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The objective of this study was to investigate the independent correlated factors for lymph node metastasis (LNM) and prognosis in T2 gastric cancer patients. A total of 135 pathologically confirmed T2 gastric cancer patients who received a gastrectomy at the Beijing University Cancer Hospital from Dec 1999 to Dec 2006 were studied retrospectively. The potential correlated factors for LNM and patients’ prognosis were analyzed, including gender, age, tumor location and size, depth of invasion, lymphatic vascular invasion (LVI), differentiation grade, histological type, Borrmann type, LNM, distant metastasis, TNM stage, and whether the patient was treated with a radical gastrectomy. LNM occurred in 69 patients, which represents a rate of LNM of 51.1 %. Multivariate logistic regression analysis showed that LVI and TNM stage were independent risk factors for LNM (p values were 0.002 and 0.029, respectively). The median follow-up time was 60.3 months. Multivariable survival analysis revealed that age (

The purpose of this study is to detect the clinicopathology of gastrointestinal stromal tumors (GISTs) occurring synchronously with gastric adenocarcinomas and to unveil the potential underlying relationship between the synchronous GIST and gastric adenocarcinoma. This study included 15 patients with incidental GISTs found during operations for gastric adenocarcinoma and 30 patients who underwent gastrectomy for gastric cancer without discovering GIST between January 2005 and December 2010 at the Beijing Cancer Institute. We collected the clinicopathological data and analyzed the KIT/PDGFRA mutational status of GISTs, corresponding gastric adenocarcinoma specimens, and the normal tissue around the cancer lesions. Additionally, as a control group, the mutational status of the patients with gastric adenocarcinoma and no other tumors was assayed. Overall, 18 GISTs were found in 15 gastric adenocarcinoma patients. Multiple GIST lesions were found in three cases (20 %). The patients' age ranged from 46 to 85 years, with an average of 67.6 years. The average size of the GISTs was 0.85 cm. All mesenchymal lesions showed low proliferative activity, were of low or very low risk, and were identified as CD117-positive by immunostaining. In GIST lesions, mutations in KIT were detected in 7 out of 13 cases, and of these mutations, 6 were found in exon 11 (46.2 %), and 1 was found in exon 9 (7.7 %). A total of five deletions and one point mutation were in exon 11, and one insertion was in exon 9. Mutations were not detected in exon 17 or 13 of KIT. There was no remarkable mutation analyzed in the gastric adenocarcinoma lesions or normal tissues from either the test or control groups. Clinicopathological profiles and molecular analysis of KIT/PDGFRA showed no obvious relationship between gastric cancer and GISTs in tumor genesis, such as similar oncogene mutations.

Objective To perform a systematic review and meta-analysis of the comparative studies reporting oncological and renal function outcomes of segmental ureterectomy (SU) versus radical nephroureterectomy (RNU) for upper tract urothelial carcinomas (UTUC). Materials and methods A literature search on Pubmed, Embase, and the Cochrane library was conducted according to the PRISMA guidelines, and a meta-analysis was performed to assess cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS), intravesical recurrence free survival (IVRFS) and surgery-related variations in estimated glomerular filtration rate (eGFR). Results A total of 11 retrospective studies with 3963 patients who underwent either SU ( n = 983; 24.8%) or RNU ( n = 2980; 75.2%) were included. Although patients treated with SU were more likely to be diagnosed with favorable pathological features, the meta-analysis of unadjusted data revealed no significant difference between both groups in terms of CSS (HR 0.90, p = 0.33) and OS (HR 0.98, p = 0.93). Accordingly, the meta-analysis of adjusted data confirmed equivalent CSS (HR = 0.90, p = 0.47) between SU and RNU. Similarly, no significant difference was found in terms of RFS (HR 1.06, p = 0.72) and IVRFS (HR 1.35, p = 0.39). However, a significant decreased risk of impaired renal function was observed after SU when compared to RNU (mean eGFR difference = 9.32 ml/1.73 m 2 , p = 0.007). Conclusion Although adverse patient and tumor characteristics were not equally balanced between treatment arms, our systematic review and meta-analysis supports similar oncological outcomes between SU and RNU, with better preservation of renal function after SU. As such, SU should be preferably used as the first-line treatment for low-risk ureter tumors, while considered for selected cases of high-risk disease.

Bottleneck feature (BNF), together with Gaussian mixture models, has achieved great success compared with acoustic features in low-resource speech recognition. However, the existing of BN layer decreases classification accuracy of deep neural networks (DNN). In this paper, we investigate a better way of extracting DNN based low-dimensional features using convex-nonnegative matrix factorization (CNMF). Firstly a DNN is trained without setting the BN layer. Secondly CNMF is applied on the weights matrix of a hidden layer to form a low-dimensional feature extraction layer. Finally a new type of high-level feature is extracted by forward passing input acoustic feature. Experiments show that the new feature produces 1.6–4.6% gain over BNF baseline system in English and Czech low-resource tasks. When dropout and maxout are introduced, 3.1–5.6% additional gain over BNF baseline system is observed while the training time reduces.

Background Early gastric cancer is defined as a lesion confined to the mucosa or submucosa, regardless of the size or lymph node metastasis. Treatment methods include endoscopic mucosal resection or endoscopic submucosal dissection, wedge resection, laparoscopically assisted gastrectomy and open gastrectomy. Lymph node metastasis is strong related with survival and recurrence. Therefore, the likelihood of lymph node metastasis is one of the most important factors when determining the most appropriate treatment. Methods We retrospectively analyzed 597 patients who underwent D2 gastrectomy for early gastric cancer. The relationship between lymph node metastasis and clinicopathological features was analyzed. Using multivariate logistic regression analyses, we created a nomogram to predict the lymph node metastasis probability for early gastric cancer. Receiver operating characteristic analyses was performed to assess the predictive value of the model. Results In the present study, 58 (9.7 %) early gastric cancer patients were histologically shown to have lymph node metastasis. The multivariate logistic regression analysis demonstrated that the age at diagnosis, differentiation status, the presence of ulcers, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in early gastric cancer. Additionally, the tumor macroscopic type, size and histology type significantly correlated with these important independent factors. We constructed a predictive nomogram with these factors for lymph node metastasis in early gastric cancer patients, and the discrimination was good with the AUC of 0.860 (95 % CI: 0.809–0.912). Conclusions We developed an effective nomogram to predict the incidence of lymph node metastasis for early gastric cancer patients.

