Bai Wei Zhao

The prognostic value of harvested lymph nodes and the metastatic lymph node ratio for gastric cancer patients: results of a study of 1,101 patients.

Aim To investigate whether the recommendation to remove 15 lymph nodes that is used in the staging system is necessary to assess gastric cancer progression and to evaluate whether our metastatic lymph node ratio dividing method, adapted from the AJCC’s (American Joint Committee on Cancer) 7th TNM staging system, is helpful for the patients with fewer than 15 harvested lymph nodes. Methods We performed a retrospective study of 1101 patients with histologically diagnosed gastric cancer who underwent a D2 gastrectomy at the Sun Yat-sen University Cancer Center between January 2001 and December 2010. The Kappa and Chi-squared tests were employed to compare the clinicopathological variables. The Kaplan-Meier method and Cox regression were employed for the univariate and multivariate survival analyses. Results In the trial, 346, 601 and 154 patients had 0–14, 15–30 and more than 30 lymph nodes harvested, respectively. The median survival times of patients with different lymph nodes harvested in N0, N1, N2 and N3a groups were 45.43, 54.28 and 66.95 months (p = 0.068); 49.22, 44.25 and 56.72 months (p<0.001), 43.94, 47.97 and 35.19 months (p = 0.042); 32.88, 42.76 and 23.50 months (p = 0.016). Dividing the patients who had fewer than 15 lymph nodes harvested by the metastatic lymph node ratio at 0, 0.13 and 0.40, the median survival times of these 4 groups were 70.6, 50.5, 53.5 and 30.7 months (p<0.001). After re-categorising these 4 groups into the N0, N1, N2, N3a groups, the histological grade, T staging, premier N staging, and restaged N staging were the independent prognostic factors. Conclusions Large numbers of lymph nodes harvested in radical gastrectomy do not cause stage migration. For those patients with a small number of harvested lymph nodes, their stage should be divided by the metastatic lymph node ratio, referred to in the TNM staging system, to assign them an accurate stage.

High level of COP1 expression is associated with poor prognosis in primary gastric cancer.

COP1 (constitutive photomorphogenic 1, also known as RFWD2) is a p53-targeting E3 ubiquitin ligase containing RING-finger, coiled-coil, and WD40-repeat domains. Recent studies have identified that COP1 is overexpressed in several cancer types and that increased COP1 expression promotes cell proliferation, cell transformation, and tumor progression. In the present study, we investigated the expression and prognostic value of COP1 in primary gastric cancer. To investigate the role of the COP1 gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were performed to examine COP1 expression in paired cancerous and matched adjacent noncancerous gastric tissues. The results revealed high COP1 mRNA (P=0.030) and protein (P=0.008) expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues. The correlated protein expression analysis revealed a negative correlation between COP1 and p53 in gastric cancer samples (P=0.005, r=-0.572). Immunohistochemical staining of gastric cancer tissues from the same patient showed a high COP1 expression and a low p53 expression. To further investigate the clinicopathological and prognostic roles of COP1 expression, we performed immunohistochemical analysis of 401 paraffin-embedded gastric cancer tissue blocks. The data revealed that high COP1 expression was significantly correlated with T stage (P=0.030), M stage (P=0.048) and TNM stage (P=0.022). Consistent with these results, we found that high expression of COP1 was significantly correlated with poor survival in gastric cancer patients (P<0.001). Cox regression analyses showed that COP1 expression was an independent predictor of overall survival (P<0.001). Our data suggest that COP1 could play an important role in gastric cancer and might serve as a valuable prognostic marker and potential target for gene therapy in the treatment of gastric cancer.

