Prognostic Impact of Microscopic Tumor Involved Resection Margin in Advanced Gastric Cancer Patients after Gastric Resection

Background

The prognosis of patients with positive surgical resection margins is dismal in gastric cancer. However, the influence of positive margin itself on prognosis is still uncertain, especially in advanced gastric cancer (AGC). The aims of the present study were to evaluate the prognostic impact of microscopic tumor involved resection margins in stage III–IV AGC after gastric resection in comparison with other well-known factors.

Methods

Among 1,536 consecutive gastric cancer patients who received intentional curative resection for stage III–IV AGC between April 2001 and December 2011 at the National Cancer Center, 35 patients (2.28 %) had positive resection margins on their final histology. A comparison of clinicopathologic characteristics, recurrence pattern, overall survival (OS), and disease-free survival (DFS) was made between positive margin (PM) patients and negative margin (NM) patients.

Results

Among the 35 PM patients, 15 (42.9 %) had proximal involved margins, 21 (60.0 %) had distal involved margins, and one (2.9 %) had both involved margins. Twenty-eight PM patients (80.0 %) were stage III, and 7 (20.0 %) were stage IV. Recurrence was significantly higher in PM than NM (63.6 % vs. 39.7 %, respectively; p = 0.005). The OS and DFS rates were significantly lower in the PM group than in the NM group (14.9 vs. 36.3 months, p < 0.001 and 11.6 vs. 27.1 months, p = 0.005, respectively). The presence of PM was an independent risk factor for both OS and DFS.

Conclusions

The presence of PM is an independent risk factor for OS and DFS. Considering the prognostic impact of PM, a sufficient resection margin should be ensured when determining the resection line in gastrectomy with curative intent. The reoperation to secure clear resection margins should be considered as a treatment of choice in the case of PM.     

Correlation of Vascular Endothelial Growth Factor Expression With Tumor Recurrence and Poor Prognosis in Patients With pN0 Gastric Cancer

Background  

Vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 play important roles in tumor angiogenesis, development, and progression. This study investigates the expression of VEGF combined with MMP-9, their correlation with clinical characteristics, and their effect on the prognosis for patients with pN0 gastric cancer after curative surgery.     

Prognostic Significance of p53 and Ki67 Proteins Expression in Greek Gastric Cancer Patients

Aim: The variability of prognosis of gastric cancer (GC) within a pathological stage necessitates the identification of subgroups of patients with a more aggressive disease. The role of p53 and Ki67 expression in gastric carcinoma is far from being fully established. The aim of the present study was to evaluate the expression of p53 and Ki67 in gastric cancer and correlate the findings with several clinicopathological features and prognosis. Materials and methods: Tissue samples from 93 patients treated by gastric resection for gastric carcinoma between 1996 and 2001 were used. Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53 and Ki67. The results were correlated with clinicopathological features and survival. Results: Stronger expression of p53 was related with tumor size greater than 5 cm and advanced stage. Stronger expression of Ki67 correlated with higher ratio of the number of metastatic lymph nodes to the total number of dissected lymph nodes (metastatic lymph node [MLN] ratio) and advanced stage. Moreover, p53 and Ki67 overexpression, tumor size greater than 5 cm, MLN ratio, depth of invasion, lymph node metastasis, stage III and IV and infiltrative macroscopic appearance were adverse prognostic factors. The levels of p53 and Ki67, the MLN ratio, the tumor size (above 5 cm) and the stage of the disease were identified as independent prognostic factors of survival.

Conclusions: In gastric cancer, the expression of p53 and Ki67 provides significant information about prognosis. The routine evaluation of p53 and Ki67 levels could be a useful tool in identification of patient with more aggressive disease and contribute to a better therapeutic approach.     

Tumor Diameter as a Prognostic Factor in Patients with Gastric Cancer

Background  The aim of this study was to evaluate the prognostic value of tumor diameter in gastric cancer. Methods  The study group comprised a series of 1215 patients who underwent curative gastrectomy. The appropriate tumor diameter cutoff value was determined. Prognostic factors were evaluated by univariate and multivariate analyses. Results  The tumor diameter cutoff value was 100 mm. Multivariate analysis showed that tumor site, macroscopic appearance, tumor diameter, depth of invasion, and presence of lymph node metastasis independently affected prognosis in all patients. Multivariate analysis of patients with larger tumors identified depth of invasion as an independent prognostic factor. A comparison between patients with smaller and larger tumors showed marked differences in the survival of those with stage II, IIIA, and IIIB tumors. A comparison of clinicopathological factors between stage II and III patients revealed that tumors occupying the entire stomach, ill-defined, undifferentiated, and serosa-penetrating tumors, and peritoneal metastases were far more frequent in patients with larger tumors. Conclusions  Tumor diameter in gastric cancer is a reliable prognostic factor that might be a candidate for use in the staging system. To improve outcomes for patients with tumors ≥100 mm in diameter, it is necessary to establish therapeutic strategies for peritoneal metastasis, particularly in stage II and III tumors.     

