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Gastric cancers, with gastric adenocarcinoma (GAC) as the most common histological type, cause quite a few of deaths. In order to improve the survival rate after GAC treatment, it is important to develop a method for early detection and therapy support of GAC. Raman spectroscopy is a potential tool for probing cancer cell due to its real-time and non-destructive measurements without any additional reagents. In this study, we use Raman spectroscopy to examine GAC samples, and distinguish cancerous gastric mucosa from normal gastric mucosa. Average Raman spectra of two groups show differences at 750 cm -1 , 1004 cm -1 , 1449 cm -1 , 1089-1128 cm -1 , 1311-1367 cm -1 and 1585-1665 cm -1 , These peaks were assigned to cytochrome c, phenylalanine, phospholipid, collagen, lipid, and unsaturated fatty acid respectively. Furthermore, we build a SENet-LSTM model to realize the automatic classification of cancerous gastric mucosa and normal gastric mucosa, with all preprocessed Raman spectra in the range of 400-1800 cm -1 as input. An accuracy 96.20% was achieved. Besides, by using masking method, we found the Raman spectral features which determine the classification and explore the explainability of the classification model. The results are consistent with the conclusions obtained from the average spectrum. All results indicate it is potential for pre-cancerous screening to combine Raman spectroscopy and machine learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To investigate the differentially expressed genes between gastric cancer and normal gastric mucosa by bioinformatics analysis, identify the important gene participating in the occurrence and progression of gastric cancer, and predict the functions of these genes., Methods: The gene expression microarray data GSE100935 (including 18 gastric cancer samples and normal gastric mucosal tissues) downloaded from the GEO expression profile database were analyzed using Morpheus to obtain the differentially expressed genes in gastric cancer, and a cluster analysis heat map was constructed. The online database UALCAN was used to obtain the expression levels of these differentially expressed genes in gastric cancer and normal gastric mucosa. The prognostic value of the differentially expressed genes in gastric cancer was evaluated with Kaplan-Meier survival analysis. GO functional enrichment analysis was performed using Fun-Rich software, and the STRING database was exploited to establish a PPI network for the differentially expressed genes., Results: A total of 45119 differentially expressed genes were identified from GSE100935 microarray data. Analysis with UALCAN showed an obvious high expression of EXD3 gene in gastric cancer, and survival analysis suggested that a high expression level of EXD3 was associated with a poorer prognosis of the patients with gastric cancer. GO functional enrichment analysis found that the differentially expressed genes in gastric cancer were involved mainly in the regulation of nucleotide metabolism and the activity of transcription factors in the cancer cells., Conclusions: EXD3 may be a potential oncogene in gastric cancer possibly in relation to DNA damage repair. The up-regulation of EXD3 plays an important role in the development and prognosis of gastric cancer, and may serve as an important indicator for prognostic evaluation of the patients.

Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. Several studies on angiogenic blocking agents in gastric cancer revealing promising results by the use of monoclonal antibodies against VEGFA or its receptor VEGFR2 or against VEGFA activating pathway. The validation of biomarkers useful to better organize the clinical trials involving anti-angiogenic therapies is crucial. Molecular markers such as RNA are increasingly used for cancer diagnosis, prognosis, and therapy guidance as in the case of the targeted therapies concerning the inhibition of angiogenesis. The aim of this study is to set the conditions for evaluating the expression of VEGFA and VEGFR2 in gastric cancer specimens and in healthy gastric mucosa by the use of RNAscope, a novel RNA in situ hybridization (ISH) method that allows the visualization of a specific gene expression in individual cells. We found the increased expression of VEGFA in the tubular glands and VEGFR2 in the endothelium of gastric cancer samples mainly in the T2, T3 and T4 stages of tumor progression as compared to the healthy controls. These results obtained by the application of this highly sensitive method for oligonucleotide detection the role of angiogenesis in gastric cancer progression already highlighted by conventional immunohistochemical methods, and offer significant promise as a new platform for developing and implementing RNA-based molecular diagnostics also in the conditions in which immunohistochemistry is not applicable.

We compared the incidence, esophagogastroduodenoscopy (EGD) findings, and histopathologic characteristics of gastric and duodenal follicular lymphomas (FL). Of 626 FL cases, primary gastric FL and secondary gastric involvement of FL were observed in 1% and 5% of the cases, respectively, which were lower incidences than duodenal FL (10% and 9%, respectively). Gastric FL usually appeared as submucosal tumors (primary, 71%; secondary, 79%), whereas duodenal FL, as granular lesions (primary, 92%: secondary, 87%). In the granular duodenal lesions, the neoplastic follicles were located sparsely on the muscularis mucosa and could be found between villi, whereas in the stomach, similar lesions were hidden within the lamina propria, and only larger lesions such as submucosal tumors could be detected on the mucosal surface. The differences in the incidences and EGD findings were considered to be associated with structural differences of the lamina propria. Typical FL features: grades 1-2 histology, follicularity, and CD10 + and/or BCL6 + and BCL2 + were usually observed in all primary and secondary gastric and duodenal FL. Gastroduodenal and bone marrow involvement were found in 12% and 33% of the cases, respectively, and there was no significant correlation between them (P=.095). Twenty-nine cases (5%) were up-staged by gastroduodenal-positive results. In conclusion, the histopathology of gastric FL was similar to that of duodenal and nodal FL; the differences in the incidence and EGD findings between gastric and duodenal FL were considered to be associated with structural difference of the lamina propria, and EGD was useful as a staging procedure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.

Aim: To investigate the expression profiles of hsa-miR-29c and hsa-miR-135b in gastric mucosal samples and their values as gastric carcinogenesis biomarkers., Methods: The expression levels of hsa-miR-29c and hsa-miR-135b in normal gastric mucosa, non-atrophic chronic gastritis, intestinal metaplasia and intestinal-type gastric adenocarcinoma were analysed using quantitative real-time PCR. The difference between hsa-miR-29c and hsa-miR-135b expression profiles in the grouped samples was evaluated by ANOVA and Student's t-test tests. The results were adjusted for multiple testing by using Bonferroni's correction. P values ≤ 0.05 were considered statistically significant. To evaluate hsa-miR-29c and hsa-miR-135b expressions as potential biomarkers of gastric carcinogenesis, we performed a receiver operating characteristic curve analysis and the derived area under the curve, and a Categorical Principal Components Analysis. In silico identification of the genetic targets of hsa-miR-29c and hsa-miR-135b was performed using different prediction tools, in order to identify possible genes involved in gastric carcinogenesis., Results: The expression levels of hsa-miR-29c were higher in normal gastric mucosal samples, and decreased progressively in non-atrophic chronic gastritis samples, intestinal metaplasia samples and intestinal-type gastric adenocarcinoma samples. The expression of hsa-miR-29c in the gastric lesions showed that non-atrophic gastritis have an intermediate profile to gastric normal mucosa and intestinal-type gastric adenocarcinoma, and that intestinal metaplasia samples presented an expression pattern similar to that in intestinal-type gastric adenocarcinoma. This microRNA (miRNA) has a good discriminatory accuracy between normal gastric samples and (1) intestinal-type gastric adenocarcinoma; and (2) intestinal metaplasia, and regulates the DMNT3A oncogene. hsa-miR-135b is up-regulated in non-atrophic chronic gastritis and intestinal metaplasia samples and down-regulated in normal gastric mucosa and intestinal-type gastric adenocarcinoma samples. Non-atrophic chronic gastritis and intestinal metaplasia are significantly different from normal gastric mucosa samples. hsa-miR-135b expression presented a greater discriminatory accuracy between normal samples and gastric lesions. This miRNA was associated with Helicobacter pylori presence in non-atrophic chronic gastritis samples and regulates the APC and KLF4 tumour suppressor genes., Conclusion: Our results provide evidence of epigenetic alterations in non-atrophic chronic gastritis and intestinal metaplasia and suggest that hsa-miR-29c and hsa-miR-135b are promising biomarkers of gastric carcinogenesis.

Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

Rationale and Objective: Recently, interest in the role of aquaporin 1 (AQP1) in human gastrointestinal carcinogenesis has developed. However, to date no studies have examined relationships between AQP1 expression and specific characteristics of gastric adenocarcinoma., Methods: We investigated 109 specimens of primary gastric adenocarcinoma and their corresponding normal gastric mucosa using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to determine AQP1 expression. We then evaluated disease free survival (DFS) and overall survival (OS) in these patients in association with AQP1 expression., Results: Both immunohistochemical and RT-PCR analyses identified increased AQP1 expression in tumors from patients with gastric adenocarcinoma (p < 0.001). The 3-year DFS and OS rates were higher in the AQP1-negative group than in the positive group (DFS: 77.2 vs. 52.8%, p < 0.001; OS: 85.1 vs. 70.7%, p < 0.001). The 5-year DFS and OS rates exhibited a similar trend (p < 0.001). Subgroup analysis of patients with early gastric adenocarcinoma (stages I and II) revealed a total 5-year OS of 90.0%, with 5-year OS being higher in the AQP1-negative group than in the positive group (95.2 vs. 84.2%). Furthermore, incidence of tumor recurrence following surgical treatment was significantly higher in the AQP1-positive group (4/19, 21.1%) compared with the negative group (0/21, 0%)., Conclusions: Our study demonstrates that AQP1 plays an important role in gastric adenocarcinoma and may therefore represent a novel therapeutic target and prognostic marker in this disease., (© 2016 S. Karger AG, Basel.)

An 80-year-old man was under annual surveillance esophagogastroduodenoscopy after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Two years after the initial ESD, a 0-IIc type metachronous EGC lesion, 8 mm in size, without an ulcer scar, was found in the gastric antrum. The estimated tumor depth was up to the mucosa, and biopsy revealed well and poorly differentiated adenocarcinoma. ESD was performed for this lesion and en bloc resection with negative margins was achieved. Histopathological examination revealed an adenosquamous carcinoma 8 mm in size invading the deep submucosal layer (1600 μm), with lymphovascular invasion, consistent with the diagnosis of non-curative resection. Additional gastrectomy was recommended for this patient; however, two months after the ESD, preoperative computed tomography revealed multiple liver metastases, and the patient was considered as an unsuitable candidate for surgical resection. Systemic chemotherapy was therefore started; however, the patient died of gastric cancer 27 mo after the second ESD. Early gastric adenosquamous carcinoma localized to the mucosa and submucosa is extremely rare and its clinical behavior is not well known. The present report is very significant in that it underscores the distinct possibility of gastric adenosquamous carcinoma being very aggressive and fatal even when detected at an early cancer.

C-erbB-2 is a cancer gene originating from cells. The high-expression and amplification of C-erbB-2 and its protein products (P185) are found in a wide variety of tumors. The abnormal expression of C-erbB-2 has great influence on the occurrence and development of gastric carcinoma. This paper aimed to analyze the expression of C-erbB-2 in the tissues of gastric carcinoma, gastric mucosal atypical hyperplasia and gastritis, and discuss its role in the occurrence and development of gastric carcinoma. The morphological differences and connections among simple intestinal metaplasia (SIM), atypical intestinal metaplasia (AIM) and dysplasia in intestinal metaplasia through hematoxylin and eosin (HE) staining were studied. Three groups were set to detect the expression condition of C-erbB-2 by immunohistochemical method (IHC). The result showed that C-erbB-2 had no significant difference in AIM and gastric carcinoma, that is, AIM was closely related to gastric carcinoma. The positive expression was demonstrated of C-erbB-2 products (P185) in medium and gastric mucosa dysplasia tissues and was 29.41% and 66.67%, respectively, while it was 25%, 50% and 77.78% in high, medium and low differentiation of gastric carcinoma. It can be seen that there was a significant difference between them (P<0.05), and the expression degree was significantly enhanced (P<0.05); the expression degree in high differentiation gastric cancer tissue was significantly higher than the middle and low differentiation gastric cancer tissue. It was concluded that C-erbB-2 played an important role in the pathogenic mechanism of gastric carcinoma, and it might act on the later period of the gastric carcinoma, which provides objective reference index for the diagnosis and prognosis of gastric carcinoma and meanwhile provides instructional theoretical reference for the application of targeted drugs in the clinical treatment of gastric carcinoma.

The coincidence of GIST and other gastric malignancies are documented well but arising GIST from congenital anomalies is still rarity in literature. To date, only a few papers have been concerned on the possibility of arising neoplasms from duplication cyst of gastrointestinal tract. There, are dominating usual cancers, neuroendocrine cancers or lymphomas but GIST has been noted only once. Here, we report a case of 73 years old female-patient with typical gastric stromal tumor comprised centrally locked an incomplete duplication cyst.