Decreased Expression of AZGP1 Is Associated with Poor Prognosis in Primary Gastric Cancer

Background 2-Zinc-glycoprotein 1 (AZGP1) is a multidisciplinary protein that participates in many important functions in the human body, including fertilization, immunoregulation and lipid mobilization. Recently, it has been shown that AZGP1 is also involved in carcinogenesis and tumor differentiation. In this study, we investigated the expression levels and prognostic value of AZGP1 in primary gastric cancers. Methods and Results We examined the expression of AZGP1 in 35 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. Furthermore, we analyzed AZGP1 expression in 248 patients who underwent resection procedures between 2005 and 2007 using immunohistochemistry. The relationships between the AZGP1 expression levels, the clinicopathological factors, and patient survival were investigated. AZGP1 expression was significantly reduced at both the mRNA (P = 0.023) and protein levels (P = 0.019) in tumor tissue samples, compared with expression in matched adjacent non-tumor tissue samples. The immunohistochemical staining data showed that AZGP1 expression was significantly decreased in 52.8% (131/248) of gastric adenocarcinoma cases. Clinicopathological analysis showed that the reduced expression of AZGP1 was significantly correlated with tumor location (P = 0.011), histological grade (P = 0.005) and T stage (P = 0.008). Kaplan–Meier survival curves revealed that the reduced expression of AZGP1 was associated with a poor prognosis in gastric adenocarcinoma patients (P = 0.009). Multivariate Cox analysis identified AZGP1 expression was an independent prognostic factor for overall survival of gastric adenocarcinoma patients (HR = 1.681, 95% CI = 1.134–2.494, P = 0.011). Conclusions Our study suggests that AZGP1 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.

Lymph Node Metastasis, a Unique Independent Prognostic Factor in Early Gastric Cancer

Background Lymph node metastasis (LNM) has been shown to be related to the prognosis of early gastric cancer (EGC). The choice of optimal treatment depends on an accurate pre-operative assessment of LNM status in EGC patients. However, in China, where EGC cases account for only a small part of gastric cancer (GC) cases, there are not enough data to make an accurate assessment. Therefore, this study, which involved a relatively large number of EGC patients, aimed to explore the relationship between clinicopathological characteristics and LNM in EGC. Methods Clinicopathological data from 205 EGC patients who underwent surgical resection at Sun Yat-Sen University Cancer Center from January 2000 to December 2011 were retrospectively analyzed. Clinicopathological characteristics were assessed to identify effective predictive factors for LNM and overall survival. Results LNM occurred in 52 (25.37%) EGC cases; of these cases, 18 occurred in intra-mucosal cancers (13 N1, 4 N2 and 1 N3), and 34 occurred in sub-mucosal cancers (22 N1, 7 N2 and 5 N3). Logistic regression analysis demonstrated that tumor differentiation (P=0.002), depth of tumor infiltration (P=0.004), vessel invasion (P=0.012), tumor size (P=0.020) and gender (P=0.022) were risk factors associated with LNM in EGC, listed in order of priority. The overall survival rate was 90.2%. Kaplan-Meier survival analysis showed that overall survival of EGC patients was significantly correlated with LNM (P=0.001), N staging (P<0.001) and invasion of lymphatic or blood vessels (P=0.010), but it was not correlated with tumor size, depth of tumor infiltration or tumor cell differentiation. Moreover, a multiple Cox regression analysis demonstrated that only N staging (P=0.001) could serve as an independent prognostic predictor in EGC patients. Conclusions Because LNM independently predicts the prognosis of EGC, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) and laparoscopic partial gastrectomy should be cautiously used in high-risk EGC patients. A pre-operative assessment of LNM status based on clinicopathological factors may be useful for therapy planning.

Poor Prognosis of Gastric Adenocarcinoma with Decreased Expression of AHRR

Background The aryl hydrocarbon receptor (AHR) repressor (AHRR), a member of growing superfamily, is a basic-helix-loop-helix/Per-AHR nuclear translocator (ARNT)-Sim (bHLH-PAS) protein. Recently, AHRR has been proposed to function as a putative new tumor suppressor gene based on some relevant studies in multiple types of human cancers. This current study aims to investigate AHHR expression and its prognostic significance in primary gastric adenocarcinoma. Methodology/Principal Findings The expression level of AHRR was analyzed using real-time quantitative PCR (RT-qPCR), western blotting, and immunohistochemical staining. It was clearly showed that the expression status of AHRR was reduced in tumor tissue samples compared with that in matched adjacent non-tumor tissue samples by RT-qPCR (P = 0.0423) and western blotting analysis (P = 0.004). Moreover, data revealed that AHRR without exon 8 (the active isoform) was the predominant form either in tumor tissues (66.7%, 8/12) or in matched adjacent non-tumor tissues (100.0%, 12/12), and the mRNA level of this isoform was significantly reduced in tumor tissues (P = 0.006). Immunohistochemistry analysis indicated that AHRR expression was significantly decreased in 175 of 410 (42.7%) gastric adenocarcinoma cases. Kaplan-Meier survival curves and Multivariate Cox analysis revealed that decreased expression of AHRR was significantly associated with poor prognosis in gastric adenocarcinoma patients. Conclusions/Significance Our data suggests that, in primary gastric adenocarcinoma, AHRR may play as a suppressor gene and its expression status has the potential to be an independent prognostic factor.