Background and Objectives Protein tyrosine kinase 7 (PTK7) plays important functions in several cancer types but its expression in gastric cancer remains unknown. This study was designed to investigate PTK7 expression in gastric cancer. Methods PTK7 expression was assessed by immunohistochemistry in 201 gastric cancer patients. The relationship between PTK7 expression and clinicopathological features and patients prognosis were statistically analyzed. Results PTK7 expression was detected in 56.72% (114 of 201) of gastric cancer patients. The immunostaining was predominantly localized in the cytoplasm. The statistical analyses showed that PTK7 expression was more frequently detected in patients with well-differentiated tumors (P = 0.001). Furthermore, PTK7 expression was significantly related to the favorable overall survival (OS; P = 0.012) and disease-free survival (DFS; P = 0.009). Multivariate Cox regression analyses revealed that PTK7 expression was an independent prognostic factor for both favorable OS (P = 0.028) and DFS (P = 0.012). Conclusion Our findings demonstrate that PTK7 can serve as a novel prognostic biomarker for gastric cancer patients. J. Surg. Oncol. 2012; 106:880–886. © 2012 Wiley Periodicals, Inc.

Background Although the role of peri-operative chemotherapy is established in the treatment of locally advanced gastric cancer, the optimal regime remains to be determined. FOLFOX has been used in palliative setting with good response rates but its role in a neoadjuvant setting is not well established. Methods This is a prospective non-randomized study comparing peri-operative FOLFOX versus adjuvant FOLFOX in patients with resectable locally advanced gastric cancer. Response to chemotherapy was assessed according to WHO criteria and pathological changes. Kaplan–Meier log rank test was used to calculate and compare survival differences. Results There were 73 patients (neoadjuvant = 36). Complete and partial response was observed in 2 (6%) and 21 (64%) patients, respectively. Four-year overall survival (OS) in the neoadjuvant arm was 78% versus 51% in the adjuvant arm (P = 0.031). Subgroup analysis found R0 resection (86% vs. 55%, P = 0.011) and patients with proximal cancers (87% vs. 14%, P

Xing X-F, Li H, Zhong X-Y, Zhang L-H, Wang X-H, Liu Y-Q, Jia S-Q, Shi T, Niu Z-J, Peng Y, Du H, Zhang G-G, Hu Y, Lu A-P, Li J-Y, Chen S & Ji J-F (2011) Histopathology59, 198–206 Phospholipase A2 group IIA expression correlates with prolonged survival in gastric cancer Aims: The secreted phospholipase A2 type IIA (PLA2G2A) gene has been identified as a modifier of intestinal adenoma multiplicity in ApcMin/+ mice. The aim of the present study was to analyse the clinical significance of PLA2G2A expression in human gastric cancer. Methods and results: Using immunohistochemistry, cytoplasmic immunoreactivity of PLA2G2A was observed in 27% (40 of 149) of gastric cancer tissues compared with negative staining in normal mucosa. The PLA2G2A expression rate in well-differentiated carcinoma was elevated significantly compared with that in poorly differentiated carcinoma (46% versus 19%, P = 0.001). Statistical analysis also revealed that PLA2G2A expression correlated negatively with depth of mural invasion, lymph node metastasis and tumour–node–metastasis (TNM) stage (P

The aim of this study was to detect metastasis-associated in colon cancer-1 (MACC1) expression in Chinese gastric cancer and analyze the relationship between MACC1 expression and postoperative survival.The expression of MACC1 and c-MET protein in a sample of 128 gastric cancer tissues was detected by immunohistochemistry. A retrospective cohort study on the prognosis was carried out and data were collected from medical records.The positive rate of MACC1 protein expression in gastric cancer was 47.66%, higher than that in adjacent noncancerous mucosa (P0.001). MACC1 protein expression was not related to the clinicopathological variables involved. Kaplan-Meier analysis revealed that the survival of MACC1 positive group tended to be better than that of MACC1 negative group, particularly in patients with stage III carcinoma (P=0.032). Cox regression analysis revealed that MACC1 protein over-expression in gastric cancer tended to be a protective factor with hazard ratio of 0.621 (P=0.057). Immunohistochemical analysis showed that the positive rate of c-MET protein expression was much higher in cases with positive MACC1 expression in gastric cancer (P=0.002), but P53 expression was not associated with MACC1 expression.MACC1 over-expression implies better survival and may be an independent prognostic factor for gastric cancer in Chinese patients.

Objective: The outcome of gastric cancer treatment in China is relatively poor compared with those in Japan and Korea. Relevant factors are not quite clear till now. The aim of this study is to present data on gastric cancer patients from a single high volume cancer center of China and to illuminate relevant factors regarding unsatisfactory outcome. Methods: A total of 2312 consecutive pathologically proven gastric carcinoma patients were treated in Beijing Cancer Hospital from January 1995 to December 2005. Clinical information including demographic information, tumor characteristics, therapeutic experience and survival was retrieved from the Database specially designed for Gastric Cancer Collaborative Group, Beijing Cancer Hospital. Results: There were 1633 males and 679 females with a median age of 58.8 years (range 19−89). Merely 181 patients were in the early stage (7.8%). Curative resection was performed in less than 72% of the patients. The number of lymph nodes harvested varied from 0 to 71 (average 9) while the median number of positive lymph node was 2 (0−37). Only in 650 patients the number of lymph nodes harvested was more than 14. At the end of follow-up, 874 patients were still alive while 1132 died. The 1, 2, 5, 10-year overall survival were 68.50%, 51.88%, 36.83%, and 30.49%, respectively. Multivariate analysis demonstrated that TNM stage, tumor location, tumor size, surgery, and vascular invasion were independent prognostic factors. Conclusion: The outcome of gastric cancer in China is not as good as expected. Early detection and standardized curative resection should be prompted at present to improve the outcome.