Lanthanum carbonate is one of the new phosphate binders used for the treatment of hyperphosphatemia in patients with chronic kidney disease. It is poorly absorbed from the gastrointestinal tract, forms insoluble complexes within the lumen, and prevents the absorption of dietary phosphate. A 63-year-old female with a 7-year history of peritoneal dialysis, who was treated with lanthanum carbonate for four years, underwent endoscopic submucosal dissection for intramucosal gastric cancer. Resected specimens showed massive accumulation of macrophages containing fine, granular, brown material in the lamina propria. This was confirmed as lanthanum deposition by scanning electron microscopy with energy dispersive x-ray spectroscopy. Although lanthanum may be poorly absorbed, increased tissue accumulation of lanthanum, particularly in the liver and bone, has been reported in animals with chronic kidney disease. This report indicates enhanced gastrointestinal absorption of lanthanum in some patients or conditions, although its clinical significance awaits further studies., (© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Aim: To investigate the expression of gastrokine 1 (GKN1) in normal gastric mucosa, precancerous lesions and gastric cancer tissues, and to analyse its correlations with tumour site and pathological pattern., Methods: Thirty gastric cancer patients (12 cases of diffuse type and 18 cases of intestinal type), 13 atrophic gastritis patients and 15 healthy volunteers with almost normal gastric mucosa (superficial gastritis) were enrolled in this study. Helicobacter pylori (H. pylori) infection was examined in all subjects. All gastric mucosa biopsy specimens were obtained. Cancer-adjacent specimens were taken from corresponding gastric cancer patients. Immunohistochemistry and real-time PCR were performed to determine the expressions of the GKN1 protein and mRNA, respectively., Results: H. pylori infection had no significant association with age, gender, tumour site or pathological pattern in all subjects. Compared with the superficial gastritis and atrophic gastritis groups, the expression of GKN1 protein (P = 0.011) and mRNA (P < 0.001) in gastric cancer was significantly decreased. The GKN1 mRNA level in diffuse type gastric cancer was significantly lower than in intestinal type gastric cancer (0.296 ± 0.076 vs 0.525 ± 0.164, P < 0.001)., Conclusion: Compared with almost normal gastric mucosa, GKN1 expression in the gastric mucosa of gastric cancer patients is decreased; this is associated with progression and prognosis of gastric cancer.

Aim: To investigate the difference in magnifying endoscopic findings of gastric epithelial dysplasias (GEDs) according to the morphologic characteristics., Methods: This study included 46 GED lesions in 45 patients who underwent magnifying endoscopy using narrow band imaging (ME-NBI) before endoscopic resection. During ME-NBI, the microvascular and microsurface (MS) patterns and the presence of light blue crest (LBC) and white opaque substance were investigated. GEDs were categorized as adenomatous, foveolar, and hybrid types, and their mucin phenotype was evaluated., Results: Of the 46 lesions, 27 (59%) were categorized as adenomatous, 15 (32%) as hybrid, and the remaining 4 (9%) as foveolar. All adenomatous GEDs showed the round pit and/or tubular MS patterns, all foveolar GEDs showed the papillary pattern, and hybrid GEDs showed mixed patterns (P < 0.001). LBC was more frequently observed in adenomatous GEDs than in hybrid or foveolar GEDs (52%, 33%, 0%, respectively), although this difference was not significant (P = 0.127). The papillary MS pattern was associated with MUC5AC and MUC6 expression, and the round pit and/or tubular MS patterns were associated with CD10 expression., Conclusion: The MS pattern in ME-NBI findings is useful for predicting the morphologic category and mucin phenotype of GEDs, and ME-NBI findings may guide decisions regarding GED treatment.

Objective: To investigated the influence of H. pylori on TLR4 and TLR9 in gastric mucosa during gastric carcinogenesis., Methods: Gastric biopsy specimens were taken from 148 patients and divided into five groups, including normal group (n = 10), chronic superficial gastritis group (n = 35), atrophy/intestinal metaplasia group (n = 35), dysplasia group (n = 34) and gastric carcinoma group (n = 34). Immunohistochemistry was used to detect the expression of TLR4 and TLR9. Geimsa staining and rapid urea test were used for determine H. pylori infection., Results: TLR4 was detected in gastric epithelium and monocytes/macrophages in superficial gastritis, atrophy/intestinal metaplasia, dysplasia or carcinoma. TLR9 was mainly accentuated in monocytes/macrophages. TLR4 positive cells in epithelium and in monocytes/macrophages with H. pylori infection were much more than those without H. pylori infection. Similar results were also found in TLR9. When gastric epithelium was accompanied with H. pylori infection, TLR4 was significant higher in superficial gastritis and atrophy/intestinal metaplasia groups compared with dysplasia and carcinoma groups. When gastric epithelium was infected by H. pylori, TLR9 was significant higher in carcinoma group compared with superficial gastritis, atrophy/intestinal metaplasia and dysplasia. TLR4 and TLR9 show significant correlation with the severity of inflammation., Conclusions: H. pylori infection was associated with increased expression of TLR4 and TLR9 in gastric mucosa. In superficial gastritis and atrophy/intestinal metaplasia the inflammation was predominately mediated by TLR4, while in gastric cancer the inflammation was mainly mediated by TLR9.

The prevalence of gastric cancer associated with Lynch syndrome (LS) is highly variable, and the underlying histologic pathway or molecular mechanisms remain unclear. From 1995 to 2012, 15 patients had been treated for both gastric and colonic adenocarcinomas and diagnosed as LS. In all cases, pathologic review, immunohistochemical analysis for mismatch-repair proteins, and microsatellite instability (MSI) tests were performed. To confirm LS, germline mutation tests and multiplex ligation-dependent probe amplification were performed. All gastric and colonic carcinomas were MSI-high and lost expressions of MLH1/PMS2 in 11 (73%) cases and MSH2/MSH6 in 4 (27%) cases. Remarkably, in a patient with LS and germline mutation of MLH1 gene, pyloric gland adenoma (PGA) transformed to adenocarcinoma during follow-up. In 2 additional cases, PGA was found adjacent to advanced gastric cancers. All PGAs in LS patients were MSI-high and lost expression of mismatch-repair proteins (MLH1/PMS2 in 2 cases and MSH2/MSH6 in 1 case), whereas none of the 14 sporadic PGAs was MSI-high or had lost expression of mismatch-repair proteins. On the basis of these observations, although very rare, we suggest the possibility that PGA may be a precursor lesion to gastric adenocarcinoma in LS and that the mismatch-repair deficient pathway of carcinogenesis is involved early in the gastric carcinogenesis pathway.

Aim: Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa., Methods: IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly., Conclusion: High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53.

Background/aims: Insulin-like growth factor-1 receptor (IGF-1R) plays critical roles in cell proliferation, differentiation, apoptosis, and transformation. Suppression of IGF-1R by means of antisense methods and specific antibodies causes cell apoptosis and growth inhibition of cancer cells. The present study aims to investigate whether there is a difference between normal and cancerous tissue with respect to IGF-1R expression and to assess the relationship between IGF-1R expression and tumor stage, degree of differentiation, and lymph node metastasis by examining IGF-1R expression in cancerous and normal tissues of gastric adenocarcinoma cases of different stages., Materials and Methods: By using immunohistochemical methods, IGF-1Rb (H-60) (1/100, Santa Cruz Biotechnology, SC-9038, Texas,USA) expression was investigated in paraffin-embedded blocks obtained from total/partial gastrectomy material pertaining to 47 gastric adenocarcinoma cases. IGF-1R expression was evaluated semi-quantitatively in terms of intensity and distribution in both normal and cancerous tissues., Results: Insulin-like growth factor-1 receptor expression mean score was 5.38 and 8.40 for cancerous and for normal gastric tissues, respectively. IGF-1R expression decreased significantly in cancerous tissues compared normal tissue (p:0.001). When all cases with and without lymph node metastasis were analyzed, IGF-1R expression was observed to decrease for cases with lymph node metastasis compared to those without lymph node metastasis (p:0.035)., Conclusion: Insulin-like growth factor-1 receptor expression in gastric cancer tissue has proven to be considerably lower than IGF-1R expression in normal gastric mucosa. Metastatic progression reduces IGF-1R expression gradually in cancer tissue.

