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Background: Small cell lung carcinoma (SCLC) is highly susceptible to metastasis in the early stages of the disease. However, the stomach is an uncommon site of metastasis in SCLC, and only a few cases of this type of metastasis have been reported. Therefore, SCLC gastric metastases have not been systematically characterized and are easily missed and misdiagnosed., Case Summary: We report three cases of gastric metastasis from SCLC in this article. The first patient presented primarily with cough, hemoptysis, and epigastric fullness. The other two patients presented primarily with abdominal discomfort, epigastric distension, and pain. All patients underwent gastroscopy and imaging examinations. Meanwhile, the immunohistochemical results of the lesions in three patients were suggestive of small cell carcinoma. Finally, the three patients were diagnosed with gastric metastasis of SCLC through a comprehensive analysis. The three patients did not receive appropriate treatment and died within a short time., Conclusion: Here, we focused on summarizing the characteristics of gastric metastasis of SCLC to enhance clinicians' understanding of this disease., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met - ) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine β-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin-eosin staining was used to detect lung metastasis. Liquid chromatography-mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans-sulfur pathway lowered Met - 's inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans-sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR., 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 © 2024 Elsevier Inc. All rights reserved.)

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events. Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

Background: Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2., Aim: To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment., Methods: Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo ., Results: The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy., Conclusion: Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

The basement membrane is an essential defense against cancer progression and is intimately linked to the tumor immune microenvironment. However, there is limited research comprehensively discussing the potential application of basement membrane-related genes (BMRGs) in the prognosis evaluation and immunotherapy of gastric cancer (GC). The RNA-seq data and clinical information of GC patients were collected from the TCGA and GEO database. Prognosis-associated BMRGs were filtered via univariate Cox regression analysis. The 4-BMRGs signatures were constructed by lasso regression. Prognostic predictive accuracy of the 4-BMRGs signature was appraised with survival analysis, receiver operating characteristic curves, and nomogram. Gene set enrichment analysis (GSEA), gene ontology, and gene set variation analysis were performed to dig out potential mechanisms and functions. The Estimate algorithm and ssGSEA were used for assessing the tumor microenvironment and immunological characteristics. Identification of molecular subtypes by consensus clustering. Drug sensitivity analysis using the "pRRophetic" R package. Immunotherapy validation with immunotherapy cohort. A 4-BMRGs signature was constructed, which could excellently predict the GC patient prognosis (5-year AUC value of 0.873). Kaplan-Meier and Cox regression analyses showed that the 4-BMRGs signature was an OS-independent prognostic factor, and that higher risk scores were associated with shorter OS. The high-risk subgroup exhibits a higher abundance of immune cell infiltration, such as macrophages. Additionally, we observed a strong correlation between 2 BMRGs (LUM, SPARC) and immune cells such as CD8 + T cells and macrophages. The high-risk subgroup appears to be more sensitive to Axitinib, DMOG, Gemcitabine and Docetaxel by pRRophetic analysis. Furthermore, the validation of the cohort that received immune therapy revealed that patients in the high-risk group who underwent immune checkpoint inhibitor treatment exhibited better response rates. Pan-cancer analysis also shows that risk scores are strongly associated with immune and carcinogenic pathways. The 4-BMRGs signature has demonstrated accuracy and reliability in predicting the GC patient's prognosis and could assist in the formulation of clinical strategies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The prognosis of advanced gastric cancer (GC) invading the gastric serosa remains poor, mainly owing to high incidence of peritoneal recurrence. Patients with peritoneal metastases are often treated with neoadjuvant intraperitoneal and systemic chemotherapies (NIPS). Good responders to NIPS often undergo conversion gastrectomy. This study aims to explore biomarkers predicting the occurrence of peritoneal metastasis (PM) and evaluating the efficacy of NIPS in GC patients., Methods: We collected six peritoneal lavage (PL) samples from two patients with PM, two without PM, and two with diminished PM after NIPS via intraperitoneal access ports. We equally isolated microRNAs from exosomes derived from PL samples for deep sequencing. Two microRNAs (hsa-let-7g-3p and hsa-miR-10395-3p) were identified, and their expression levels were examined in PL samples of 99 GC patients using qRT-PCR. Moreover, we performed in vivo and in vitro functional assays to investigate effects of these microRNAs on metastasis and chemoresistance of GC cells., Results: Exosomal microRNA expression profiling of six PL samples indicated that the microRNA signature in exosomes of PLs from patients with diminished PM was similar to that from patients without PM. Expression levels of hsa-let-7g-3p and hsa-miR-10395-3p were associated with PM. In vivo and in vitro functional assays confirmed that hsa-let-7g-3p and hsa-miR-10395-3p are involved in GC metastasis and chemoresistance., Conclusion: PL-derived exosomes in GC contain large amounts of microRNAs related to PM. Moreover, hsa-let-7g-3p and hsa-miR-10395-3p could be used as biomarkers predicting PM and NIPS efficacy and are involved in GC metastasis and chemoresistance., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