A new wearable colorimetric fiber for heavy metal ion detection and adsorption has been synthesized by first aminating a commercially available polyacrylonitrile fiber with ethylenediamine and then covalently immobilizing 4-(2-pyridylazo)-1,3-benzenediol (PAR) on the modified fiber through a Mannich reaction. The fiber was characterized by X-ray powder diffraction spectra (XRD), scanning electron microscope (SEM), FTIR and UV-vis spectroscopy, and its acid exchange capacity, colorimetric properties, response speed, selectivity, reusability, photostability and adsorption capacity were investigated. In neutral aqueous solutions, the PAR immobilized fiber responds selectively to heavy metal ions, such as Hg(2+), Pb(2+), Cd(2+), Zn(2+), Ni(2+) and Cu(2+) with a color change from red-orange to dark-brown. Its visual detection limit for Pb(2+) is 1 x 10(-6)mol/L. Moreover, the selectivity increases with a decrease in pH, i.e. at pH 3.0, it shows a color change only for Hg(2+) and Cu(2+). This fiber also shows excellent reusability (50 times), high photostability (30 days under direct exposure to sunlight) and high adsorption capacity for Hg(2+) (0.74 mmol/g).

A novel halochromic fiber was synthesized by first aminating commercially available polyacrylonitrile fiber with ethylenediamine and then immobilizing phenolphthalein covalently through a Mannich reaction. The fiber was characterized by XRD, SEM, FTIR and UV–vis spectroscopy. The halochromic properties, response speed and durability of this functional fiber have been investigated. This halochromic fiber exhibited remarkable color change from pale yellow to violet in a wide range of alkaline solutions (pH > 10.1) with short response time ( 300 times).

A reusable chelating fiber containing polyamino–polycarboxylic acid ligands was prepared via the stepwise modification of polyacrylonitrile fiber with diethylenetriamine and chloroacetic acid. The amination and carboxylmethylation conditions were optimized, and the modified fiber was characterized by elemental analysis, XRD, SEM and FTIR. For Cd2+ in water, this chelating fiber has prominent adsorption abilities such as low adsorption limitation (0.001 mg/L), high adsorption capacity (1.34 mmol/g) and fast response speed (half-saturation adsorption time less than 0.5 min based on 1 mg/mL Cd2+). The effectiveness of this chelating fiber has been proved by using it to treat actual sewage water, where the concentration of Cd2+ was reduced from 0.540 to below 0.001 mg/L. This level easily meets drinking water standards (0.003 mg/L) issued by the World Health Organization. Moreover, this chelating fiber is also very effective at treating other metal ions such as Cu2+, Ca2+, Zn2+, Mg2+, Pb2+, Ni2+, Ag+ and Hg2+.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy due to its unique capacity to selectively trigger apoptosis in cancer cells. However, TRAIL therapy is greatly hampered by its resistance. A preclinical successful strategy is to identify combination treatments that sensitize resistant cancers to TRAIL. In the present study, we fully assessed TRAIL sensitivity in 9 gastric cancer cell lines. We found combined administration of paclitaxel (PTX) markedly enhanced TRAIL-induced apoptosis in resistant cancer cells both in vitro and in vivo. The sensitization to TRAIL was accompanied by activation of mitochondrial apoptotic pathway, upregulation of TRAIL receptors and downregulation of anti-apoptotic proteins including C-IAP1, C-IAP2, Livin and Mcl-1. Noticeably, we found PTX could suppress the activation of mitogen-activated protein kinases (MAPKs). Inhibition of MAPKs using specific inhibitors (ERK inhibitor U0126, JNK inhibitor SP600125 and P38 inhibitor SB202190) facilitated TRAIL-mediated apoptosis and cytotoxicity. Additionally, SP600125 upregulated TRAL receptors as well as downregulated C-IAP2 and Mcl-1 suggesting the anti-apoptotic role of JNK. Thus, PTX-induced suppression of MAPKs may contribute to restoring TRAIL senstitivity. Collectively, our comprehensive analyses gave new insight into the role of PTX on enhancing TRAIL sensitivity, and provided theoretical references on the development of combination treatment in TRAIL-resistant gastric cancer.

Background Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood. Methods We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants. Results We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab. Conclusions Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0476-2) contains supplementary material, which is available to authorized users.

Xenotransplantation of human cancers into immunodeficient mice is a very useful approach for studying human tumor biology. However, the occasional occurrence of lymphomagenesis in some mice can spoil the model and must be investigated in detail. We found that a high percentage (32.5%, 26/80) of cancer patient-derived xenografts (PDXs) resembled lymphoma in NOD/SCID mice. Of the 26 xenografts, 23 were human-derived expressing human CD45 (hCD45+) and proved to be of the B-cell subtype (CD3-/CD20+) and they were all positive for Epstein - Barr virus (EBV). The remaining 3 xenografts proved to be mouse-derived for both hCD45- and negative amplification of a human gene. The most interesting finding is that gastric cancer had much higher rates (24/126, 19.0%) of lymphoma formation in the PDX model than did colorectal cancer (1/43, 2.3%). Statistical analysis revealed that cancer type and inflammation in the parent tumor are significantly associated with lymphomagenesis. Further validation discovered lymphomagenesis by inoculating only gastritis mucosa. Therefore, our findings suggest that it is necessary to take precautions when directly xenografting cancer tissues with remarkable baseline inflammation, such as gastric cancer into immunodeficient NOD/SCID strains. Further, the established xenograft models should be validated by both leukocyte markers and human gene signatures.

