Chang-Hua Zhang

(-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer

AIM To demonstrate that (-)-Epigallocatechin-3-gallate (EGCG) inhibits vascular endothelial growth factor (VEGF) expression and angiogenesis induced by interleukin-6 (IL-6) via suppressing signal transducer and activator of transcription 3 (Stat3) activity in gastric cancer. METHODS Human gastric cancer (AGS) cells were treated with IL-6 (50 ng/mL) and EGCG at different concentrations. VEGF, total Stat3 and activated Stat3 protein levels in the cell lyses were examined by Western blotting, VEGF protein level in the conditioned medium was measured by enzyme-linked immunosorbent assay, and the level of VEGF mRNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR). Stat3 nuclear translocation was determined by Western blotting with nuclear extract, and Stat3-DNA binding activity was examined with Chromatin immunoprecipitation (ChIP) assay. IL-6 induced endothelial cell proliferation was measured with 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazoliumbromide assay, in vitro angiogenesis was determined with endothelial cell tube formation assay in Matrigel, and IL-6-induced angiogenesis in vitro was measured with Matrigel plug assay. RESULTS There was a basal expression and secretion of VEGF in AGS cells. After stimulation with IL-6, VEGF expression was apparently up-regulated and a 2.4-fold increase was observed. VEGF secretion in the conditioned medium was also increased by 2.8 folds. When treated with EGCG, VEGF expression and secretion were dose-dependently decreased. IL-6 also increased VEGF mRNA expression by 3.1 folds. EGCG treatment suppressed VEGF mRNA expression in a dose-dependent manner. EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression. When treated with EGCG or AG490, VEGF expressions were reduced to the level or an even lower level in the tumor cells not stimulated with IL-6. However, PD98059 and LY294002 did not change VEGF expression induced by IL-6. EGCG inhibited Stat3 nucleus translocation, and Stat3-DNA binding activity was also markedly decreased by EGCG. Furthermore, EGCG inhibited IL-6 induced vascular endothelial cell proliferation and tube formation in vitro and angiogenesis in vitro. CONCLUSION EGCG inhibits IL-6-induced VEGF expression and angiogenesis via suppressing Stat3 activity in gastric cancer, which has provided a novel mechanistic insight into the anti-angiogenic activity of EGCG.

High CpG island methylator phenotype is associated with lymph node metastasis and prognosis in gastric cancer

Several studies have found that the promoter CpG island is frequently methylated in gastric cancer. The CpG island methylator phenotype (CIMP) defines concordant methylation of multiple promoter CpG island loci in a subset of gastric cancer. However, the relationship between CIMP and lymph node metastasis in gastric cancer is unknown. Our study aimed to characterize the role of CIMP in lymph node metastasis. Clinical specimens from 120 patients were analyzed and PCR was used to detect the methylation status of five genes (ALX4, TMEFF2, CHCHD10, IGFBP3, and NPR1). We measured the level of mRNA for the five genes by real‐time RT‐PCR. Microsatellite instability and Helicobacter pylori infection status were assayed by capillary electrophoresis and real‐time PCR, respectively. DNA methylation in the five genes was correlated with low expression of the respective mRNA. With CIMP as the dependent variable, CIMP‐high gastric cancer tended to show more distant lymph node metastasis, higher pathologic tumor classification, more pathologic metastasis, and higher pathologic TNM status. Microsatellite instability and H. pylori status were not significant predictors of prognosis. CIMP‐high gastric cancer showed significantly worse survival compared with that of CIMP‐low/CIMP‐negative gastric cancer (P < 0.001). Our results show that there is an association between CIMP status and lymph node metastasis in gastric cancer and CIMP‐high was an independent prognostic factor. (Cancer Sci 2012; 103: 73–79)

Spleen Preservation in Radical Surgery for Gastric Cardia Cancer

BackgroundIn gastric cardia cancer (GCC), the spleen is usually removed when the tumor is resected. This allows thorough lymph node dissection in the splenic hilus. However, the long-term effect of splenectomy on patient survival is controversial. The purpose of this study was to investigate the effect of spleen preservation on survival following radical resection for gastric cardia cancer.MethodsWe reviewed the records of 116 GCC patients (Siewert types II and III) who underwent radical resection with D2 or D3 lymphadenectomy between July 1994 and December 2003. Survival status was ascertained in December 2004 and data from 108 patients were analysed. Of these 108 patients, 38 underwent splenectomy and 70 had splenic preservation. Clinicopathological features and prognostic data of the splenectomy(+) and splenectomy(−) groups were compared.ResultsSeventy-four patients (68.5%) had lymph node involvement; 18 (16.7%) had involvement of nodes in the splenic hilus. Postoperative morbidity in the two groups was similar. Overall 5-year survival was higher in the splenectomy(−) group than the splenectomy(+) group (38.7% versus 16.9%, P =.008). Multivariate regression indicated that tumor invasion (P =.009) and lymph node metastasis (P = .001) were independent prognostic factors – they predicted decreased survival – with or without splenectomy. Although splenectomy was be associated with lower survival, it was not an independent prognostic factor (P =.085).ConclusionsSplenectomy does not improve survival of patients who undergo curative resection for gastric cardia cancer. Thus, the spleen should be preserved in patients without direct cancer invasion of the spleen.

