The Role of HER2 in Self-Renewal, Invasion, and Tumorigenicity of Gastric Cancer Stem Cells.

BACKGROUND: Deregulation of HER2 expression could affect the biological characteristics of gastric cancer cells and treatment option for gastric cancer patients. This research aims to investigate the impact of HER2 on biological characteristics of gastric cancer stem cells (GCSCs) and prognosis of gastric cancer patients. METHODS: HER2 knockdown in GCSCs were constructed by lentivirus transfection. Alterations of proliferation, self-renewal, invasion, migration, colony formation, and tumorigenicity of GCSCs were examined. The changes of gene expressions after HER2 interference in GCSCs were detected by gene microarray. The impact of concentration of serum HER2 and expression of HER2 in tumor tissues on survival of 213 gastric cancer patients was also analyzed. RESULTS: Down-regulation of HER2 decreased the self-renewal, colony formation, migration, invasion, proliferation, and chemotherapy resistance of GCSCs. However, the tumorigenicity of GCSCs in vivo was increased after down-regulation of HER2. The results of gene microarray showed that HER2 gene might regulate the signal transduction of mTOR, Jak-STAT, and other signal pathways and affect the biological characteristics of GCSCs. Furthermore, survival analyses indicated that patients with high concentration of HER2 in serum had a favorable overall survival. However, there was no significant correlation between expression of HER2 in tumor tissue and overall survival. CONCLUSION: Interference of HER2 in GCSCs decreased the capacity of self-renewal, proliferation, colony formation, chemotherapy resistance, invasion, and migration but might increase the tumorigenicity in vivo. Patients with high concentration of HER2 in serum seemed to have a favorable prognosis.

Learning curve for gastric cancer patients with laparoscopy-assisted distal gastrectomy: 6-year experience from a single institution in western China.

Laparoscopy-assisted distal gastrectomy (LADG) is widely used for gastric cancer (GC) patients nowadays. This study aimed to investigate the time trend of outcomes so as to describe the learning curve for GC patients with LADG at a single medical institution in western China over a 6-year period.A total of 246 consecutive GC patients with LADG were divided into 5 groups (group A: 46 patients from 2006 to 2007; group B: 47 patients in 2008; group C: 49 patients in 2009; group D: 73 patients in 2010; and group E: 31 patients in 2011). All surgeries were conducted by the same surgeon. Comparative analyses were successively performed by Mann-Whitney U test or Student t test among the 5 different groups for the clinical data, including clinicopathologic characteristics, surgical parameters, postoperative course, and survival outcomes, through which the learning curve was described.There were no differences in the baseline information among the 5 groups (P > 0.05), and the proportion of advanced GC patients with LADG slightly increased from 58.7% to 77.4% during the 6 years. Besides, the proportion of D2/D2+ lymphadenectomy and the number of retrieved lymph nodes gradually grew from 60.9% to 80.6% and from 20.0 to 28.8, respectively. In addition, the operation time decreased from 299.2 to 267.8 minutes, while the estimated blood loss dropped from 175.2 to 146.8 mL. Furthermore, some surgical parameters (surgical duration and blood loss) and postoperative course (such as postoperative complications, the time to ambulation, to first flatus, and to first liquid intake as well as the length of hospital stay) were all observed to be significantly different between group A and other groups (P < 0.05), illustrating a similar downward trend and remaining stable to form a plateau after 46 cases in group A. However, no difference on overall survival was found among these 5 groups, and multivariate analysis indicated that factors, such as age, tumor differentiation, tumor size, and T stage as well as N stage, were independent prognostic factors for patients with LADG.Improvement on surgical parameters and postoperative course can be seen over the past years, and the cutoff value of the learning curve of LADG for surgeons with rich experience in open operation might be 46 cases.

A new predictive model combined of tumor size, lymph nodes count and lymphovascular invasion for survival prognosis in patients with lymph node-negative gastric cancer.

