retrospectively analyzed. Actuarial survival was calculated. Factors associated with overall survival were identified. RESULTS Four operative deaths occurred in pneumonectomy patients. The overall 5-year survival rate was 22.7%; median survival was 24.8 months. Factors favoring survival included complete resection (p < 0.001), N2-negative disease (p < 0.001), and pulmonary great vessel invasion (p < 0.001). Multivariate analysis of 131 patients undergoing lung resection found three factors associated with increased survival: pulmonary great vessel involvement (relative risk [RR] of death, 0.365; 95% confidence interval [CI], 0.208 to 0.639; p < 0.001), R0 resection (RR, 0.387; 95% CI, 0.209 to 0.714; p = 0.002), and postoperative chemotherapy (RR, 0.255; 95% CI, 0.134 to 0.487; p < 0.001). Male sex (RR, 2.962; 95% CI, 1.479 to 5.934; p = 0.002) and N2-positive disease (RR, 3.220; 95% CI, 1.640 to 6.323; p < 0.001) were associated with decreased survival. CONCLUSIONS N2-positive, T4 NSCLC with mediastinal involvement is not suitable for resection. T4 NSCLC patients with pulmonary great vessel involvement had better survival rates than other T4 subgroups. Pneumonectomy should be done with caution due to a high mortality risk and poor prognosis. Further studies are warranted to assess the role of sex on survival.

Three-field vs two-field lymph node dissection for esophageal cancer: A meta-analysis

AIM To assess the effects of 3-field lymphadenectomy for esophageal carcinoma. METHODS We conducted a computerized literature search of the PubMed, Cochrane Controlled Trials Register, and EMBASE databases from their inception to present. Randomized controlled trials (RCTs) or observational epidemiological studies (cohort studies) that compared the survival rates and/or postoperative complications between 2-field lymphadenectomy (2FL) and 3-field lymphadenectomy (3FL) for esophageal carcinoma with R0 resection were included. Meta-analysis was conducted using published data on 3FL vs 2FL in esophageal carcinoma patients. End points were 1-, 3-, and 5-year overall survival rates and postoperative complications, including recurrent nerve palsy, anastomosis leak, pulmonary complications, and chylothorax. Subgroup analysis was performed on the involvement of recurrent laryngeal lymph nodes. RESULTS Two RCTs and 18 observational studies with over 7000 patients were included. There was a clear benefit for 3FL in the 1- (RR = 1.16; 95%CI: 1.09-1.24; P < 0.01), 3- (RR = 1.44; 95%CI: 1.19-1.75; P < 0.01), and 5-year overall survival rates (RR = 1.37; 95%CI: 1.18-1.59; P < 0.01). For postoperative complications, 3FL was associated with significantly more recurrent nerve palsy (RR = 1.43; 95%CI: 1.28-1.60; P = 0.02) and anastomosis leak (RR = 1.26; 95%CI: 1.05-1.52; P = 0.09). In contrast, there was no significant difference for pulmonary complications (RR = 0.93; 95%CI: 0.75-1.16, random-effects model; P = 0.27) or chylothorax (RR = 0.77; 95%CI: 0.32-1.85; P = 0.69). CONCLUSION This meta-analysis shows that 3FL improves overall survival rate but has more complications. Because of the high heterogeneity among outcomes, definite conclusions are difficult to draw.

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non-small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non–small cell lung cancer (NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age≥65 years (P = 0.011), smoking status (P = 0.009), intracranial symptoms (P = 0.022), clinical T category (P = 0.010), clinical N category (P = 0.003), increased partial thromboplastin time (P < 0.001), and platelet count (P < 0.001). Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration (median, 17.3 months versus 11.1 months; P≤0.001). A similar result was observed for platelet counts (median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases (R2 = 1.698, P < 0.001 and R2 = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.

MCM4 expression in esophageal cancer from southern China and its clinical significance.

Purpose and Experimental Design: MCM4 is a member of Minichromosome maintenance protein family. MCM2–7 proteins play an essential role in eukaryotic DNA replication and have been identified as components of DNA replication licensing factors. So far, no research on MCM4 has been reported in esophageal cancer. In this study, we detected via RT-PCR the expression status of MCM4 in esophageal cancer from southern China and therefore disclose the relationship between MCM4 and esophageal cancer. Results: 65% (39/60) cases showed increased expression of MCM4 in the carcinomas when compared with normal esophageal epithelia in which no or low MCM4 expression was detected in most cases. Twenty of sixty cases (33%) showed increased expression of MCM4 in the adjacent epithelia. Furthermore, MCM4 expression in esophageal carcinomas was significantly higher than the one in the adjacent epithelia (chi square value is 12.037, P<0.001). Significant difference for the expression status of MCM4 was found between the patients with histopathological stage T3 and stage T1 (chi square value=4.038, P<0.05). Conclusions: The increased expression of MCM4 might be associated with pathological staging of esophageal cancer. The alterations of MCM4 are possibly related to the earlier event of esophageal carcinogenesis. MCM4 is probably a valuable molecular marker involved in the development and/or genesis of esophageal cancer.