Long non-coding RNA TUG1 promotes colorectal cancer metastasis via EMT pathway.

Colorectal cancer (CRC) is the third most common malignancy in developed countries, and its incidence rate has been continuously increasing in developing countries over the past few decades. Taurine-upregulated gene 1 (TUG1) plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the role of TUG1 in CRC, and whether knockdown of TUG1 expression could affect cell proliferation, migration and invasion of CRC cell lines. Here, we reported that TUG1 was upregulated in CRC. Further experiments revealed that TUG1 knockdown significantly inhibited cell proliferation, migration and invasion of CRC in vitro. Above all, knockdown of TUG1 may represent a rational therapeutic strategy for CRC patients in future.

Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer.

Lymph node metastasis is a significant factor in gastric cancer prognosis. It is well known that cancer cells secrete lymphangiogenic factors, thereby promoting lymphangiogenesis. However, the effects of lymphatic endothelial cell (LEC)‐secreted factors on the process of lymphangiogenesis and tumor cell metastasis remain unclear. We established an animal model and successfully isolated LECs from afferent lymph vessels of sentinel lymph nodes (SLNs) in animal models. A microarray analysis was performed to characterize gene expression profile in afferent LECs induced by metastatic cancer cells. There were significant differences in 846 genes between normal LECs and LECs with lymph node metastasis. Among these genes, we found that expression of CXCL1 was upregulated, which was confirmed by quantitative reverse‐transcriptase polymerase chain reaction. In a coculture system, gastric cancer cells induced CXCL1 secretion from LECs, which was associated with the NF‐κB pathway. CXCL1 stimulated LECs migration and tube formation involving FAK‐ERK1/2‐RhoA activation and reorganization of F‐actin. In human gastric cancer specimens, CXCR2 expression was positively correlated with TNM (Tumor, node, metastasis) stage and lymphatic vessel density. These results suggested that LECs of afferent SLNs had specific expression profiles, which were distinct from those of normal lymphatic vessels and appeared to promote metastasis. The expression pattern described in our study, including CXCL1 in LECs and its receptor CXCR2 in cancer cells, offers a promising therapeutic target for gastric cancer.

Is albumin administration beneficial in early stage of postoperative hypoalbuminemia following gastrointestinal surgery?: a prospective randomized controlled trial

BACKGROUND Surgeons commonly see postoperative hypoalbuminemia, but whether exogenous albumin administration is beneficial for these patients is unclear. METHODS A prospective, randomized study design was used, allocating 127 hypoalbuminemic patients into the albumin or saline group after gastrointestinal surgery. We investigated the development of postoperative hypoalbuminemia, nutritional status, postoperative fluid balance, postoperative complications, and postoperative hospital stay. RESULTS Plasma albumin concentrations of both groups decreased after operations (P <.01). No significant differences were found between groups (P >.05) in changes in postoperative plasma albumin concentration from baseline levels. Postoperative plasma albumin, total protein, and prealbumin levels were similar in the 2 groups. While 3-day and 5-day recovery ratios were similar, 7-day recovery ratios were lower in the albumin group (P <.05). No significant difference was found in overall fluid administration, urine output, or the incidence of postoperative complications between groups (23.4% for albumin group and 12.7% for control group, P = .116). CONCLUSIONS Albumin administration in the early stage of postoperative hypoalbuminemia following gastrointestinal surgery is not beneficial in correcting hypoalbuminemia or in clinical outcomes.