Objective: To investigate the effect of vascular endothelial growth factor (VEGF), P53 and telomerase on angiogenesis in gastric carcinoma tissue., Methods: A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF, P53 and telomerase expression using immunohistochemical methods. Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed., Results: Microvascular density (MVD) and the expression of VEGF, P53 and telomerase were positively correlated. Expression of VEGF and P53 protein were related to tumor type and lymph metastasis, and also a correlation was observed between P53 and VEGF. The telomerase expression had no correlation with VEGF, and P53., Conclusions: VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis. Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF. Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53., (Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the expression and clinical significance of gastric dramatic down-related gene (GDDR) in gastric cancer and precancerous lesion tissues., Methods: Immunohistochemical staining was performed to detect the expression of GDDR in 240 cases of gastric tissues, including 40 cases of normal gastric mucosa (NGM), 40 cases of chronic superficial gastritis (CSG), 40 cases of chronic atrophic gastritis (CAG), 40 cases of intestinal metaplasia (IM), 20 cases of mild dysplasia (MD), 20 cases of severe dysplasia (SD) and 40 cases of gastric cancer (GC)., Results: The mean rank order of GDDR were 190.70, 182.70, 146.24, 104.40, 70.33, 47.20 and 40.20 in NGM, CSG, CAG, IM, MD, SD and GC, respectively. The expression of GDDR significantly decreased in CAG, IM, MD, SD and GC as compared with normal controls and CSG (P<0.01)., Conclusion: The gradually down-regulated expression of GDDR is an early molecular event in the development of gastric cancer. GDDR may play an important role in the early diagnosis of gastric cancer and may be utilized as a molecular diagnostic marker and a new target of anti-tumor molecular therapy in early stage of gastric cancer.

Poor nutrition and weight loss are important factors contributing to poor quality of life (QOL) after gastrectomy in patients with gastric cancer. Ghrelin is a hormone produced by the stomach that, plays a role in appetite increase and fat storage. The present study aims to clarify the location of ghrelin mRNA in the stomach, changes in blood ghrelin concentrations after gastrectomy and whether or not they are associated with the reconstruction method in patients with gastric cancer. We collected seven normal mucosa samples from different parts of six totally resected stomachs with gastric cancer. We extracted RNA from the normal mucosa, synthesized cDNA from total RNA (1 μg), and then quantified ghrelin mRNA using quantitative real-time polymerase chain reaction (Q-PCR). Ghrelin blood concentrations were measured using enzyme-linked immunosorbent assay (ELISA) kits in 74 patients with gastric cancer (total gastrectomy (TG), n=23; distal gastrectomy (DG), n=30; proximal gastrectomy (PG), n=11; pylorus preserving gastrectomy (PPG), n=10). In order, the ghrelin gene was expressed most frequently in the gastric body, followed by the fornix, cardia, antrum and pylorus ring. Blood ghrelin concentrations after surgery similarly changed in all groups. The average blood ghrelin concentrations were significantly higher in the DG and PPG groups than in the TG group on postoperative days (POD) 1, 7, 30, 90 and 180. However, blood ghrelin concentrations did not significantly differ between the DG and TG groups on POD 270 and 360. Cells that produce ghrelin are supposed to be located mostly in the fundic gland of the stomach. We speculate that the production of ghrelin from other organs increases from around nine months after total gastrectomy. Therefore, evaluating the nutritional status and the weight of patients at nine months after total gastrectomy is important to help these patients improve their QOL.

Gastric duplication cyst is a very rare gastrointestinal tract malformation that accounts for 2%-4% of alimentary tract duplications. Most cases are diagnosed within the first year of life, following presentation of abdominal pain, vomiting, and weight loss and clinical discovery of an abdominal palpable mass. This case report describes a very uncommon symptomatic gastric duplication cyst diagnosed for the first time in adulthood. Only a few other case reports of similar condition exist, and all were identified by endosonography. The current case involves a 52-year-old male who presented with a one-month history of progressive iron deficiency anemia without overt gastrointestinal bleeding. The patient underwent esophagogastroduodenoscopy, which revealed a 2.0 cm pinkish subepithelial lesion, suspected to be a gastrointestinal stromal tumor (GIST) and source of gastrointestinal bleeding. The endosonography showed inhomogeneous hypoechoic lesions with focal anechoic areas arising from a second and third layer of the gastric wall. Differential diagnoses of GIST, neuroendocrine tumor, or pancreatic heterotopia were made. The lesion was removed using an endoscopic submucosal resection technique. Histopathology revealed an erosive gastric mass composed of a complex structure of dilated gastric glands surrounded by fibro-muscular tissue, fibroblasts, and smooth muscle bundles, which led to the diagnosis of gastric duplication., (© 2013 Baishideng Publishing Group Co., Limited. All rights reserved.)

Background/aims: This study was performed to determine the association between RUNX3 expression and Helicobacter pylori infection in premalignant gastric lesions., Methods: We examined 107 patients with gastric epithelial dysplasia who had undergone endoscopic mucosal resection or submucosal dissection. All tissue samples were evaluated by RUNX3 staining and subclassified by immunophenotype. H. pylori infection in dysplastic lesions and the normal surrounding tissue was examined by silver staining, and cagA status was assessed by polymerase chain reaction., Results: The loss of RUNX3 expression was observed in 62 cases (57.9%), and an association with H. pylori infection was found in 54 cases (50.5%). The infection rate with the cagA-positive H. pylori strain was 63.0%. In RUNX3-negative lesions, the rate of H. pylori infection (p=0.03) and the frequency of category 4 lesions (according to the revised Vienna classification) were high (p=0.02). In addition, the gastric mucin phenotype was predominant. In RUNX3-negative category 4 lesions, the rate of cagA-positive H. pylori infection rate was high but not significantly increased (p=0.08)., Conclusions: Infection with H. pylori is associated with inactivation of RUNX3 in early gastric carcinogenesis. This mechanism was prominent in gastric cancer with a gastric mucin phenotype.

Background: Inflammation is a common phenomenon present in gastric mucosa of patients infected with H. pylori. Activation of the RAGE/multiligand axis is thought to be a relevant factor in cancer-mediated inflammation. RAGE is a membrane receptor, belonging to the immunoglobulin family, and the over-expression of RAGE has been associated with increased invasiveness and metastasis generation in different types of cancer, including gastric cancer. Furthermore recent experiences show that the use of its soluble form (sRAGE) or silencing of the gene coding for this receptor could provide therapeutic benefits in cancer., Aim: To evaluate the immunohistochemical expression of RAGE, MUC-1, β-Catenin free and phosphorylated, Cyclin-D1 and GSK3 in gastric biopsy specimens infected with H. pylori., Material and Methods: Immunohistochemical analysis was carried out in gastric biopsies from 138 patients: 55 with inflammatory injury (no atrophic gastritis), 42 with pre-cancerous conditions (atrophy or intestinal metaplasia) and 41 with dysplastic lesions or in situ adenocarcinoma., Results: There was a high rate of positive RAGE expression in the three groups of biopsies. Biopsies with dysplasia or in situ carcinoma had a significantly higher percentage of RAGE expression than the other groups of biopsies., Conclusions: The increased RAGE expression reported in both dysplasia and incipient cancer support the role of the multiligand/RAGE axis in gastric carcinogenesis.