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 factors in patients with recurrence after complete resection of esophageal squamous cell carcinoma

BACKGROUND Recurrence following complete resection of esophageal squamous cell carcinoma (SCC) still remains common. The aim of this study was to investigate the prognostic factors in patients with recurrence after complete resection of esophageal SCC. METHODS The medical records of 190 patients with recurrent disease after complete resection of esophageal SCC were retrospectively reviewed. Recurrence pattern was classified as loco-regional recurrence and distant metastases. The Kaplan-Meier method was used for the survival analysis. Cox proportional hazards model was used for multivariate analysis. RESULTS Mediastinal nodal clearance area was the most common sites of loco-regional recurrence, whereas lung, liver and bone were the most common sites for distant metastases. The median survival after recurrence was 8 months. The 1, 3, 5-year post-recurrence survival rates were 45.9%, 10.6% and 6.4%, respectively. The overall 1, 3, 5-year survival rates were 76.6%, 27.3% and 12.3%, respectively. The independent prognostic factors included time of recurrence (≥12 months vs. <12 months, HR: 3.228, 95% CI: 2.233-4.668), pattern of recurrence (local-regional recurrence vs. distant metastases, HR: 1.690, 95% CI: 1.170-2.439), and treatment of recurrence [no treatment vs. treatment (radiotherapy or surgery or chemotherapy), HR: 0.642, 95% CI: 0.458-0.899]. CONCLUSIONS Our retrospective study showed that time of recurrence, pattern of recurrence and treatment of recurrence were independent prognostic factors in patients with recurrence after complete resection of esophageal SCC.

Relationship between epidermal growth factor receptor gene mutation and copy number in Chinese patients with non-small cell lung cancer

Epidermal growth factor receptor (EGFR) gene mutation and copy number are useful predictive markers that guide the selection of non-small cell lung cancer (NSCLC) patients for EGFR-targeting therapy. This study aimed to investigate the correlation between EGFR gene mutation and copy number and clinicopathologic characteristics of Chinese patients with NSCLC. NSCLC specimens collected from 205 patients between November 2009 and January 2011 were selected to detect EGFR gene mutations with real-time polymerase chain reaction (RT-PCR) and to detect EGFR gene copy number with fluorescence in situ hybridization (FISH). EGFR mutations primarily occurred in females, non-smokers, and patients with adenocarinomas (all P < 0.001). Tissues from 128 (62%) patients were FISH-positive for EGFR, including 37 (18%) with gene amplification and 91 (44%) with high polysomy. EGFR gene mutation was correlated with FISH-positive status (R = 0.340, P < 0.001). Multivariate analysis showed that not smoking (OR = 5.910, 95% CI = 2.363–14.779, P < 0.001) and having adenocarcinoma (OR = 0.122, 95% CI = 0.026–0.581, P = 0.008) were favorable factors for EGFR gene mutation. These results show a high frequency of EGFR FISH positivity in NSCLC tissues from Chinese patients and a significant relevance between EGFR gene mutations and FISH-positive status. Among the FISH-positive samples, EGFR gene mutation occurred more frequently in samples with gene amplification compared to those with high polysomy, suggesting that EGFR mutation and gene amplification should be used as clinical decision parameters to predict response to EGFR-targeting therapy.

Peripheral Direct Adjacent Lobe Invasion Non-small Cell Lung Cancer Has a Similar Survival to That of Parietal Pleural Invasion T3 Disease

Introduction: The postoperative prognosis of peripheral adjacent lobe invasion non-small cell lung cancer (NSCLC) is unclear. The purpose of this study was to determine the postoperative prognosis of NSCLC with direct adjacent lobe invasion by comparing it with that of visceral pleural invasion (primary lobe) T2 disease, and parietal pleural invasion T3 disease, and hence determine its most appropriate T category. Methods: A retrospective analysis was conducted to assess the survival of patients with peripheral direct adjacent lobe invasion NSCLC (group A), and it was compared with that of patients with visceral pleural invasion of the primary lobe (group B) and parietal pleural invasion (group C). All patients were node-negative on pathologic examination. Kaplan-Meier method was used to compare the postoperative survival between groups. Results: A total of 263 patients were analyzed. The overall survival rates in groups A (n = 28), B (n = 167), and C (n = 68) at 5 years were 40.7, 54.6, and 41.9%, respectively; corresponding median survival in three groups were 53, 71, and 40 months, respectively. The survival difference among three groups was statistically significant (p = 0.031). A similar survival was observed between groups A and C, whereas group B had a much better survival than other groups. Conclusions: Peripheral adjacent lobe invasion NSCLC has a similar survival prognosis with that of parietal pleural invasion T3 disease and hence should be classified as T3 rather than T2. However, further studies are warranted.