In big data era, researchers pay more attention to the correlation between biological information of patient samples and related clinical information of diseases. The large volume correlation analysis will help predict the initiation, development and outcome for specific diseases. Disease-related biobank is the core facility bridging the gap between the clinical information and biological information of the disease. The volume, diversity, and especially the quality, and standardization of sample and sample-related information will influence the outcome of big data prediction. Therefore, the establishment of quality management system, and implement of standard inspection and test method are very urgent for continuous improvement of biobanks.

Background Systemic chemotherapy is the key treatment for advanced gastric cancer. The benefit of adjuvant surgery following preoperative chemotherapy in gastric cancer with liver metastasis has not been well established. Methods Forty-nine gastric cancer patients diagnosed with synchronous liver metastasis initially treated with chemotherapy were categorized into the following two groups: surgery group: 25 patients who underwent gastrectomy and subsequently received postoperative chemotherapy and control group: 24 patients who received chemotherapy alone. Results The median overall survival of patients in the surgery group and control group was 20.5 and 9.1 months, respectively, (P = 0.006). The median progression-free survival in the surgery group was 10.9 months, with statistical significance when compared with 5.0 months in the control group (P = 0.001). Multivariate analysis demonstrated that response to chemotherapy was the only independent factor in predicting prognosis. The survival of patients who achieved partial response (PR) was prolonged if they received adjuvant surgery (P = 0.024). No significant difference in the survival of patients underwent combined hepatic resection when compared with patients performed gastrectomy only. Conclusions For gastric cancer with synchronous liver metastasis, adjuvant gastrectomy followed by chemotherapy might be beneficial for survival comparing with chemotherapy alone, especially in patients response to initial preoperative chemotherapy. Electronic supplementary material The online version of this article (doi:10.1186/s12957-015-0627-1) contains supplementary material, which is available to authorized users.

Purpose: Cortactin is commonly expressed in several human cancers, which may alter their invasive or metastatic properties. Eighty five kilodalton form (p85) and 80-kDa form (p80) of cortactin are two separate bands in SDS-PAGE representing different conformational states. The objective of this study was to investigate cortactin expression in colorectal cancer (CRC). Experimental Design: Cortactin expression was studied in an eight paired laser capture microdissection (LCM) CRC tissues and matched non-cancerous epithelia by immunoblotting. The expression in 58 CRC and two cell lines, HCT8 and HCT116, was studied respectively by immunohistochemistry and confocal laser scanning immunofluorescence. Results: Dominant expression of p85 was identified in LCM-procured CRC tissues compared with equal intensity of p85 and p80 forms in non-cancerous tissues, while the amount of total cortactin was approximate. Immunohistochemistry analysis demonstrated that cortactin located in the cytoplasm of tumor cells and adjacent non-cancerous cells, and its expression was negatively correlated with TNM staging and lymphatic invasion status. However, the invasion fronts in 3 of 58 primary tumors and 28 of 39 available lymph node metastases were intensively stained. Further, immunofluorescence analysis showed that cortactin was distributed in cytoplasm and enriched in the front of the extending lamellipodia at adhering side of cultured cancer cells. Conclusions: Our results demonstrated the dominant expression of p85 form of cortactin in CRC for the first time. The enrichment of cortactin in the invasion front of some tumor cells and in the extending lamellipodia of cultured cancer cells suggests that cortactin may help cancer cell movement.

Objective: To study the regulation of Fas receptor (Fas)/Fas ligand (FasL) expression by IFN-γ in cholangiocarcinoma cell lines. Methods: We studied the expressions of Fas and FasL gene in the human cholangiocarcinoma cell line QBC939 by RT-PCR, Western blot, and immunohistochemistry and their apoptosis effects on human T cell line Jurkat cell. At the same time, we investigated the regulative effect of IFN-γ on them. Results: Fas, FasL mRNA and protein were expressed by cholangiocarcinoma cells. We also found IFN-γ could up-regulate the expressions of these two genes. However, IFN-γ could also down-regulate the ability of them to make Jurkat cells apoptotic. With the increasing of dosage and time, the effect was enhanced. Conclusion: IFN-γ could regulate the expression of Fas and FasL in cholangiocarcinoma cells, and might influence the ability of cholangiocarcinoma to regulate immune escape. This study provides new theoretical basis for immunological therapy of cholangiocarcinoma.

Objective: To detect promoter hypermethylation of p16 gene in matched pre- and post-operative plasma of patients with gastric adenocarcinoma for evaluating the effectiveness of therapeutic intervention. Methods: Tissue samples, pre- and post-operative plasma of 84 patients were collected. Plasma of 15 healthy people was collected as control. After sodium-bisulfite treatment, extracted DNA was amplified for p16 promoter by methylation-specific polymerase chain reaction (MSP). The PCR products were detected by both gel-ethidium bromide electrophoresis and high performance liquid chromatogram (HPLC). Results: Among 84 patients, p16 hypermethylation was detected in 26 (31.0%) cancer tissues and 2 (0.02%) tumor-adjacent tissues and 12 (14.3%) pre-operative plasma, while negative in plasma of healthy people. For positive plasma cases, the paired tumor tissues were confirmed to be methylated. Within available 30 pairs of matched pre- and post-operative plasma, 6 pre-operative plasma was positive, and only 1 of 6 plasma remained hypermethylated after surgery. The results detected by HPLC exactly matched those by gel-electrophoresis. Conclusion: The alteration of status of p16 hypermethylation in post-operative plasma is considered the consequences of surgical intervention. Although p16 hypermethylation has no role in pre-operative staging of gastric cancer, detecting hypermethylated p16 in plasma could be utilized in monitoring patients after surgery.

