Yihong Sun

Morbidity and Mortality of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: A Randomized Controlled Trial

PURPOSE The safety and efficacy of radical laparoscopic distal gastrectomy (LG) with D2 lymphadenectomy for the treatment of advanced gastric cancer (AGC) remain controversial. We conducted a randomized controlled trial to compare laparoscopic and conventional open distal gastrectomy with D2 lymph node dissections for AGC. PATIENTS AND METHODS Between September 2012 and December 2014, 1,056 patients with clinical stage T2-4aN0-3M0 gastric cancer were eligible for inclusion. They were randomly assigned to either the LG with D2 lymphadenectomy group (n = 528) or the open gastrectomy (OG) with D2 lymphadenectomy group (n = 528). Fifteen experienced surgeons from 14 institutions in China participated in the study. The morbidity and mortality within 30 days after surgery between the LG (n = 519) and the OG (n = 520) groups were compared on the basis of the modified intention-to-treat principle. Postoperative complications were stratified according to the Clavien-Dindo classification. RESULTS The compliance rates of D2 lymphadenectomy were similar between the LG and OG groups (99.4% v 99.6%; P = .845). The postoperative morbidity was 15.2% in the LG group and 12.9% in OG group with no significant difference (difference, 2.3%; 95% CI, -1.9 to 6.6; P = .285). The mortality rate was 0.4% for the LG group and zero for the OG group (difference, 0.4%; 95% CI, -0.4 to 1.4; P = .249). The distribution of severity was similar between the two groups (P = .314). CONCLUSION Experienced surgeons can safely perform LG with D2 lymphadenectomy for AGC.

An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.

OBJECTIVES To investigate whether and how much gastric cancer patients after curative resection could benefit from chemotherapy. PATIENTS AND METHODS Meta-analysis was conducted with all the qualified clinical randomized trials which compared adjuvant chemotherapy with surgery alone. The database includes MEDLINE, EMBase and CBM disc, and the censor data were up to November 2007. Primary outcomes were relative risk (RR) on death and disease-free survival (DFS); secondary outcomes include RR of adverse reactions of the two arms. Sub-group analysis and sensitivity analysis were also performed. All the calculations and statistical tests were done with the RevMan 4.2.8 software. RESULTS Finally, 23 trials which included 4919 patients (2441 in the adjuvant chemotherapy arm, 2478 in the observation arm) achieved all the criteria. Among them, 19 studies reported the survival rate at the end of follow-up, 60.6% alive among 2286 patients in the adjuvant chemotherapy arm, 53.4% alive among 2313 patients in the observation arm, with the RR on death of 0.85 (95%CI: 0.80-0.90). Eight studies reported the DFS, and the observation arm had a shorter DFS (RR: 0.88, 95%CI: 0.77-0.99). Grade 3/4 of myelosuppression and GI toxicity occurred more frequently in the treatment arm. Nine studies reported the recurrence rate and suggested that the treatment arm had a lower recurrence rate (RR: 0.78, 95%CI: 0.71 approximately 0.86). CONCLUSIONS Statistically, adjuvant chemotherapy could improve the survival rate and disease-free survival rate in gastric cancer after curative resection and reduce the relapse rate. However, the clinical benefits of adjuvant chemotherapy still need to be improved. Additionally, post-operative chemotherapy could be tolerated.