The Clinical Significance and Risk Factors of Solitary Lymph Node Metastasis in Gastric Cancer

Aims To assess the clinical significance and risk factors of solitary lymph node metastasis (SLM) in gastric carcinoma and establish a more accurate method to evaluate the possibility of lymph node metastasis (LM). Methods A total of 385 patients with gastric carcinoma who underwent D2 lymphadenectomy at the Cancer Center of Sun Yat-Sen University were included in this research. Then we used a group of data from Sun Yat-sen University Gastrointestinal Hospital (SYSUGIH) to validate the accuracy of our developed method. The χ2 test, Kaplan–Meier analysis, log-rank test, COX model, and discriminate analysis were used to analyze the data with SPSS13.0. Results We found that the LM number and pathological T staging were independent prognostic risk factors. CEA grading, LN status by CT, and T staging by CT were independent risk factors for LM in gastric carcinoma. In addition, we developed the equation Y = -5.0 + X 1 + 1.8X 3 + 0.7X 4 (X 1 = CEA grading, X 3 = LN status by CT, X 4 = T staging by CT) to evaluate the situation of LM. The data from SYSUGIH shows this equation has a better accuracy compared with CT. Conclusions SLM is an independent risk factor in gastric cancer. And there was no survival difference between the skip metastasis group and the other SLM group (P = 0.659). It is inappropriate for the patient with SLM doing a standard D2 lymphadenectomy, due to the fact that LM rarely occurs in the splenic artery, splenic hilum. The risk factors for LM include CEA grading, LN status by CT, and T staging by CT. And we can use Y = -5.0 + X 1 + 1.8X 3 + 0.7X 4 (X 1, CEA grading, X 3 = LN status by CT, X 4 = T staging by CT, the critical value is 0.3) to estimate the possibility of LM, which has a better accuracy compared with CT.

The prognosis of gastric cancer patients with marginally elevated carcinoembryonic antigen (CEA) values after D2 radical gastrectomy

To investigate the clinical significance of the postoperative serum carcinoembryonic antigen (CEA) levels in gastric cancer patients who underwent D2 radical gastrectomy and to identify the prognostic factors for patients with marginally elevated postoperative CEA levels.

Decreased expression of transcription elongation factor A-like 7 is associated with gastric adenocarcinoma prognosis.

Background We sought to investigate the expression levels and prognosis value of TCEAL7 in primary gastric cancer. Methods and Results We investigated TCEAL7 and other homologous five members of the TCEAL family expression in normal gastricepithelial cell line and gastric cancer cell lines using real-time quantitative PCR. Furthermore, we examined the expression of TCEAL7 in 39 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative PCR and western blotting. Moreover, we analyzed TCEAL7 expression in 406 gastric cancer patients using immunohistochemistry. The relationships between the TCEAL7 expression levels, the clinicopathological factors, and patient survival were investigated. RT- qPCR data showed that mRNA expression level of TCEAL7 was significantly lower in the gastric cancer cell lines comparing with the levels of other five members of the TCEAL family. Results also revealed decreased TCEAL7 mRNA (P = 0.025) and protein (P = 0.012) expression in tumor tissue samples compared with matched adjacent non-tumor tissue samples. Immunohistochemical staining data showed that TCEAL7 expression was significantly decreased in 43.3% of gastric adenocarcinoma cases. The result also showed that the low TCEAL7 expression was significantly correlated with female, larger tumor size, higher histological grade and worse nodal status. Kaplan–Meier survival curves revealed that the reduced expression of TCEAL7 was associated with a poor prognosis in gastric adenocarcinoma patients (P<0.001). Based on a univariate analysis that included all 406 patients, TCEAL7 expression was found to have statistically significant associations with overall survival (P<0.001). Multivariate analysis also demonstrated that TCEAL7 expression (P = 0.009), age, tumor size, histological grade, lymphovascular invasion, T stage, N stage and M stage were independent risk factors in the prognosis of gastric cancer patients. Conclusions Our study suggests that TCEAL7 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.