351例胃癌术后患者的预后因素分析

目的 探讨胃癌术后影响胃癌患者生存的因素.方法 将2004年1月至2009年12月期间在笔者所在医院行手术治疗并获随访的351例胃癌患者作为研究对象,对其临床病理资料及随访资料进行单因素和多因素分析.结果 单因素分析显示患者年龄以及肿瘤部位、T分期、N分期、TNM分期和分化程度与预后有关(P＜0.05);多因素分析显示肿瘤部位、T分期、N分期和术后化疗是影响胃癌术后生存率的独立因素(P＜0.05).结论 肿瘤部位、浸润深度、淋巴结转移率及术后辅助化疗是影响胃癌术后生存的重要因素.对于有淋巴结转移或处于TNMⅢ期的胃癌患者,术后化疗可以提高其生存率.     

CD151 Overexpression is Associated with Poor Prognosis in Patients with pT3 Gastric Cancer

Introduction

CD151, a transmembrane protein of the tetraspanin family, is implicated in the regulation of cell-substrate adhesion and cell migration. Overexpression of CD151 has been reported in several cancers and controls MET-dependent neoplastic growth by enhancing receptor signaling. However, association of CD151 overexpression with MET or tumor progression has not been reported in gastric cancer.

Materials and Methods

We conducted immunohistochemical analysis of CD151 overexpression in 491 pT3 gastric carcinomas and analyzed the relationship with MET overexpression and prognostic significance.

Results

CD151 was highly expressed in 119 gastric carcinomas (24.2 %) and was significantly associated with higher pN stages. Patients with CD151-positive gastric cancer showed shorter overall (p = 0.003) and disease-free survival (p = 0.001) compared with patients with CD151-negative gastric carcinoma. CD151 overexpression was an independent prognostic factor for overall survival [hazard ration (HR) 1.335; 95 % CI 1.005–1.775; p = 0.046] and disease-free survival (HR 1.903; 95 % CI 1.348–2.685; p < 0.001). Co-overexpression of CD151 and MET was observed in 30 (6.1 %) gastric cancers and was more frequent in advanced pN stages than in other groups. Moreover, co-overexpression of CD151 and MET was a strong independent prognostic factor for overall survival (HR 3.163; 95 % CI 1.958–5.108; p < 0.001) and disease-free survival (HR 3.834; 95 % CI 2.145–6.852; p < 0.001).

Conclusion

CD151 overexpression is an independent prognostic factor and could be a potential molecular therapeutic target in patients with advanced gastric cancers. Further studies are needed to establish the biological significance of CD151/MET co-overexpression and the potential of targeting both molecules as a therapeutic strategy.     

Extranodal Extension of Nodal Metastases Is a Poor Prognostic Indicator in Gastric Cancer: a Systematic Review and Meta-analysis

Introduction

The extranodal extension (ENE) of nodal metastases (the extension of neoplastic cells through the nodal capsule into the perinodal soft tissue) is a histological feature that has been considered a prognostic factor in several cancers, but the role in gastric cancer was not yet investigated. We aimed to investigate the prognostic role of ENE in patients affected by gastric cancer through a systematic review and meta-analysis.

Material and Methods

Two independent authors searched major databases until 09/30/2015 to identify studies providing data on gastric cancer patients’ prognostic parameters and comparing patients with ENE (ENE+) vs intra-nodal extension (ENE?). The data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) with 95 % confidence intervals (CI), adjusted for potential confounders.

Results

Nine studies followed up 3250 patients with gastric cancer (1064 ENE+ and 2186 ENE?). ENE+ was associated with a significantly higher risk of all-cause mortality (RR?=?1.70; 95 % CI: 1.43–2.03, I ²?=?66 %; HR?=?2.14; 95 % CI: 1.66–2.75, I ²?=?0 %), cancer-specific mortality (RR?=?1.59; 95 % CI: 1.42–1.79; HR?=?1.52; 95 % CI: 1.19–1.96), and disease recurrence (RR?=?3.43, 95 % CI: 1.80–6.54, I ²?=?0 %).