Background/aims: To investigate the expression of human epidermal growth factor 2 (HER-2) and Nuclear factor-Kb (NF-KB) in gastric cancer, and the relation of these two parameters with stage, grade and metastasis of gastric cancer., Methodology: The serum level of HER-2 in 75 gastric cancer patients and control participants were determined by enzyme-linked immunosorbent assay (ELISA) kits. Expression of HER-2 and NF-KB protein were detected by immunohistochemical staining (SP method) of paraffin-embedded tissues in 75 tumors (observed group) and 22 normal gastric specimens. The clinical pathological data was statistically analyzed., Results: Serum HER-2 level were significantly increased in study group compared with those in the control group (p<0.001). The HER-2 level of 8.2 ng/mL as the cutoff value has a 79% sensitivity and an 82% specificity for predicting gastric cancer. The positive rate of HER-2 and NF-KB in the observed group was 24.00% (18/75) and 62.67% (47/75) respectively. The expression of HER-2 and NF-KB were not correlated with age and gender, but with stage, grade and metastasis (p<0.05). The expression of NF-KB was correlated with tumor size (p<0.05), while HER-2 was not (p<0.05). When HER-2 was positive, N F-KB had a positive rate of 94.44% (17/18), but a positive rate of 52.63% (30/57) when HER-2 was negative. Expression of NF-KB in gastric cancer tissue was correlated with HER-2 expression (X2 = 8.514, p<0.01)., Conclusions: These data suggest that the expression of NF-KB in gastric cancer tissue is correlated with HER-2 expression, and they may play a very important role in the progress of gastric cancer.

Background: Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model., Methods: To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis., Results: The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival., Conclusions: These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.

Background: Gastric Cardiac Cancer (GCC) has high incidence and poor prognosis requiring early screening of high-risk populations. Minichromosome maintenance (MCM) proteins are used as diagnostic-biomarkers in many cancers but not validated for GCC. We evaluate MCM protein 2 (MCM2), comparing it with the validated markers Ki67 and PCNA., Methods: GCC and corresponding cardiac precancerous samples were immunostained with Ki67, MCM2 and PCNA antibodies., Results: 90% of dysplasia samples expressed MCM2, whereas Ki67 and PCNA were expressed in 67% and 80% respectively. The sensitivity and negative predictive values of MCM2 were also superior at 90% and 87%, respectively. Ki67 and PCNA expression was correlated with MCM2, but their expressions seldom reached surface layers, whereas MCM2 manifested mostly in easily accessible superficial layers. Labeling indices (LI) of Ki67 and PCNA were also lower. Significant associations between LI (MCM2), LI (PCNA), and TNM-stages, lymph node metastases and GCC grade were found (P<0.05). Increased protein expressions were associated with reduced overall and disease-free survival (P<0.05). Although Ki67 and PCNA were significant prognostic factors, there was no significant improvement in multivariate statistical analyses, in contrast to LI (MCM2) findings., Conclusions: MCM2 is a sensitive, specific and efficient biomarker of GCC having potential use in clinic.

Background/aim: Autophagy has dual roles in tumorigenesis: tumor-promoting or tumor-suppressing. The aim of the present study was to examine autophagy-related markers by immunohistochemistry in gastric carcinoids and adenocarcinomas in rodent models and patients., Methods: Gastric carcinoids in Mastomys were induced by loxtidine treatment. Spontaneously developed gastric adenocarcinomas in Japanese cotton rats and INS-GAS transgenic mice were included. Patient tissue samples of gastric carcinoids or adenocarcinomas were collected. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG-6, also called beclin-1), ATG-5 and ATG-16., Results: In tumor-free Mastomys, ATG-5, ATG-16 and beclin-1 were immunepositive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were negative in the tumors, whereas beclin-1 was positive in four of five animals. In carcinoid patients, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten, and beclin-1 negative in three of ten patients. In cotton rats, ATG-5 and ATG-16 were negative in all tumors. Beclin-1 was negative in three of five rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunopositive cells per gland were reduced by about 50% in comparison with wild-type mice. In adenocarcinoma patients, ATG-5 and ATG-16 were negative in eight of ten, and beclin-1 positive in all ten patients., Conclusions: An impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients. ATG-5 and ATG-16 might be better markers than beclin-1 in assessing autophagy in these lesions.

Background and Aims: The etiology of gastric cancer is unclear; its therapeutic effect is poor; the anatomical factor and lack of specific diagnostic markers are part of the reason. Recent reports indicate corticotropin releasing hormone (CRH) is associated with the pathogenesis of cancer. This study is designed to assess the levels of CRH in gastric tissue of a group of patients with gastric cancer and gastric chronic inflammation., Methods: Fifty-two patients with gastric cancer (GC) and 213 patients with gastric chronic inflammation were recruited into this study. The levels of CRH in the gastric biopsies were assessed. The correlation between the levels of CRH in the gastric biopsies and the tumorigenesis was assessed., Results: High levels of (458.6 pg/mg protein) CRH were detected in the biopsies of 52 patients with gastric cancer, which were also detected in the gastric biopsies of 213 patients with chronic gastritis (less than 100 pg/mg protein). CRH was below the detectable levels in the normal gastric mucosa. Of the 213 patients with chronic gastritis, 50 patients developed into cancer 3-5 years after the first diagnosis of chronic gastric cancer., Conclusions: CRH may be involved in the pathogenesis of gastric cancer.

Gastritis cystica profunda (GCP) is a rare condition caused by ectopic entrapment of gastric glands, probably secondary to the disruption of muscularis mucosae. GCP is often associated with gastric adenocarcinoma, and loss of the KCNE2 subunit from potassium channel complexes is considered a common primary target molecule leads to both GCP and malignancy. In this study, we, for the first time, analyzed the expression of KCNE2 in surgically excised tissue from human gastric cancer associated with GCP and confirmed that reduced KCNE2 expression correlates with disease formation.