BACKGROUND: Various factors may affect the clinical prognosis of lymph node-negative gastric cancer (GC) patients. This study aimed to provide evaluable prognostic information of combination of tumor size (Ts), lymph nodes count (LNs) and lymphovascular invasion (LVI) in lymph node-negative GC patients. METHODS: A total of 1,019 node-negative GC patients were enrolled in this retrospective study from 2000 to 2010. The cutoff points of Ts and LNs were determined using X-tile and patients were randomly categorized into training and validation sets by the sample size ratio 1:1. The clinicopathologic characteristics were analyzed and survival prognostic factors were identified, whereas the survival prediction accuracy was also compared by C-index during the different independent prognostic factors. RESULTS: The cutoff points for Ts were 3cm and 5cm, while 14 was the cutoff point for LNs. Age, T stage, Ts, LNs and LVI were identified as independent prognostic factors in node-negative GC patients, and a new prognostic predictive model, TsNL staging system which was composed of Ts, LNs and LVI, was proposed in this study. Compared with T staging system, significant improvement of predictive accuracy for TsNL system was found. Furthermore, nomogram based on TsNL was more accurate in prognostic prediction than that based on Ts, LNs and LVI, separately. CONCLUSIONS: Age, T stage, Ts, LNs and LVI were independent prognostic factors in lymph node-negative GC patients. The TsNL staging system, composed of Ts, LNs and LVI, which was closely associated with clinicopathologic features, may improve the prognostic prediction accuracy in node-negative GC patients.

Clinical significance of putative markers of cancer stem cells in gastric cancer: A retrospective cohort study.

Cancer stem cells (CSCs) are thought as the source of tumor maintaining and many CSCs markers have been identified. Regarding the heterogeneity in gastric cancer (GC), TNM stage is not enough to accurately predict the prognosis. The aim of this study was to investigate the clinical significance of CSCs markers (Lgr5, Oct4, CD133, EpCAM, CD54 and Sox2) and establish a new model based on these markers to accurately predict prognosis of GC. We retrospectively enrolled 377 GC tissues from January 2006 to October 2012 to perform immunohistochemistry (IHC), and 93 pairs of GC tissues and corresponding adjacent normal gastric tissues to perform quantitative PCR (qPCR) from December 2011 to October 2012. The clinicopathological and follow-up characteristics were collected. In IHC, Oct4, CD133 and EpCAM were independently related to tumor progression, while Sox2 were associated with well or moderate differentiation (all p<0.05). Cox regression showed that Oct4-EpCAM was an independently prognostic factor, indicating that double low expression of Oct4-EpCAM group had significantly better prognosis than control group (p=0.035). Regarding qPCR, CD133 was an independent prognostic factor, showing that the prognosis of patients with CD133 high expression was significantly worse than that of patients with CD133 low expression (p<0.001). The prognostic prediction accuracy of nomogram based on Oct4-EpCAM expression in IHC was significantly better than TNM stage alone (p=0.003). Low expressions of Oct4-EpCAM in IHC and CD133 in qPCR were favorable prognostic factors in GC. The nomogram based on Oct4-EpCAM was valuable in prognostic prediction of GC patients.

Clinical characteristics and prognostic factors of primary gastric lymphoma: A retrospective study with 165 cases.

Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma. This retrospective study aimed to analyze the clinical characteristics, prognostic factors, and roles of different treatment modalities in patients with PGL.From January 2003 to November 2014, 165 patients who were diagnosed with PGL at West China Hospital were enrolled in this study. The clinical features, treatment, and follow-up information were analyzed.In this study, diffuse large B-cell lymphoma (DLBCL) (108, 65.5%) and mucosa-associated lymphoid tissue (MALT) lymphoma (52, 31.5%) were two predominant histological subtypes. One-year and 5-year overall survival (OS) rates of all patients were 95.2% and 79.5%, respectively; in whom 110 (66.7%) underwent surgery, 110 (66.7%) received chemotherapy, 12 (7.3%) received radiotherapy, and 10 (6.1%) received Helicobacter pylori eradication. And 75 patients (45.5%) were treated with at least 2 different types of therapies. Elevated lactic dehydrogenase (LDH) levels, poor performance status (PS), advanced stage, International Prognostic Index (IPI) score ≥3, conservative treatment, and high-grade histological subtype were associated with worse prognosis in univariate analysis. Cox regression analysis showed that LDH levels, PS, staging, and histological subtype were independent predictors of survival outcomes. In the DLBCL type, 5-year OS was significantly better in the surgically treated group (80.1%) than that of patients conservatively treated (49.8%) (P = 0.001). Surgical treatment had almost no impact on OS in the MALT type than conservative treatment (P = 0.597). The proportion of patients received conservative treatment increased from 4.5% in period 1 to 51.7% in period 4.High LDH levels, poor PS, advanced staging, and malignant pathological type at diagnosis are significantly associated with poor OS. Our data suggest that surgery is superior in prognosis over conservative treatment in the DLBCL type, but not in the MALT type. Recently, conservative treatment is becoming more preferred approach in patients with PGL.