In recent years,great progress has been achieved in the application of immune checkpoint inhibitors (ICI) in tumor immunotherapy.However,a variety of adverse reactions induced by ICI have been reported.Despite the high overall incidence of adverse reactions caused by ICI,some adverse reactions,such as immune-related pancreatitis,are rare in clinical practice.In this paper,a case of immune-related pancreatitis after treatment of advanced gastric cancer with nivolumab was identified.We analyzed the cause,treatment,incidence,and risk factors of the adverse reaction,aiming to improve the clinical diagnosis,treatment,and safe medication of rare adverse reactions associated with ICI.

Although gastric cancer with para-aortic lymph node (PAN) metastasis is commonly regarded as unresectable, surgeons have explored the optimal treatment for patients with PAN metastases limited to No.16a2/b1 in the past few decades. Preoperative systemic therapy combined with D2 gastrectomy plus PAN dissection may improve the prognosis of these patients. In this multicenter phase II trial, 29 gastric cancer patients with PAN metastasis limited to No.16a2/b1 will receive preoperative treatment with nab-paclitaxel, oxaliplatin, S-1 (nab-POS: nab-paclitaxel, oxaliplatin, S-1) and sintilimab followed by D2 gastrectomy plus PAN dissection; and postoperative treatment with oral S-1, intravenous sintilimab and intraperitoneal paclitaxel. The end points for the study are 3-year overall survival, 3-year disease-free survival, pathological response rate, incidence of postoperative complications and adverse events.

Background : Epidemiological studies evaluating the associations between the consumption of cruciferous vegetables (CV) and diverse health outcomes have generated inconsistent findings. Therefore, we carried out an umbrella review to systematically summarize existing evidence on this topic. Methods : This study had been registered at PROSPERO (no. CRD42021262011). Relevant systematic reviews and meta-analyses of observational studies were identified by searching PubMed, Web of science, and Embase databases from inception up to March 15, 2021. Observational studies investigating the association between CV intake and multiple health outcomes in humans were eligible for inclusion. The validated AMSTAR (A Measurement Tool to Assess Systematic Reviews) instrument was utilized for assessing the methodological quality of the included systematic reviews. For each meta-analysis, we assessed the summary effect size by using fixed and random effects models, 95% prediction intervals, heterogeneity, evidence of small-study effects, and excess significance bias. Results : Our umbrella review included 41 meta-analyses of 303 individual studies involving 13 394 722 participants. Twenty-four health outcomes including cancers ( n = 23), cardiovascular disease ( n = 12), mortality ( n = 5), and metabolic diseases ( n = 1) were evaluated. The summary random effects estimates were significant at P < 0.05 in 24 meta-analyses - all of which reported decreased risks of health outcomes. All were of moderate methodological quality in our study. Of the 41 meta-analyses, we observed suggestive evidence for beneficial associations between gastric cancer, lung cancer, endometrial cancer, and all-cause mortality. Moreover, 16 associations were supported by weak evidence, including breast cancer, lung cancer, renal cell carcinoma, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, colon cancer, colorectal adenoma, colorectal neoplasm, non-Hodgkin lymphoma, and total cancer. Conclusions : It revealed that CV intake might be associated with beneficial effects on several health-related outcomes (gastric cancer, lung cancer, endometrial cancer, and all-cause mortality). Other associations could be genuine, but substantial uncertainty remains. Additional studies are needed to evaluate the relationship between the consumption of CV and various health outcomes as well as robust randomized controlled trials in the future.

Although recent advances in systemic chemotherapy have improved the clinical outcomes of gastric cancer patients with peritoneal metastasis, the peritoneum still represents a common site of treatment failure and disease recurrence. Neoadjuvant intraperitoneal-systemic chemotherapy has been acknowledged as a more aggressive treatment for gastric cancer patients with peritoneal metastasis. In this multicenter phase III randomized controlled trial, 238 patients will be randomly separated into two groups in a 2:1 ratio after laparoscopic exploration. The experimental arm will receive the proposed neoadjuvant intraperitoneal-systemic chemotherapy regimen, whereas the control group will receive a Paclitaxel + S-1 (PS) chemotherapy regimen. The endpoints for the study are overall survival, response rate, gastrectomy radicality rate, progression-free survival and adverse events.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1-T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1-T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1-T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov).