Gastric plasmacytoma (GP) is a rare variant of gastric lymphomas. In the exceptional event that a patient presents with GP, the lesion occupies the mucosal layer in the vast majority of cases. Here we report a case of nodular plasmacytoma confined to the submucosa with no evidence of Helicobacter pylori (Hp) infection. The patient was a 59-year old female presenting with no particular symptoms. The tumor was well-demarcated and consisted of a diffuse monomorphic proliferation of plasma cells with numerous lymphoid follicles scattered throughout the tumor. The mucosal surface was intact and not associated with any tumor nodules. The cells were diffusely positive for CD79a, Bob1, EMA and IgA and consistently negative for CD3, CD19, CD20, PAX5, CD56, IgM and IgG. Additionally, in situ hybridization demonstrated clonality in the form of λ light-chain restriction. This submucosal nodular proliferation pattern of plasmacytoma is poorly recognized and considered to be a novel variant of lymphoma., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3489998708673079.

Background and Aim: Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract with potential for malignant transformation, are mainly treated by open surgery or laparoscopic resection. The aim of this retrospective study was to evaluate the clinical efficacy, safety, and feasibility of endoscopic submucosal dissection (ESD) for large-size (2-5 cm) GISTs in the esophagus and stomach., Methods: A total of 31 patients with large-size GISTs in the esophagus (6 patients) and stomach (25 patients) underwent ESD between September 2008 and December 2011. Demographics, clinical data, therapeutic outcomes, complications, pathological characteristics, risk classification, and follow-up outcomes were recorded., Results: ESD was successfully performed in 31 patients at age of 59.06 ± 7.23 years (range: 46-74). The mean time of the procedure was 70.16 ± 16.25 min (range: 40-105). Perforation for 2-10 mm occurred in six patients (19.35%) and was endoscopically repaired with clips or nylon bands, with no conversions to open surgery. Intraoperative bleeding occurred in three patients (9.68%) and was corrected with argon plasma coagulation or hot biopsy forceps. No mortalities occurred. The mean size of the resected tumors was 2.70 ± 0.72 cm (range: 2.0-5.0). Out of the 31 patients, 24 (77.42%) were at very low risk and 7 (22.58%) were at low risk. Positive rate of CD117, DOG-1, and CD34 were 83.87%, 12.90%, and 100%, respectively. A follow up for 14.29 ± 8.99 months (range: 3-39) showed no recurrence or metastasis., Conclusions: ESD appears to be an effective, safe, and feasible treatment for large-size GISTs in the esophagus and stomach., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P=0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa.

Background/aims: By detecting the expression and distribution of insulin-like growth factor-2, proliferating cell nuclear antigen, and matrix metalloproteinase-7 in cancer cells and the expression of α-actin in interstitial myofibroblasts, we studied their differences and their relationship in intestinal type and diffuse type gastric cancer with Lauren classification., Materials and Methods: Clinical and pathological data of 50 patients with gastric adenocarcinoma who underwent primary surgical resection between 2003 and 2008 in Qianfoshan Hospital were collected. The cancer was classified as intestinal or diffuse type with Lauren classification. Immunohistochemical technique was used to detect the protein expression of insulin-like growth factor-2, proliferating cell nuclear antigen, matrix metalloproteinase-7, and α-actin in both gastric cancer tissue and normal gastric mucosa., Results: The expression of insulin-like growth factor-2, proliferating cell nuclear antigen, matrix metalloproteinase-7, and α-actin in the gastric tissue was significantly higher than in the normal gastric mucosa. Insulin-like growth factor-2 was mainly expressed in the nucleus in diffuse gastric cancer and in the cytoplasm in intestinal type. The expression of insulin-like growth factor-2 in the nucleus was correlated with depth of tumor invasion, lymph node metastasis and staging. Proliferating cell nuclear antigen and matrix metalloproteinase-7 showed higher expression in diffuse than in intestinal type gastric cancer. The overexpression of proliferating cell nuclear antigen was relevant to lymph node metastasis in gastric cancer. The overexpression of matrix metalloproteinase-7 was relevant to invasion, lymph node metastasis, distant metastasis, and staging in gastric cancer. There was no significant difference in α-actin expression between the intestinal type and diffuse type gastric cancer. The overexpression of α-actin was relevant to cancer invasion and lymph node metastasis., Conclusions: The expression patterns of insulin-like growth factor-2 and the expression intensity of proliferating cell nuclear antigen and matrix metalloproteinase-7 were significantly different between diffuse type and intestinal type gastric cancer cells, but the expression pattern and intensity of the interstitial myofibroblast marker showed no significant difference. The clinical pathology distinction between intestinal type and diffuse type gastric cancer may be due mainly to the change in the genetic structure and the phenotype of epithelial cells, and interstitial myofibroblasts and cancer cells jointly promote the invasion and metastasis of gastric cancer.

Homeobox (HOX) gene family is known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. However, less is known about the involvement of HOX gene family with gastric cancerogenesis. Here, we screened the expression of HOX gene family in gastric cancers and explored the relationships between them by cDNA microarray. We found several differentially expressed HOX genes in gastric cancers, especially HOXA10 (11/12) and HOXA13 (11/12) with significantly higher expression in the cancerous tissues. Furthermore, we validated HOXA13 as a novel prognostic marker in gastric cancer based on immunohistochemistry and statistical analysis. HOXA13 expression was significantly up-regulated in cancerous tissues compared with the corresponding non-cancerous mucosa (P < 0.001). Up-expression of HOXA13 was significantly correlated with T stage (P = 0.002), M stage (P = 0.024), advanced UICC stage (P < 0.001), histological differentiation (P = 0.005), and relapse (P = 0.001). Patients with positive HOXA13 expression had a obviously lower overall survival (OS) and disease-free survival (DFS) rate than patients with negative HOXA13 expression (HR 3.331, 95 % CI 1.722-6.442, P < 0.001; HR 3.289, 95 % CI 1.703-6.351, P < 0.001, respectively). Univariate and multivariate Cox analysis confirmed that HOXA13 could serve as a significant independent prognostic factor for DFS and OS. Therefore, our results indicated that several HOX genes might be closely involved in the process of the gastric tumorigenesis. Furthermore, up-expression of HOXA13 might be associated with highly aggressive phenotype of gastric cancer. HOXA13 was a significant independent prognostic factor and could serve as a putative biomarker for diagnosis and prognosis of gastric cancer.

A disintegrin and metalloproteinase-17 (ADAM17, also named as tumor necrosis factor-alpha-converting enzyme) is a member of the ADAM family. Of all ADAMs, the strongest evidence for a role in malignancy exists for ADAM17. Especially, it has been demonstrated that ADAM17 expression was significantly increased in human gastric cancer. The aim of this study was to investigate the association between ADAM17 expression and the clinicopathological features of patients with gastric cancer. The expression of ADAM17 was detected by real-time quantitative RT-PCR in gastric cancer and adjacent non-cancerous tissues. In addition, ADAM17 expression was analyzed by immunohistochemistry in 220 clinicopathologically characterized gastric cancer cases. The expression levels of ADAM17 mRNA and protein in gastric cancer tissues were both significantly higher than those in non-cancerous gastric mucosa. In addition, positive expression of ADAM17 correlated with the degree of tumor differentiation, depth of invasion, lymph node metastases, distant metastases, and TNM stage (all P<0.05). Furthermore, multivariate analysis suggested that lymph node metastases, distant metastases, TNM stage, and ADAM17 expression were independent prognostic indicators for gastric cancer. Our data suggest for the first time that the increased expression of ADAM17 in gastric cancer is associated significantly with aggressive progression and poor prognosis. ADAM17 may be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of gastric cancer.