Discussion

Judging from our results, ENE in gastric cancer patients should be considered for prognostic purposes from the gross sample to the pathology report.

     

The Prognostic Impact of Isolated Tumor Cells in Lymph Nodes of T2N0 Gastric Cancer: Comparison of American and Japanese Gastric Cancer Patients

Background  The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. Methods  Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. Results  ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P = .22, .86 respectively). Conclusions  The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.     

Prognostic Value of Cytokeratin-Positive Bone Marrow Cells of Gastric Cancer Patients

BACKGROUND: Epithelial cells in the bone marrow of patients with gastric cancer suggest tumor dissemination; however, their prognostic implications are controversial. We prospectively evaluated the correlation of bone marrow findings, recurrence rate, and disease-free survival after long-term follow-up. METHODS: Bone marrow were aspirated from both iliac crests and stained with monoclonal cytokeratin (CK)-18 antibody in 209 patients before their initial operation. Patients were followed up for a median of 56 months. RESULTS: Overall, 39 (19%) of 209 patients and 15 (14%) of 109 R0-resected patients had CK-positive cells. CK-positive patients had more local, regional, and distant recurrence than CK-negative patients (P < .05). We found a significantly shorter disease-free survival (P < .05) in the patients with >2 CK-positive cells per 2 x 10(6) bone marrow cells (mean, 35 months) than in patients with 2 CK-positive cells per 2 x 10(6) bone marrow cells was an independent prognostic factor for tumor-related death (P < .05). CONCLUSIONS: Not only the mere presence of CK-positive epithelial cells in bone marrow, but also the cell number, correlates with prognosis. Our findings suggest that classifying CK-positive bone marrow cells in these patients will facilitate future studies.     

Prognostic Significance of Host- and Tumor-Related Factors in Patients with Gastric Cancer

Background  

Various factors regarding the biological state of tumors or the nutritional status of patients have been reported individually to correlate with prognosis. Identification of defined patient groups based on a prognostic score may improve the prediction of survival and individualization of therapy. The aim of the present study was to identify clinically useful parameters obtainable before treatment that could be used for predicting clinical outcomes in patients with gastric cancer.     

Prognostic Significance of Epidermal Growth Factor Receptor Expression in Colon Cancer Patients Undergoing Curative Surgery

Background To investigate the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for prediction of cancer behavior and clinical outcomes in colon cancer patients undergoing potentially curative surgery. Methods EGFR determination using a commercially available immunohistochemistry kit was performed in tissues from 149 colon cancer patients receiving primary surgical treatment and in 25 normal colon mucosa specimens from noncancer patients. EGFR positivity was correlated in univariate and multivariate analyses with disease recurrence and survival. In addition, p27, p53, and vascular endothelial growth factor expression were assessed by immunohistochemistry in 104 patients and correlated with EGFR tumor expression and clinical outcome. Results EGFR expression was detected in approximately one third of colon cancer patients (53 of 149; 35.6%). In 126 curatively treated patients, EGFR expression was correlated with disease recurrence and worse survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, Dukes’ staging, p27, and EGFR expression were the only independent covariates. In particular, in Dukes’ A and B patients the 5-year survival probability was 96% for EGFR-negative and high p27 expression cases and was 30.7% for EGFR-positive and low p27 expression cases. Conclusions EGFR expression was an independent prognostic indicator of disease recurrence and poor survival in colon cancer patients undergoing curative surgery. In the context of novel therapeutic options such as molecularly targeted therapies, these findings suggest that anti-EGFR drugs could be evaluated in the adjuvant treatment of EGFR-positive colon cancer patients.     