Reduced expression of uroplakin 1A is associated with the poor prognosis of gastric adenocarcinoma patients.

Background The aim of this study was to investigate the expression and prognostic significance of Uroplakin1A (UPK1A) in gastric adenocarcinoma patients. Functional studies were also analyzed in vitro. Methodology/Principal Findings Real-time quantitative PCR (RT-qPCR), western blotting, and immunohistochemical (IHC) staining methods were used to analyze the expression of UPK1A in primary gastric adenocarcinoma tissue samples. Compared with matched adjacent non-tumor, the expression of UPK1A in fresh surgical specimens was reduced, which was confirmed by RT-qPCR (P<0.01) and western blotting analysis (P<0.01). The paraffin specimens from a consecutive series of 445 gastric adenocarcinoma patients who underwent surgery between 2003 and 2006 were analyzed by IHC staining. The relationship between UPK1A expression, clinicopathological factors, and survival were evaluated. IHC staining analysis revealed that the reduced expression of UPK1A was observed in 224 cases (50.3%). Additionally, the correlation analysis of clinicopathological factors demonstrated that reduced expression of UPK1A was significantly associated with histological grade (P = 0.022), node metastasis (P<0.001) and tumor node metastasis (TNM) stage (P = 0.008) (7th edition of the International Union Against Cancer (UICC)). Furthermore, Kaplan-Meier survival analysis revealed that the reduced expression of UPK1A was significantly associated with poor prognosis (P = 0.043). Cox hazards model analysis indicated that UPK1A expression was an independent risk factor at the 0.1 level (P = 0.094). The function of UPK1A in cell cycle, migration, and invasion was investigated by overexpressing UPK1A in the MKN45 gastric cancer cell line. The elevated expression of UPK1A cells induced G1 phase arrest and significantly inhibited migration and invasion. Conclusions/Significance The reduced expression of UPK1A might play a role in the progression of gastric cancer. Thus, UPK1A could be a potential favorable biomarker associated with gastric cancer prognosis.

Low expression of CDK10 correlates with adverse prognosis in gastric carcinoma

Background: Cyclin-dependent kinase (CDK) 10, is reported to play an essential role in the progression from the G2 to M phase of the cell cycle. Recently, reduced expression of CDK10 has been observed in several cancerous human tissue, suggesting that CDK10 is a tumor suppressor gene. However, data on its expression pattern and clinical relevance in gastric cancer are not sufficient. Therefore, this study aims to investigate CDK10 expression and its prognostic significance in primary gastric adenocarcinoma. Methodology/Principal Findings: The expression level of CDK10 was analyzed using qRT-PCR, western blotting, and immunohistochemistry on tissue samples from 189 post-resection gastric cancer patients. The expression of CDK10 mRNA was reduced in tumor tissue samples compared with matched adjacent non-tumor tissue samples (P=0.013); this finding was confirmed by western blot analysis (P=0.016). Immunohistochemistry data indicated that CDK10 expression was significantly decreased in 92 of 189 (48.7%) gastric cancer cases. Kaplan-Meier survival curves revealed that decreased expression of CDK10 was strongly associated with a poor prognosis in gastric cancer patients (P<0.001). Multivariate Cox analysis identified CDK10 expression as an independent prognostic factor for overall survival (P=0.011). Conclusions/Significance: Our data suggest that reduced CDK10 expression independently predicts a poor prognosis in patients with gastric cancer. CDK10 can may serve as a valuable prognostic marker and a potential target for gene therapy.