Background/aims: Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to gastric carcinogenesis. The aim of this research was to detect the 8-OHdG and the expression of hOGG1and MnSOD, in human gastric mucosa with chronic atrophic gastritis (CAG) and gastric carcinoma (GC) comparing with normal controls (NC)., Methodology: The level of 8-OHdG in gastric biopsy specimens was assessed with immunohistochemistry. The expression level of hOGG1and MnSOD in gastric tissues was assessed with Western blot., Results: The 8-OHdG staining in CAG and GC mucosa was stronger than control (p<0.01). hOGG1 was expressed to a lower degree in GC and CAG when compared to the control group (both p<0.01) and the level of GC was even lower than CAG (p<0.05). MnSOD was expressed to a greater degree in GC group when compared to the control (p<0.05)., Conclusions: CAG patients who express 8-OHdG highly should be monitored for the potentially occurrence of GC. The lower lever of hOGG1 in CAG and GC with higher level of 8-OHdG implies that hOGG1 is closely related to oxidative DNA damage and may lead to carcinoma. The increasing expression of MnSOD in the gastric mucosa may indicate the occurrence of gastric cancer.

Background: DOK2 is known as the substrate of chmeric p210bcr/abl oncoprotein characterizing chronic myelogenous leukemia with Philadelphia chromosome. Reduced DOK2 expression was recently reported in lung adenocarcinoma, suggesting that this protein acts as a tumor suppressor in solid tumors. The purpose of this study was to determine the significance of DOK2 in gastric cancer., Methods: The study subjects were 118 patients who underwent curative surgery for gastric cancer, as well as 7 gastric cancer cell lines. The tissues and cell lines were analyzed for DOK2 gene and protein expressions by histopathology and immunohistochemistry, and also using a microsatellite marker for loss of heterozygosity. Correlation of survival with clinicopathological parameters was investigated by univariate and multivariate analyses., Results: DOK2 expression was confirmed in the normal gastric mucosa. Considerable differences in the gene expression were noted among the gastric cell lines. Positive DOK2 expression was noted in the noncancerous regions of all pathological specimens, whereas 59 (50.0%) specimens of 118 patients were negatively stained in the tumor. Loss of heterozygosity was observed in 54.5% of DOK2(-) cases. DOK2(-) patients were more likely to develop recurrence than DOK2(+) and showed poorer 5-year overall survival (59.1%) than DOK2(+) (76.4%, P = .0403). Multivariate analysis identified pT (hazard ratio [HR] = 2.748, 95% confidence interval [95% CI] = 1.061-8.927, P = .0361), pN (HR = 2.486, 95% CI = 1.264-4.932, P = .0086), and DOK2(-) (HR = 2.343, 95% CI = 1.211-4.727, P = .0112) as significant and independent determinants of poor survival., Conclusions: Our data suggest the potential usefulness of DOK2 as a marker of poor prognosis in patients with gastric cancer after curative resection.

High-resolution magic-angle sample spinning (HR-MAS) (1)H NMR spectroscopy of tissue biopsies combined with chemometric techniques has emerged as a valuable methodology for disease diagnosis and environmental assessments. However, the tissue mass required for such experiments is of the order of 10 mg, and this can compromise the metabolic evaluation because of tissue heterogeneity. Tissue availability is often a limitation for clinical studies due to histopathological requirements, which are currently the gold standard for diagnosis, for example, in the case of tumors. Here, we introduce the use of a rotating micro-NMR detector that optimizes the coil filling factor such that mass-limited samples can be measured. We show the results for measuring nanoliter volume tissue biopsies using a commercial HR-MAS probe for the first time. The method has been tested with bovine muscle and human gastric mucosal tumor tissue samples. The gain in mass sensitivity is approximate up to 17-fold, and the adequate spectral resolution (3 Hz) allows the measurement of the metabolite profiles in nanoliter volume samples, thereby limiting the ambiguity resulting from heterogeneous tissues; thus, the approach presents diagnostic potential for studies by metabonomics of mass-limited biopsies.

Background/aims: Gastric gastrointestinal stromal tumors (gastric GISTs) are the most common gastric submucosal tumors with potential for malignant transformation. Our aim was to assess the efficacy and safety of ESE for gastric GISTs., Methodology: Small gastric GISTs were dealt with ESE between May 2007 and October 2010., Results: A total of 69 patients (42 men, 27 women; mean age 47.28±10.10 years) were treated. The mean diameter of the specimens was 1.87±0.57cm (range 0.7-3.0cm). The rates of intra-operative bleeding, delayed bleeding, perforation and surgery related complications were 7.25% (5/69), 1.45% (1/69), 33.33% (23/69) and 5.80% (4/69), respectively. The rate of perforation was 43.2% (19/44) at the fundus of the stomach and 16% (4/25) at the body (p=0.02). The mean time of the procedure was 41.07±10.79 minutes. Nineteen patients with perforation were treated by titanium clips and the rest by laparoscopy. Immunohistochemistry revealed that the positive rates of CD117 and CD34 were 88.41% and 68.12%, respectively. The gastric GISTs were all at low risk. At a mean follow-up period of 17.97±10.75 months (range 1 to 40 months) all of the patients were disease free., Conclusions: ESE with a cross-shaped incision is possibly a very good choice for small gastric GISTs.

The primary aim is to compare individuals with intestinal metaplasia (IM), chronic active gastritis (CAG), and normal gastric mucosa (NGM) in terms of apoptosis, proliferation, and Bcl-2 expression. The secondary aim is to determine whether these parameters are different between patients with and without gastric cancer in first-degree relatives. We enrolled 106 patients whose histopathological results were consistent with IM (n: 42), CAG (n: 51), or NGM (n: 13). Antral biopsies were immunohistochemically stained for Bcl-2 and Ki-67 expression. Apoptosis was detected using TUNEL assay. While no significant difference was determined between three groups with regard to apoptosis and Bcl-2 expression (p>0.05), Ki-67 expression was significantly higher in the IM group when compared with the CAG and NGM groups (29.90±22.87 vs. 18.18±16.22 vs. 18.54±20, respectively; p=0.012). Helicobacter pylori was determined to increase apoptosis (49.3% vs. 25.7%, p<0.05), nevertheless, it had no significant effect on proliferation and Bcl-2 expression. Bcl-2 and Ki-67 expression and apoptosis were not different among patients with and without a history of gastric cancer in first degree relatives. Although intestinal metaplasia cases demonstrate an increase in proliferation, no elevation is observed in apoptosis. This can be an important factor in the progression to gastric cancer., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Previous reports had indicated that there was a possible correlation of dystroglycan (DG) with biological behavior of cancer cells and cancer patients' survival. However, the role of DG expression in gastric cancer was rarely studied. In this study, α-DG and β-DG expression were determined by immunohistochemistry in specimens of primary cancer, metastatic lymph node, distal metastatic lesion, and their normal counterpart tissues in 20 gastric cancer patients. Correlations between α-DG and β-DG expression and prognosis were retrospectively analyzed. Our results found that positive expression of α-DG in normal mucosa, paired primary tumor, metastatic lymph node and distal metastatic site was detected in 95%, 70%, 25%, and 5% specimens, individually. Regarding β-DG,it was 70%, 55%, 10%, and 10%, individually. Patients who had lower α-DG expression in tumors than in normal counterparts showed poor survival (p = 0.002), whereas such a correlation was not found in the case of β-DG (p = 0.079). Difference of α-DG between primary tumor and its normal counterparts was an independent prognostic factor in gastric cancer with distal metastasis. This study showed DG expression was gradually reduced during tumor progression. Different expression of α-DG, but not β-DG, between primary tumor and normal specimen, correlated with patient survival, implicating a potential marker for gastric cancer prognosis.