Objective: To investigated p53 gene mutation in plasma of gastric cancer patients. Methods: DNA extracted from plasma and matched tumor and tumor-adjacent non-cancerous tissues of 96 gastric cancer patients, and DNA from 20 healthy volunteers were studied. Exon 5, 6, 7, and 8 of p53 were amplified by Polymerase Chain Reaction (PCR). The mutation status was analyzed by denaturing high-performance liquid chromatography (DHPLC), followed by direct sequencing of cases with aberrant chromatographic patterns. Results: Heterozygous mutations of p53 gene were detected in 19.9% (19/96) of primary tumor tissues and 5.2% (5/96) of corresponding plasma. All p53 gene mutations detected in plasma DNA consisted with mutations in the matched primary tumor samples. Neither the tumor-adjacent gastric mucosa tissues nor control plasma from healthy volunteers showed p53 gene mutation. No correlation was found between p53 mutation status and clinicopathological features of gastric cancer patients. Conclusion: p53 gene mutation in plasma can be detected in tissues and plasma of gastric cancer patients, which could be applied in screening and surveillance of this disease.

Gastric cancer is a heterogeneous disease characterized by poor clinical outcomes and limited targeted treatment options. Among them, diffuse-type gastric cancer (DGC) is the subtype with worst prognosis. Here we describe the first proteomic landscape of DGC. We carried out proteome profiling and targeted exome DNA sequencing of 84 DGC samples. We analyzed the 1,008 (168 x 6) raw files together for uniformed quality control and protein identification with 1% global protein false discovery rate (FDR), which resulted in the identification of 11,340 gene products (GPs). A SAM (significance analysis of microarray) analysis identified 1,641 proteins as differentially expressed between T (tumor) and N (nearby) with statistical significance (FDR q value0.5/ < -0.5), including 1,211 up-regulated and 430 down-regulated GPs. Gene Ontology annotation indicated that tumor proteomes were significantly enriched in cell cycle, DNA replication, checkpoint, E2F, WNT, p53 signaling, epithelial mesenchymal transition (EMT), and inflammation/cytokine-receptor interaction pathways, and the proteomes of the nearby tissues are enriched in metabolism pathways, such as fatty acid metabolism, oxidative phosphorylation, and amino acid metabolism. Notably, many gastric makers (ANXA10, VSIG1, CLDN18, CTSE, TFF2, MUC5AC and MUC6) and signature proteins for stomach functions, including digestion, absorption, secretion, and stomach acid generation (PGC, GIF, GAST, and ATP4A), were lost in tumors. Based on proteome profiling alone, DGC can be subtyped into 3 major classes (PX1-3) that exhibit distinct proteome features and correlate with distinct clinical outcomes (Gehan-Breslow-Wilcoxon P = 0.024). PX1 exhibits proteome stability and the best overall survival; PX2 exhibits dysregulation in DNA replication and cell cycle, and is most sensitive to chemotherapy; PX3 features hyper-activated immune response and is not responsive to chemotherapy. We identified seven-marker proteins that can stratify DGC patients into these three subtypes, opening a door for proteome subtyping in clinical application and intervention. Furthermore, we nominated drug target candidates taking into consideration both the altered DGC proteome and association data with patients’ overall survival. This study revealed the altered signaling pathways in DGC and demonstrated the advantage of proteomic approach in molecular subtyping of cancer. Citation Format: Sai Ge, Xia Xia, Chen Ding, Bei Zhen, Quan Zhou, Jinwen Feng, Jiajia Yuan, Rui Chen, Yumei Li, Zhongqi Ge, Jiafu Ji, Lianhai Zhang, Jiayuan Wang, Zhongwu Li, Yumei Lai, Ying Hu, Yanyan Li, Yilin Li, Jing Gao, Lin Chen, Jianming Xu, Chunchao Zhang, Sung Yun Jung, Mingwei Liu, Lei Song, Wanlin Liu, Gaigai Guo, Tongqing Gong, Yin Huang, Yang Qiu, Tieliu Shi, Weimin Zhu, Yi Wang, Fuchu He, Lin Shen, Jun Qin, CNHPP. A proteomic landscape of diffuse-type gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2204. doi:10.1158/1538-7445.AM2017-2204

Our aim is to evaluate the safety and efficacy of two treatment strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) plus simultaneous versus staged cytoreductive surgery (CRS) in patients with occult peritoneal metastasis of gastric cancer (GC).We retrospectively reviewed 26 GC patients who were potential curatively resectable by pre-operative evaluation and found occult peritoneal metastasis by diagnostic laparoscopy. Patients were treated by HIPEC plus either simultaneous CRS (CRS+HIPEC group, n = 11) or staged CRS after systematic chemotherapy (HIPEC+Chemo+CRS group, n = 15).There is no mortality observed in both groups. The treatment complications in two group is comparable (P = 0.683), with 26.7% (4/15) in HIPEC+Chemo+CRS group, and 36.4% (4/11) in CRS+HIPEC group, respectively. The compliance of patients undergoing subsequent chemotherapy is higher in HIPEC+Chemo+CRS group (93.3%, 14/15) than that of CRS+HIPEC group (45.5%, 5/11) (P = 0.021). The mean interval time between CRS and first post-CRS systematic chemotherapy were 42.0 ± 12.0 days in HIPEC+Chemo+CRS group versus 69.8 ± 36.3 in CRS+HIPEC group (P = 0.163), respectively. The median OS in the HIPEC+Chemo+CRS group was 25.0 months, while 28.2 months in the CRS+HIPEC group (P = 0.738).For resectable GC patients with laparoscopic findings of occult peritoneal metastasis, HIPEC plus staged CRS is with better tolerance and compliance than simultaneous CRS.