Background: Estrogen-related receptor-α (ESRRA) is an orphan nuclear receptor, expressing at high level in exuberant metabolism organs and acting as transcription factor. High expression was found in many malignances but no research was done in gastric cancer (GC), where lipid metabolism disorder is common. Methods: Kaplan-Meier plot was utilized to find the relationship between ESRRA expression and patients' prognoses. The expression level of ESRRA was measured by real-time PCR. The protein expression levels were tested with western-blot and immunohistochemistry. Cell cycle and apoptosis was identified with flow cytometry. RNA-seq, bioinformatics analysis, dual-luciferase assay and ChIP assay were used to predict and validate ESRRA's target gene and binding motif. Animal models were also introduced in our study. Results: ESRRA expression is notably higher in GC cell lines and high ESRRA levels are correlated to poor prognoses. ESRRA silencing decreased GC cell viability, migration, and invasion capacities. Its downstream gene DSN1 was spotted by RNA-seq and confirmed by later bioinformatics analyses, dual-luciferase, and ChIP assays. Western-blot showed G2M arrest caused by ESRRA silencing was via CDC25C-CDK1-Cyclin B1 pathway. Conclusion: ESRRA/DSN1/CDC25C-CDK1-Cyclin B1 is of great importance in GC development. ESRRA could be a potential target as well as prognostic marker in GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: Advanced signet ring cell (SRC) carcinoma has a worse prognosis. Therefore, early diagnosis and prevention is particularly important; SRC tumors have lower R0 resection rate and are thought to be less chemosensitive than non-SRCC. Consequently, a novel postoperative adjuvant treatment is urgently needed to improve clinical outcomes., Patient Concerns: A 41-year-old female with advanced gastric SRC carcinoma was treated with radical gastrectomy and oxaliplatin-based regimen for 6 cycles after surgery. She was suspected of recurrence with the high level of carbohydrate antigen (CA) 72-4., Diagnoses: The gastroscopy revealed SRC carcinoma of gastric antrum and poorly differentiated adenocarcinoma in some areas. The diagnosis of postoperative pathology report was gastric cancer with stage III C (T4a, N3a, M0)., Interventions: The level of CA72-4 rapidly increased during the 2 follow-up after the completion of conventional treatment, ex vivo-cultured allogeneic natural killer (NK) cell infusion was offered to prevent recurrence., Outcomes: Intravenous injections of NK cells combination with surgical treatment and chemotherapy showed therapeutic effects in this patient with possible relapse. The patient remained disease-free 46 months after the infusion of NK cells until the latest follow-up., Lessons: CA72-4 appeared to be the most sensitive and specific marker in the gastric cancer patient, and the high level of CA72-4 may indicate the risk of recurrence. This case report provide rationale for NK cell infusion following the rapid increase of CA72-4 to prevent recurrence., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Texture analysis (TA) can quantify intra-tumor heterogeneity using standard medical images. The present study aimed to assess the application of positron emission tomography (PET) TA in the differential diagnosis of gastric cancer and gastric lymphoma., Methods: The pre-treatment PET images of 79 patients (45 gastric cancer, 34 gastric lymphoma) between January 2013 and February 2018 were retrospectively reviewed. Standard uptake values (SUVs), first-order texture features, and second-order texture features of the grey-level co-occurrence matrix (GLCM) were analyzed. The differences in features among different groups were analyzed by the two-way Mann-Whitney test, and receiver operating characteristic (ROC) analysis was used to estimate the diagnostic efficacy., Results: InertiaGLCM was significantly lower in gastric cancer than that in gastric lymphoma (4975.61 vs. 11,425.30, z = -3.238, P = 0.001), and it was found to be the most discriminating texture feature in differentiating gastric lymphoma and gastric cancer. The area under the curve (AUC) of inertiaGLCM was higher than the AUCs of SUVmax and SUVmean (0.714 vs. 0.649 and 0.666, respectively). SUVmax and SUVmean were significantly lower in low-grade gastric lymphoma than those in high grade gastric lymphoma (3.30 vs. 11.80, 2.40 vs. 7.50, z = -2.792 and -3.007, P = 0.005 and 0.003, respectively). SUVs and first-order grey-level intensity features were not significantly different between low-grade gastric lymphoma and gastric cancer. EntropyGLCM12 was significantly lower in low-grade gastric lymphoma than that in gastric cancer (6.95 vs. 9.14, z = -2.542, P = 0.011) and had an AUC of 0.770 in the ROC analysis of differentiating low-grade gastric lymphoma and gastric cancer., Conclusions: InertiaGLCM and entropyGLCM were the most discriminating features in differentiating gastric lymphoma from gastric cancer and low-grade gastric lymphoma from gastric cancer, respectively. PET TA can improve the differential diagnosis of gastric neoplasms, especially in tumors with similar degrees of fluorodeoxyglucose uptake., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Competing Interests: The authors declare that they have no conflict of interest.