A nomogram composed of clinicopathologic features and preoperative serum tumor markers to predict lymph node metastasis in early gastric cancer patients.

Predicting lymph node metastasis (LNM) accurately is of great importance to formulate optimal treatment strategies preoperatively for patients with early gastric cancer (EGC). This study aimed to explore risk factors that predict the presence of LNM in EGC. A total of 697 patients underwent gastrectomy enrolled in this study, were divided into training and validation set, and the relationship between LNM and other clinicopathologic features, preoperative serum combined tumor markers (CEA, CA19-9, CA125) were evaluated. Risk factors for LNM were identified using logistic regression analysis, and a nomogram was created by R program to predict the possibility of LNM in training set, while receiver operating characteristic (ROC) analysis was applied to assess the predictive value of the nomogram model in validation set. Consequently, LNM was significantly associated with tumor size, macroscopic type, differentiation type, ulcerative findings, lymphovascular invasion, depth of invasion and combined tumor marker. In multivariate logistic regression analysis, factors including of tumor size, differentiation type, ulcerative findings, lymphovascular invasion, depth of invasion and combined tumor marker were demonstrated to be independent risk factors for LNM. Moreover, a predictive nomogram with these independent factors for LNM in EGC patients was constructed, and ROC curve demonstrated a good discrimination ability with the AUC of 0.847 (95% CI: 0.789-0.923), which was significantly larger than those produced in previous studies. Therefore, including of these tumor markers which could be convenient and feasible to obtain from the serum preoperatively, the nomogram could effectively predict the incidence of LNM for EGC patients.

Superiority of lymph node ratio-based staging system for prognostic prediction in 2575 patients with gastric cancer: validation analysis in a large single center.

This study aimed to evaluate the prognostic significance of node ratio (Nr), the ratio of metastatic to retrieved lymph nodes, and to investigate whether a modified staging system based on Nr can improve prognostic ability for gastric cancer patients following gastrectomy. A total of 2572 patients were randomly divided into training set and validation set, and the cutoff points for Nr were produced using X-tile. The relationships between Nr and other clinicopathologic factors were analyzed, while survival prognostic discriminatory ability and accuracy were compared among different staging systems by AIC and C-index in R program. Patients were categorized into four groups as follows: Nr0, Nr1: 0.00-0.15, Nr2: 0.15-0.40 and Nr3: > 0.40. Nr was significantly associated with clinicopathologic factors including macroscopic type, tumor differentiation, lymphovascular invasion, perineural invasion, tumor size, T stage, N stage and TNM stage. Besides, for all patients, Nr and TNrM staging system showed a smaller AIC and a larger C-index than that of N and TNM staging system, respectively. Moreover, in subgroup analysis for patients with retrieved lymph nodes < 15, Nr was demonstrated to have a smaller AIC and a larger C-index than N staging system. Furthermore, in validation analysis, Nr, categorized by our cutoff points, showed a larger C-index and a smaller AIC value than those produced in previous studies. Nr could be considered as a reliable prognostic factor, even in patients with insufficient (< 15) retrieved lymph nodes, and TNrM staging system may improve the prognostic discriminatory ability and accuracy for gastric cancer patients undergoing radical gastrectomy.