Cytokines are soluble proteins that exert their functions by binding specific receptors. Many cytokines play essential roles in carcinogenesis and have been developed for the treatment of cancer. In this study, we identified a novel potential cytokine using immunogenomics designated colon-derived SUSD2 binding factor (CSBF), also known as chromosome 10 open reading frame 99 (C10orf99). CSBF/C10orf99 is a classical secreted protein with predicted molecular mass of 6.5 kDa, and a functional ligand of Sushi Domain Containing 2 (SUSD2). CSBF/C10orf99 has the highest expression level in colon tissue. Both CSBF/C10orf99 and SUSD2 are down-regulated in colon cancer tissues and cell lines with different regulation mechanisms. CSBF/C10orf99 interacts with SUSD2 to inhibit colon cancer cell growth and induce G1 cell cycle arrest by down-regulating cyclin D and cyclin-dependent kinase 6 (CDK6). CSBF/C10orf99 displays a bell-shaped activity curve with the optimal effect at ~10 ng/ml. Its growth inhibitory effects can be blocked by sSUSD2-Fc soluble protein. Our results suggest that CSBF/C10orf99 is a novel potential cytokine with tumor suppressor functions.

Purpose Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of anti-angiogenic agents in gastric cancer. Design A systematic search of PubMed, Embase and conference databases is performed to identify clinical trials with specific anti-angiogenic agents in gastric cancer treatment Results The risk of disease progression (37–52%) and death (19–22%) with ramucirumab as second-line treatment decreases in phase III trials in advanced gastric cancer. No significant improvement in overall survival (OS) with the addition of bevacizumab to chemotherapy is shown. Bevacizumab or ramucirumab combined with traditional chemotherapy is associated with higher adverse event rate compared to chemotherapy alone. Except for apatinib, phase II trials of other tyrosine kinase inhibitors (TKIs) may improve overall response rate, but there are no significant improvements in OS and progression-free survival (PFS) when combined with chemotherapy. Conclusion Phase III trials in advanced gastric cancer have demonstrated improved outcome with ramucirumab as second-line treatment. Most of the other studies on anti-angiogenic agents in gastric cancer have reported improvement in response rate but not in OS compared to chemotherapy alone. Future research is expected in optimizing the anti-angiogenic therapy combined with traditional treatment.

Purpose: Metastasis is the leading cause of death for gastric carcinoma. An epigenetic biomarker panel for predicting gastric carcinoma metastasis could have significant clinical impact on the care of patients with gastric carcinoma. The main purpose of this study is to characterize the methylation differences between gastric carcinomas with and without metastasis. Experimental Design: Genome-wide DNA methylation profiles between 4 metastatic and 4 nonmetastatic gastric carcinomas and their surgical margins (SM) were analyzed using methylated-CpG island amplification with microarray. The methylation states of 73 candidate genes were further analyzed in patients with gastric carcinoma in a discovery cohort (n = 108) using denatured high performance liquid chromatography, bisulfite-sequencing, and MethyLight. The predictive values of potential metastasis-methylation biomarkers were validated in cohorts of patients with gastric carcinoma in China (n = 330), Japan (n = 129), and Korea (n = 153). Results: The gastric carcinoma genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared with SMs. Significant differential methylation was validated in the CpG islands of 15 genes (P < 0.05) and confirmed using bisulfite sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Methylation changes of GFRA1, SRF, and ZNF382 resulted in up- or downregulation of their transcription. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations was consistently and coordinately associated with gastric carcinoma metastasis and the patients' overall survival throughout discovery and validation cohorts in China, Japan, and Korea. Conclusion: Methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of gastric carcinoma metastasis. Clin Cancer Res; 20(17); 4598–612. ©2014 AACR.

To investigate the expression of serum endothelial cell specific molecule 1 (ESM-1) in gastric cancer and to evaluate the effect of serum ESM-1 as a potential serum biomarker.Serum ESM-1 was detected by enzyme-linked immunosorbent assay (ELISA) and CEA, CA19.9, CA72.4 were detected by electrochemiluminescence immunoassay (ECLIA) in 102 patients with gastric cancer preoperatively. At the same time, serum ESM-1, CEA, CA19-9, CA72-4 in 41 healthy adults volunteers were detected with the same method. In addition, the follow-up data of all the patients were collected.Compared to healthy volunteers, the serum ESM-1 level in gastric cancer patients increased (P0.01). The sensitivity and specificity of serum ESM-1 were 73.9% and 51.2% respectively. In contrast, the sensitivities of CEA, CA19-9 and CA72-4 were only 16.1%, 18.3% and 23.2% respectively. High level of serum ESM-1 indicated poor outcomes (P0.05).Serum ESM-1 increases in the peripheral blood of the gastric cancer patients. It may be a potential serum marker to help diagnosis and prediction of prognosis of gastric cancer patients.