Background: 14-3-3ơ is an intracellular, phosphoserine binding protein and proposed to be involved in tumorigenesis. However, the expression dynamics of 14-3-3ơ and its clinicopathological/prognostic significance in human tumors are still controversial., Methods: The method of immunohistochemistry (IHC) and Western blot were utilized to examine the protein expression of 14-3-3ơ in gastric cancer and paired normal adjacent gastric mucosal tissues. Receive operating characteristic (ROC) curve analysis was employed to determine a cutoff score for 14-3-3ơ expression in a training set (n = 66). For validation, the ROC-derived cutoff score was subjected to analysis of the association of 14-3-3ơ expression with patient outcome and clinical characteristics in a testing set (n = 86) and overall patients (n = 152)., Results: The expression frequency and expression levels of 14-3-3ơ were significantly higher in gastric cancer than in normal gastric mucosal tissues. Correlation analysis demonstrated that high expression of 14-3-3ơ in gastric cancer was significantly correlated with clinical stage and tumor invasion. Furthermore, in the testing set and overall patients, Kaplan-Meier analysis showed that elevated 14-3-3ơ expression predicted poorer overall survival (OS) and progression-free survival (PFS). Importantly, high 14-3-3ơ expression was also associated with shortened survival time in stage III and stage IV gastric cancer patients. Multivariate analyses revealed that 14-3-3ơ expression was an independent prognostic parameter in gastric cancer., Conclusions: These findings provide evidence that high expression of 14-3-3ơ may be important in the tumor progression and servers as an independent molecular marker for poor prognosis of gastric cancer. Thus, overexpression of 14-3-3ơ identifies patients at high risk and is a novel therapeutic molecular target for this tumor.

The aim of this study was to investigate the expression of Nrf2 and IGF-1 in benign, premalignant, and malignant gastric lesions, and to explore the role of Nrf2 and IGF-1 in gastric carcinoma carcinogenesis. Nrf2 and IGF-1 expression was detected in normal gastric mucosa, hyperplastic polyp, intraepithelial neoplasia, and adenocarcinoma by immunohistochemistry. There was no expression of Nrf2 and IGF-1 in normal gastric mucous membrane. With the elevation of Nrf2, IGF-1 expression, their co-expressions were highly elevated from benign proliferative lesions to malignant lesions. There were significant differences between hyperplastic polyps, intraepithelial neoplasias, and adenocarcinoma (hyperplastic polys vs. intraepithelial neoplasia: P=0.012; hyperplastic polyps vs. adenocarcinoma: P=0.023; and intraepithelial neoplasia vs. adenocarcinoma: P=0.027; hyperplastic polyps vs. adenocarcinoma: P=0.0000, respectively). Nrf2 expression and IGF-1 expression were correlated positively (r=0.337, P=0.037). The increased expression of Nrf2 and IGF-1 may be related to gastric carcinogenesis. Elevated Nrf2 and IGF-1 may play important roles in promoting tumor progression., (Copyright © 2011. Published by Elsevier GmbH.)

The study's objective was to assess the expressions of Fas and FasL proteins in gastric cancer in correlation with chosen clinicohistological parameters. Fas and FasL expression was analyzed in 68 patients with gastric cancer, using the immunohistochemical method. The expression of Fas was found to be lower in gastric cancer cells than in healthy mucosa, both in the lining epithelium and in glandular tubes (28% vs. 48% and 44%; p < 0.001). The expression of FasL was also markedly lower in cancer cells than in glandular tubes, yet higher than in the lining epithelium (51% vs. 73% and 14%; p < 0.01). Positive expressions of FasL and Fas were lower in less advanced gastric cancer cells (T1, T2), than in more advanced tumors (T3, T4), but only in the case of FasL was this difference statistically significant (p < 0.05). Our findings seem to confirm the theory of the impact of apoptotic disorders at the level of Fas receptor and FasL protein in the process of gastric cancer formation and growth, which is manifested in the varied expressions of these proteins in gastric cancer and in the normal lining and glandular epithelium of the stomach. However, the lack of significant differences in the expressions of Fas and FasL in correlation to other clinicohistological parameters indicates the existence of mechanisms that have a greater impact on the process of differentiation of gastric cancers. This in our opinion eliminates these proteins as prognostic factors.

CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n=9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n=43) and hereditary (n=3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low- and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containing isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors.

Helicobacter pylori infection is one of the most significant risk factors for gastric cancer. The infection is established early in life and persists lifelong leading to a sustained chronic inflammation. Iron is essential for most living organisms. Bacteria use several mechanisms to acquire iron from their hosts, including the synthesis of the potent iron chelators known as siderophores. Hosts cells may express the siderophore-binding protein neutrophil gelatinase-associated lipocalin (NGAL/lipocalin-2 (Lcn2)) in response to infection, thus preventing bacterial iron uptake. We have characterized here the pattern of expression of NGAL/Lcn2 in gastric mucosa (45 non-neoplastic and 38 neoplastic tissue samples) and explored the connection between NGAL/Lcn2 expression and H. pylori infection. Immunohistochemical analysis showed high NGAL/Lcn2 expression in normal and gastritis-affected mucosa compared to low expression in intestinal metaplasia, dysplasia, and gastric cancer. In normal and gastritis-affected mucosa (n=36 tissue samples), NGAL/Lcn2 was more frequently seen in epithelial cells located at the neck and base of the glands in H. pylori-positive cases than in similar epithelial cells of noninfected cases (Fisher's exact test, p=0.04). In conclusion, the high expression of NGAL/Lcn2 in normal and gastritis-affected mucosa infected with H. pylori suggests that NGAL/Lcn2 is upregulated locally in response to this bacterial infection. It is discussed whether this may have a causal relation to the development of gastric cancer.