Quantitative proteomics study of breast cancer cell lines isolated from a single patient: Discovery of TIMM17A as a marker for breast cancer

The proteins involved in breast cancer initiation and progression are still largely elusive. To gain insights into these processes, we conducted quantitative proteomic analyses with 21T series of breast cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC‐MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. Gene ontology analysis revealed that proteins involved in metabolic processes were the most deregulated in both tumorigenesis and metastasis. Interaction network analysis indicated that ERBB2 signaling played a critical role in tumorigenesis. In addition to known markers such as ERBB2 and E‐cadherin, novel markers, including BRP44L, MTHFD2 and TIMM17A, were found to be overexpressed in 21T breast cancer cells and verified in additional breast cell lines. mRNA expression analysis as well as immunohistochemistry analysis in breast cancer tissues indicated that expression level of TIMM17A was directly correlated with tumor progression, and survival analysis suggested that TIMM17A was a powerful prognosis factor in breast cancer. More interestingly, overexpression and siRNA knockdown experiments indicated an oncogenic activity of TIMM17A in breast cancer. Our study provides a list of potential novel markers for breast cancer tumorigenesis and metastasis using a unique cell model. Further studies on TIMM17A as well as other markers on the list may reveal mechanisms that result in more effective therapeutics for cancer treatment.

Reduced expression of the chromatin remodeling gene ARID1A enhances gastric cancer cell migration and invasion via downregulation of E-cadherin transcription

The chromatin remodeling gene AT-rich interactive domain-containing protein 1A (ARID1A) encodes the protein BAF250a, a subunit of human SWI/SNF-related complexes. Recent studies have identified ARID1A as a tumor suppressor. Here, we show that ARID1A expression is reduced in gastric cancer (GC) tissues, which are significantly associated with local lymph node metastasis, tumor infiltration and poor patient prognosis. ARID1A silencing enforces the migration and invasion of GC cells, whereas ectopic expression of ARID1A inhibits migration. The adhesive protein E-cadherin is remarkably downregulated in response to ARID1A silencing, but it is upregulated by ARID1A overexpression. E-cadherin overexpression significantly inhibits GC cell migration and invasion, whereas CDH1 (coded E-cadherin) silencing promotes migration. Restored expression of CDH1 in ARID1A-silenced cell lines restores the inhibition of cell migration. Luciferase reporter assays and chromatin immunoprecipitation indicate that the ARID1A-associated SWI/SNF complex binds to the CDH1 promoter and modulates CDH1 transcription. ARID1A knockdown induces evident morphological changes of GC cells with increased expression of mesenchymal markers, indicating an epithelial-mesenchymal transition. ARID1A silencing does not alter the level of β-catenin but induces a subcellular redistribution of β-catenin from the plasma membrane to the cytoplasm and nucleus. Immunohistochemical studies demonstrate that reduced expression of E-cadherin is associated with local lymph node metastasis, tumor infiltration and poor clinical prognosis. ARID1A and E-cadherin expression show a strong correlation in 75.4% of the analyzed GC tissues. They are synergistically downregulated in 23.5% of analyzed GC tissues. In conclusion, ARID1A targets E-cadherin during the modulation of GC cell migration and invasion.

Loss of RACK1 Promotes Metastasis of Gastric Cancer by Inducing a miR-302c/IL8 Signaling Loop

Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine expression of IL8 in vitro and in vivo. microRNA (miRNA; miR) array identified that RACK1 modulated the expression of a series of miRNAs, including the miR-302 cluster, and RACK1 modulated the IL8 expression and tumor invasion through miRNA-302c. Moreover, upregulation of IL8 in turn decreased the level of miRNA-302c and induced IL8 expression in a feedback manner. Tissue microarray also indicated that RACK1 was correlated with invasion/metastasis phenotype, IL8 expression, as well as 5-year survival in clinical cases of gastric cancer. Together, our results imply that loss of RACK1 in gastric cancer links epigenetics to inflammatory cytokines to promote tumor metastasis.

Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma.