AIM To investigate the differential expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in gastric cancer tissues and its significance related to tumor growth and spread. METHODS Formalin-fixed biopsy specimens of intestinal metaplasia (n = 90), dysplasia (n = 53), gastric adenocarcinoma (n = 180), metastases in lymph nodes and the liver (n = 15), and lesion-adjacent normal gastric mucosa (controls; n = 145) were obtained for analysis from the Peking University Cancer Hospital's Department of Pathology and Gastrointestinal Surgery tissue archives (January 2003 to December 2011). The biopsied patients' demographic and clinicopathologic data were retrieved from the hospital's medical records database. Each specimen was subjected to histopathological typing to classify the tumor node metastasis (TNM) stage and to immunohistochemistry staining to detect the expression of the cancer stem cell marker LGR5. The intergroup differences in LGR5 expression were assessed by Spearman's rank correlation analysis, and the relationship between LGR5 expression level and the patients' clinicopathological characteristics was evaluated by the χ(2) test or Fisher's exact test. RESULTS Significantly more gastric cancer tissues showed LGR5(+) staining than normal control tissues (all P < 0.01), with immunoreactivity detected in 72.2% (65/90) and 50.9% (27/53) of intestinal metaplasia and dysplasia specimens, respectively, 52.8% (95/180) of gastric adenocarcinoma specimens, and 73.3%% (11/15) of metastasis specimens, but 26.9% (39/145) of lesion-adjacent normal gastric mucosa specimens. Comparison of the intensity of LGR5(+) staining showed an increasing trend that generally followed increasing dedifferentiation and tumor spread (normal tissue < dysplasia, < gastric adenocarcinoma

The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study. Circulating PD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.Expression of PD-L1 in advanced gastric cancer patients was significantly up-regulated compared with health people (P=0.006). The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis (P=0.026 and P=0.041, respectively). Although we didn't find significant difference in all advanced gastric cancer patients with different PD-L1 expression, the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients (65.6% vs. 44.7%, P=0.028).PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.

Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1-amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer.

A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.

Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATP-competitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1–3, in patients with FGFR2-amplified gastric cancer. Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2. Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents. Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572–83. ©2013 AACR.

The CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) gene is a novel tumor suppressor with frequent epigenetic inactivation. In this study, we showed the role played by CMTM3 in gastric cancer cells as a tumor suppressor gene, and examined the correlation between CMTM3 expression and clinicopathological parameters using immunohistochemistry in gastric cancer patients with different pathological stages (n = 350). We found that CMTM3 expression was reduced or silenced by epigenetic regulation in gastric cell lines, and dramatically downregulated in primary gastric cancer tissues. Restoration of CMTM3 significantly affected migration and invasion of AGS and SGC-7901 cells (P

To investigate Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expressions in gastric cancer and to evaluate its clinical significance.LGR5 expression was assessed by immunohistochemistry in 257 gastric cancer patients after surgery. The relationships between LGR5 expression and clinicopathological features and patients prognosis were statistically analyzed.The expression of LGR5 was significantly higher in gastric cancers as a cancer stem cell marker than in adjacent normal tissues (P0.001), and more frequently in patients with intestinal type, well-moderate differentiation and stage I and II (P0.05). Although we found gastric cancer patients with LGR5 positive expression had a poorer prognosis, it didn't meet statistical significance (P0.05). LGR5 negative expression was significantly related to the favorable overall survival in stage I and II gastric cancer patients (P0.05). Furthermore, patients with high LGR5 expression tended to be more likely to get progression and have poorer progress-free survival (P0.05). Multivariate Cox regression analysis revealed that LGR5 expression was an independent factor of overall survival for the patients with stage I and II gastric cancer (P0.05).Our results show that LGR5 may play an important role in tumorigenesis and progression and would be a powerful marker to predict the prognosis of patients with stage I and II gastric cancer.

Tumor organoids are three-dimensional (3D) cultures of cancer cells. They can be derived from the tumor cell lines, patient-derived xenografts and tumor tissues from cancer patients, thereby providing an attractive in vitro assay to optimize anticancer treatment. Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in 5-15% of colorectal cancers (CRC). Despite the remarkable clinical activities achieved by vemurafenib in treating B-RAF V600E metastatic melanoma, their clinical efficacy in B-RAF V600E CRC is far less impressive. BGB-283, currently under clinical development for RAF and RAS mutated solid tumors, is a novel inhibitor of the RAF dimer with inhibitory activities against RAF family kinases. In this study, we evaluated the anti-proliferative effect of BGB-283 and compared it to BRAF inhibitor vemurafenib in CRC patient tumor derived organoids models. BGB-283 exhibited therapeutic potentials in tumors with mutations in the MAPK pathway. Herein, we reported the establishment of tumor organoid models from 19 CRC patients’ tumor tissues with a success rate of 83%. Organoids maintained many characteristics of their original tumors based on their histology. Our studies using primary CRC tumor organoids showed that in contrast to vemurafenib, which only inhibited B-RAF V600E CRC tumors, BGB-283 had inhibition effect on both B-RAF V600E and KRAS mutated tumors. These findings support BGB-283 as a promising clinical stage antitumor agent in treating CRC harboring B-RAF V600E and KRAS mutations. In addition, we showed that patient-derived organoids can be a valuable tool to test drug sensitivity in a personalized treatment and help to fill the gap between tumor genetics and patient trials. Citation Format: Xiaoran Wu, Chunyan Fu, Xi Yuan, Lianhai Zhang, Xiaohong Wang, Jiafu Ji, Lusong Luo. 3D colorectal cancer organoids as preclinical models for assessment of activity of RAF inhibitor BGB-283. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4260.

The prognosis for ovarian metastasis of gastric cancer is poor. There is no currently available treatment for this disease. The purpose of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) in female gastric cancer patients with metachronous ovarian metastasis. From January 2000 to December 2010, 62 patients developed ovarian metastasis after undergoing gastrectomy with D2 lymphadenectomy. Thirty-two patients underwent CRS plus HIPEC, and 30 patients underwent CRS alone. The median age of all 62 patients was 44 years (range 19–71 years). Metastatic carcinoma involving bilateral ovaries was observed in 50 patients (80.6 %). The median survival time in the CRS + HIPEC group was 15.5 months (95 % confidence interval [CI] 12.1–18.9 months) but was only 10.4 months (95 % CI 8.5–12.2 months) in the CRS group (P = 0.018). Among the 32 patients with pelvic peritoneal metastasis, a stratified analysis revealed that the median survival period for the 15 patients treated with CRS + HIPEC was significantly higher than that for the patients treated with CRS alone (P = 0.046). Among the 30 patients who suffered from ovarian metastasis alone, the median survival times were similar in both groups (P = 0.141). A multivariate analysis revealed that CRS + HIPEC and a low Peritoneal Cancer Index (PCI) were independent predictors for improved survival. In conclusion, our study indicates that employing the HIPEC procedure after CRS could improve the survival time of patients with ovarian metastasis with few complications; however, we do not recommend HIPEC treatment for ovarian metastasis alone.