High-expression of DJ-1 and Loss of PTEN Associated with Tumor Metastasis and Correlated with Poor Prognosis of Gastric Carcinoma

Background and aims: DJ-1 and PTEN have been shown to involve in multiple cell processes and play an important role in cancer development and progression. However, their relationship with gastric carcinoma (GC) has not been identified yet. The purpose of this study is to clarify the relationship of DJ-1 and phosphatase and tensin homolog (PTEN) with clinicopathological parameters and prognosis in GC. Methods: 114 specimens were collected from GC patients and expression of DJ-1 and PTEN in tissue microarray was evaluated by immunohistochemical staining. Correlation between immunostainings and clinicopathological parameters, follow-up data of patients, was analyzed statistically. Results: High expression of DJ-1 was found in 66.7% (76/114) and associated with tumor depth (P=0.003), lymph node metastasis (P=0.011), distant metastasis (P=0.001) and advanced clinical stage (P=0.001). Loss or downregulation of PTEN was found in 58.7% (67/114) and associated with advanced clinical stage (P=0.018) and high expression of DJ-1 in tumor cells (P=0.006). In univariate survival analysis, high-expression of DJ-1 or loss of PTEN was significantly associated with poor prognosis of GC patients. However, only tumor depth (P=0.011) and coexistence of DJ-1 and PTEN abnormal expression (P=0.009) emerged as strong independent prognostic factors for overall survival of GC patients. Conclusions: the present study indicates that DJ-1 and PTEN may play their roles in progression of GC in a cooperating pattern. Co-existence of abnormal DJ-1 and PTEN expression is likely to serve as an independent predictive factor for prognosis of GC patients.

The prognostic value of lymph nodes dissection number on survival of patients with lymph node-negative gastric cancer.

Objective. The study was designed to explore the prognostic value of examined lymph node (LN) number on survival of gastric cancer patients without LN metastasis. Methods. Between August 1995 and January 2011, 300 patients who underwent gastrectomy with D2 lymphadenectomy for LN-negative gastric cancer were reviewed. Patients were assigned to various groups according to LN dissection number or tumor invasion depth. Some clinical outcomes, such as overall survival, operation time, length of stay, and postoperative complications, were compared among all groups. Results. The overall survival time of LN-negative GC patients was 50.2 ± 30.5 months. Multivariate analysis indicated that LN dissection number (P < 0.001) and tumor invasion depth (P < 0.001) were independent prognostic factors of survival. The number of examined LNs was positively correlated with survival time (P < 0.05) in patients with same tumor invasion depth but not correlated with T1 stage or examined LNs >30. Besides, it was not correlated with operation time, transfusion volume, length of postoperative stay, or postoperative complication incidence (P > 0.05). Conclusions. The number of examined lymph nodes is an independent prognostic factor of survival for patients with lymph node-negative gastric cancer. Sufficient dissection of lymph nodes is recommended during surgery for such population.

Use of absorbable hemostatic gauze with medical adhesive is effective for achieving hemostasis in presacral hemorrhage

BACKGROUND Management of presacral hemorrhage is always challenging. Herein we describe the use of an absorbable hemostatic gauze with α-cyanoacrylate medical adhesive to achieve hemostasis. METHODS In this study, we conducted total mesorectal excision for the treatment of rectal cancer in 258 patients from March 2006 to May 2009. Intraoperative presacral hemorrhage developed in 5 (2%) patients during rectal mobilization. RESULTS In these 5 patients, massive bleeding could not be controlled by pressure and pelvic packing with gauze. An absorbable hemostatic gauze spread with medical adhesive was compressed onto the bleeding vessel for at least 20 minutes. Hemostasis was achieved successfully and was maintained during the surgery. Patients recovered uneventfully and no postoperative events were noted. CONCLUSIONS The use of an absorbable hemostatic gauze with medical adhesive is a simple and effective method for achieving hemostasis when massive presacral hemorrhage occurs. However, its effectiveness needs to be confirmed in a controlled study in a properly selected patient population.

Systematic review of nasogastric or nasojejunal decompression after gastrectomy for gastric cancer

BACKGROUND The aim of this meta-analysis was to evaluate the necessity of nasogastric or nasojejunal decompression after gastrectomy for gastric cancer. METHODS Medline, Embase and the Cochrane Library were searched. Only prospective randomized controlled trials (RCTs) that compared subjects with and without nasogastric or nasojejunal decompression after gastrectomy were eligible in this meta-analysis. Time to flatus, time to first oral intake, length of hospital stay, reinsertion rate, anastomotic leakage, pulmonary complications, morbidity and mortality were evaluated. RESULTS Eight studies finally fulfilled the inclusion criteria. This meta-analysis enrolled 1141 patients, 570 randomized to routine decompression and 571 randomized to no decompression. Time to first oral intake was significantly shorter in the non-decompression group (WMD = 0.53, 95% CI: 0.28 to 0.77; p < 0.001). Additionally, subjects with nasogastric or nasojejunal decompression experienced a longer hospital stay (p = 0.001). Time to flatus, anastomotic leakage, reinsertion rates, pulmonary complications, morbidity and mortality rates were similar between the two groups. CONCLUSION Nasogastric or nasojejunal decompression does not facilitate the recovery of bowel function or reduce the risk of postoperative complications. Therefore, routine nasogastric or nasojejunal decompression is unnecessary after gastrectomy for gastric cancer.