Loss of RUNX3 Expression Correlates with Differentiation, Nodal Metastasis, and Poor Prognosis of Gastric Cancer

Background  RUNX3 is a major growth regulator of gastric epithelial cells that is involved in gastric tumorigenesis in both humans and mice. In this study, we investigated the involvement of RUNX3 in tumor progression, and in the prognosis of human gastric cancer. Methods  We analyzed the extent of RUNX3 protein expression by immunohistochemistry in 95 primary gastric adenocarcinomas, and correlated expression levels with clinicopathological parameters. We examined the effects of pFlag/RUNX3 on cell growth, apoptosis, and caspase-3 expression in AGS and SNU1 gastric cancer cell lines by colony-forming assay, terminal deoxynucleotidyl transferase (TdT)-mediate deoxyuridine triphosphatase (dUTP) nick-end labeling (TUNEL) assay, and Western blot analysis, respectively. The pFlag/RUNX3 effects on AGS invasion and migration potentials were also evaluated. Results  RUNX3 expression was lost in 37 (39%) cases of gastric cancer. The expression of RUNX3 in diffuse- and mixed-type cancers was less frequent than expression in intestinal-type cancer (P < 0.001 and P = 0.001, respectively). In addition, the loss of RUNX3 expression was associated with lymph node metastasis (P = 0.02), and correlated with poor gastric cancer survival (P = 0.018). The growth of gastric cancer cells was suppressed after pFlag/RUNX3 transfection. The re-expression of RUNX3 resulted in the upregulation of caspase-3 and promoted apoptosis. Furthermore, Re-expression of RUNX3 induced significant inhibitions of AGS cell invasion and migration in vitro. Conclusions  This work shows that loss of RUNX3 expression is highly associated with lymph node metastasis and poor prognosis of gastric cancer. The re-expression of RUNX3 may induce apoptosis and inhibit the growth as well as invasion/migration of cancer cells. These results indicate that the targeting of the RUNX3 pathway could represent a potential modality for treating gastric cancer.     

Prognostic Significance of Tumor Size in T3 Gastric Cancer

Background  Clinical significance of tumor size remains elusive in gastric cancer. The aim of this study was to evaluate the prognostic value of tumor size in T3 gastric cancer. Methods  A total of 273 patients with T3 gastric cancer who underwent curative D2 gastrectomy between 1996 and 2005 were evaluated. In terms of average value of tumor size, patients were divided into two groups according to tumor size: small-size group (SSG, tumor ≤6 cm) and large-size group (LSG, tumor >6 cm). The prognostic value of tumor size and the correlation between tumor size and other clinicopathologic factors were investigated. Results  LSG accounted for 34.8% in all patients. Tumor size was correlated with histological type, lymphatic invasion, venous invasion, and resection type. The prognosis of LSG patients was worse than that of SSG patients. Multivariate analysis showed that type of resection, status of lymph nodes, metastatic lymph node ratio, and tumor size were defined as independent prognostic factors for patients with T3 gastric cancer. A comparison between LSG patients and SSG patients showed differences in the survival of those with stage IIIB and IV disease. Conclusions  Tumor size is a simple and reliable prognostic factor for patients with T3 gastric cancer; it might be a candidate for the gastric cancer staging system.     

Decreased Expression of RASSF6 Is a Novel Independent Prognostic Marker of a Worse Outcome in Gastric Cancer Patients after Curative Surgery

Background  

Our previous study observed that the expression of RASSF6, a member of the Ras-association domain family, was down-regulated in gastric cancer cells. The present study further investigated the clinical significance of RASSF6 in gastric cancer.     

High-Level Expression of S100A4 Correlates with Lymph Node Metastasis and Poor Prognosis in Patients with Gastric Cancer

Background  

The present study investigated the clinical significance of S100 calcium binding protein A4 in the development, progression, and metastasis of gastric cancer.     

VEGF-ASODN转染对胃癌细胞VEGF表达及生长的抑制作用

目的研究血管内皮细胞生长因子（VEGF）-反义寡核苷酸（ASODN）转染胃癌细胞SGC-7901对其VEGF表达和生长的抑制作用。方法人工合成硫代磷酸化VEGF-ASODN,转染胃癌细胞SGC-7901,24h后实时荧光定量RT-PCR检测细胞VEGF mRNA起始拷贝数,ELISA法检测细胞及培养液上清中VEGF蛋白含量,Western blot法检测细胞生存素（survivin）蛋白含量,流式细胞仪检测细胞凋亡情况,用MTT实验检测转染对细胞活性的影响,用细胞生长曲线表示转染对细胞生长的影响。结果VEGF-ASODN能显著降低VEGF mRNA水平、降低胃癌细胞及其培养液中VEGF蛋白含量、降低survivin蛋白含量、增加细胞凋亡、抑制细胞活性及生长（P〈0.05）。结论VEGF-ASODN转染胃癌细胞SGC-7901能显著抑制VEGF和survivin蛋白表达、增加细胞凋亡、抑制细胞生长。