Background S100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression. Methods S100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated. Results S100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells. Conclusions Our results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.

Background: Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. Principal Findings: We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12-20q13.1 (12/72), 20q13.1-20q13.2 (11/72) and 20q13.2-20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. Conclusions: This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets. © 2012 Fan et al., published_or_final_version

Background This study assessed the postoperative morbidity and mortality occurring in the first 30 days after radical gastrectomy by comparing gastric cancer patients who did or did not receive the FOLFOX7 regimen of neoadjuvant chemotherapy. Methods We completed a retrospective analysis of 377 patients after their radical gastrectomies were performed in our department between 2005 and 2009. Two groups of patients were studied: the SURG group received surgical treatment immediately after diagnosis; the NACT underwent surgery after 2-6 cycles of neoadjuvant chemotherapy. Results There were 267 patients in the SURG group and 110 patients in the NACT group. The NACT group had more proximal tumours (P = 0.000), more total/proximal gastrectomies (P = 0.000) and longer operative time (P = 0.005) than the SURG group. Morbidity was 10.0% in the NACT patients and 17.2% in the SURG patients (P = 0.075). There were two cases of postoperative death, both in the SURG group (P = 1.000). No changes in complications or mortality rate were observed between the SURG and NACT groups. Conclusion The FOLFOX7 neoadjuvant chemotherapy is not associated with increased postoperative morbidity, indicating that the FOLFOX7 neoadjuvant chemotherapy is a safe choice for the treatment of local advanced gastric cancer.

S100A6 has been implicated in a variety of biological functions as well as tumorigenesis. In this study, we investigated the expression status of S100A6 in relation to the clinicopathological features and prognosis of patients with gastric cancer and further explored a possible association of its expression with epigenetic regulation. S100A6 expression was remarkably increased in 67.5% of gastric cancer tissues as compared with matched noncancerous tissues. Statistical analysis demonstrated a clear correlation between high S100A6 expression and various clinicopathological features, such as depth of wall invasion, positive lymph node involvement, liver metastasis, vascular invasion, and tumor-node metastasis stage (P < 0.05 in all cases), as well as revealed that S100A6 is an independent prognostic predictor (P = 0.026) significantly related to poor prognosis (P = 0.0004). Further exploration found an inverse relationship between S100A6 expression and the methylation status of the seventh and eighth CpG sites in the promoter/first exon and the second to fifth sites in the second exon/second intron. In addition, the level of histone H3 acetylation was found to be significantly higher in S100A6-expressing cancer cells. After 5-azacytidine or trichostatin A treatment, S100A6 expression was clearly increased in S100A6 low-expressing cells. In conclusion, our results suggested that S100A6 plays an important role in the progression of gastric cancer, affecting patient prognosis, and is up-regulated by epigenetic regulation.

This pilot study was undertaken to assess the effect of weekly docetaxel, cisplatin and fluorouracil (DCF) as a preoperative treatment for gastric cancer with multiple synchronous hepatic metastases. Gastric cancer patients with synchronous multiple liver metastasis were first given preoperative chemotherapy consisting of two courses (each course consisted of 6-week administration and 2-week withdrawal) of weekly DCF regimen. Following the operation, postoperative chemotherapy and hepatic arterial infusion (HAI) treatment were performed as required. Eight patients completed two courses of preoperative chemotherapy with weekly DCF regimen. No toxicity of grade 3 or more was observed during the course of chemotherapy. The response rate was 100% according to the RECIST criteria. Seven of the patients have survived for over 1 year, and six of them are still alive after more than 1 year. Because of the unexpected high response to weekly DCF, we consider that it should be verified through phase II and III trials as an important part of the comprehensive treatment for gastric cancer with liver metastasis.

The endothelial cell-specific molecule-1 (ESM-1) gene is involved in various biological events. This study was designed to clarify its clinical significance and explore its biological behavior in gastric cancer (GC).ESM-1 mRNA expression was evaluated by real-time PCR in GC (n = 34) and matched adjacent normal tissues (n = 14). The expression of ESM-1 protein was investigated by immunohistochemistry in GC (n = 159) and matched normal tissues (n = 40), and its correlation with the clinicopathological features and overall survival of patients was analyzed. Microvessel density (MVD) in GC was assessed by anti-CD34 and the pattern of ESM-1 expression in tumor-related vascular was evaluated. The effect of ESM-1 promotion of proliferation in the GC MKN28 cell line and human microvascular endothelial cell line HMEC-1 were tested using the MTT assay.ESM-1 mRNA was significantly overexpressed in GC compared with adjacent noncarcinoma controls (P 0.01). ESM-1 protein was predominantly expressed in GC. ESM-1 expression was associated with distant metastasis and Borrmann type IV (P 0.05) and was strongly associated with vascular invasion (P = 0.0057). Patients with ESM-1 expression showed lower 5-year survival rate (P = 0.0339). Multivariate analysis revealed that ESM-1 was an independent prognostic factor. In GC, CD34-MVD of GC vessels positively expressing ESM-1 was higher than that of GC with negative vessels expression of ESM-1 (P 0.05). Besides, ESM-1 antibody dose-dependently impaired MKN28 and HMEC-1 growth.ESM-1 is overexpressed in GC and can serve as a tumor biomarker to predict survival of GC patients, and it might promote tumor angiogenesis and growth in GC and, hence, may represent a potential therapeutic target.