Clinical significance of 2,3-dioxygenase (IDO) has been studied in types of tumors, but the role that IDO played in gastric adenocarcinoma (GAC) is still unclear. Here, we aim to investigate the prognostic value of IDO expression in patients with GAC. We examined intratumoral IDO expression in retrospectively enrolled 357 patients with GAC undergoing gastrectomy at Zhongshan Hospital of Fudan University in 2008 by immunohistochemical staining. The Kaplan-Meier method and Cox regression models were used to evaluate the prognostic value of IDO expression and its association with clinical pathological factors. We generated a predictive nomogram by integrating IDO expression with the TNM staging system for overall survival of GAC patients. High expression of intratumoral IDO predicted a dismal outcome. Intratumoral IDO expression gave a further discrimination for the prognosis of GAC patients. By Cox multivariate analysis, IDO expression was defined as an independent prognosticator. The generated nomogram performed well in predicting the 3- and 5-year overall survival of GAC patients. Conclusively, IDO is a potential prognostic biomarker for overall survival of patients with GAC after gastrectomy.

FOXO3a promotes gastric cancer cell migration and invasion through the induction of cathepsin L

Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis.

Tumor-infiltrating Neutrophils is Prognostic and Predictive For Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer.

Objective: This study was aimed to investigate the prognostic value of tumor-infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. Background: TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. Methods: The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. Results: TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. Conclusions: TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.

Overexpression of Ras-GTPase-activating protein SH3 domain-binding protein 1 correlates with poor prognosis in gastric cancer patients.

AIMS Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a downstream effector of Ras signalling, and is overexpressed in several types of human malignancy. However, its role in gastric cancer remains unclear. The aim of this study was to investigate the prognostic significance of G3BP1 in gastric cancer. METHODS AND RESULTS G3BP1 mRNA and protein levels in paired frozen tumour samples were detected by real-time polymerase chain reaction and western blotting, respectively. Paraffin-embedded tumour samples were used for immunohistochemistry. Gastric cancer cells were used to detect the tumorigenic role of G3BP1 in vitro. We found that G3BP1 protein expression was markedly increased in gastric cancer tissues as compared with corresponding non-malignant mucosa, whereas corresponding changes in mRNA levels were not observed. G3BP1 staining was positively correlated with tumour size, vascular invasion, T classification, lymph node metastasis, TNM stage, and reduced overall survival. Further analysis identified G3BP1 as an independent prognostic factor for poor prognosis, and combining G3BP1 with TNM stage generated a better predictive model for patient outcomes. G3BP1 also promoted proliferation, migration/invasion and extracellular signal-related kinase and AKT activation in gastric cancer cells. CONCLUSIONS Our data define G3BP1 as a novel independent prognostic factor that is correlated with gastric cancer progression.

Survival benefit of greater number of lymph nodes dissection for advanced node-negative gastric cancer patients following radical gastrectomy

OBJECTIVE A common clinicopathological factor except for T stage that could significantly influence the clinical outcome of advanced node-negative gastric cancer patients following radical gastrectomy was unknown. This study was designed to investigate the clinicopathological characteristics of these patients, and to evaluate the outcome indicators and improve the risk stratification. METHODS A total of 195 patients harboring advanced gastric adenocarcinoma with no lymph node and distant metastases and following radical gastrectomy were retrospectively analyzed from the prospectively collected database of Zhongshan Hospital of Fudan University between 2006 and 2010. RESULTS The 3-year and 5-year overall survival rates of this study population were 85.0 and 69.6%. Factors influencing the overall survival were the degree of tumor differentiation, the depth of invasion and the number of lymph nodes resected (LN, cutoff = 18). Lymph node was recognized as an independent prognostic factor for overall survival of advanced node-negative gastric cancer patients, and the prognosis of the patients with greater number of lymph nodes resected (LN ≥ 18) was significantly better than those with lymph node < 18, and only the patients with T3/T4 stage could be significantly stratified by lymph node. Based on this condition, a new staging system named tumor-node-metastasis staging system for T3/T4 node-negative gastric cancer was constructed, which could have statistically different overall survival between subgroups. CONCLUSIONS Lymph node was an independent prognostic factor of patients with advanced node-negative gastric cancer, and retrieval of more than 18 lymph nodes should be warranted. In addition, these patients with lesser number of lymph nodes resected might need aggressive postoperative treatment and closer follow-up.