Objective: To explore the diagnostic value of laparoscopy in the postoperative recurrence of peritoneal metastasis in gastric cancer, and to investigate the efficacy of bidirectional intraperitoneal and systemic (BIPS) chemotherapy for the recurrence. Methods: The descriptive case series study was conducted. Case inclusion criteria: (1) gastric cancer patients without synchronous distant metastasis received D2 radical gastrectomy; (2) postoperative adjuvant chemotherapy was administered; (3) no other distant metastasis except recurrence of peritoneal metastasis; (4) age of 18-75 years; (5) Eastern Cooperative Oncology Group (ECOG) performance-status score≤2; (6) pretreatment evaluation suggested that surgery and chemotherapy could be tolerated. Eight consecutive gastric cancer patients with postoperative recurrence of peritoneal metastasis who met the above criteria at Department of Gastrointestinal Surgery of Ruijin Hospital from September 2015 to September 2016 were enrolled into the study. There were 6 males and 2 females with the median age of 52 (38-68) years. They received laparoscopy or laparotomy first, and then were evaluated with reference to the Sugarbaker peritoneal cancer index (PCI) and the peritoneal metastasis classification of gastric cancer developed by the Japanese Gastric Cancer Research Association. A peritoneal access port was implanted in the subcutaneous space of the lower abdomen and the patients received chemotherapy for 21 days as a course of treatment. All the patients received intraperitoneal 20 mg/m(2) of paclitaxel (PTX) via implanted subcutaneous peritoneal access ports and intravenous 50 mg/m(2) of PTX at day 1 and day 8, meanwhile 80 mg/m(2) of Tigio was orally administered per day for 14 consecutive days, followed by 7 days of interval. Follow-up ended on December 15, 2019. Results: Of these 8 patients with recurrence of peritoneal metastasis after gastric cancer surgery, 1 case underwent laparotomy and loop stoma of terminal ileum because of complete colonic obstruction, and the remaining 7 cases underwent laparoscopy successfully and the recurrence of peritoneal metastasis was clearly diagnosed. Two patients with ovarian metastasis underwent laparoscopic bilateral adnexectomy. The median follow-up time was 17.5 (1.5 to 39.0) months, the median number of BIPS chemotherapy course was 11 (1 to 30), and the median survival time (MST) after BIPS chemotherapy was 17.0 months. The major adverse reaction in BIPS treatment was mainly myelosuppression, of which grade 3/4 leukopenia and neutropenia developed in 1 and 2 cases respectively. No BIPS-related death occurred. The MST of gastric cancer after radical gastrectomy was 40.0 months. Conclusions: Laparoscopy is a safe and feasible method for diagnosing the recurrence of peritoneal metastasis of gastric cancer. BIPS chemotherapy is effective and safe for its treatment and deserves further study.

Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data showed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.

Background: Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC)., Methods: In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m 2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate., Discussion: This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent., Trial Registration: World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552, Registered Prospectively on the 16th July, 2019.

Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein-Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.

Objective: To investigate the clinical value of laparoscopic peritoneal dialysis catheter implantation in peritoneal chemotherapy for gastric cancer with peritoneal metastasis. Methods: From January 2019 to June 2019, the clinical data of 6 patients diagnosed as gastric cancer with peritoneal metastasis were retrospectively analyzed in the Gastrointestinal Surgery Department of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine. Five were male and 1 was female. The median age was 69.5 (28-77) years. The median body mass index (BMI) was 22.8 (19.6-23.5). All procedures were performed under general anesthesia with endotracheal intubation. The patient's body position and facility layout in the operating room were consistent with those of laparoscopic gastrectomy. The operator's position: the main surgeon was located on the right side of the patient, the first assistant stood on the left side of the patient, and the scopist stood between the patient's legs. Surgical procedure: (1) trocar location: three abdominal trocars was adopted, with one 12 mm umbilical port for the 30° laparoscope (point A). Location of the other two trocars was dependent on the procedure of exploration or biopsy as well as the two polyester cuff position of the peritoneal dialysis catheter: Usually one 5 mm port in the anterior midline 5 cm inferior to the umbilicus point was selected as point B to ensure that the distal end of the catheter could reach the Douglas pouch. The other 5 mm port was located in the right lower quadrant lateral to the umbilicus to establish the subcutaneous tunnel tract, and the proximal cuff was situated 2 cm away from the desired exit site (point C).(2) exploration of the abdominal cavity: a 30° laparoscope was inserted from 12 mm trocar below the umbilicus to explore the entire peritoneal cavity. The uterus and adnexa should be explored additionally for women. Once peritoneal metastasis was investigated and identified, primary laparoscopic peritoneal dialysis catheter implantation was performed so as to facilitate subsequent peritoneal chemotherapy. Ascites were collected for cytology in patients with ascites. (3) peritoneal dialysis catheter placement: the peritoneal dialysis catheter was introduced into the abdominal cavity from point A. Under the direct vision of laparoscopy, 2-0 absorbable ligature was reserved at the expected fixation point of the proximal cuff (point B) for the final knot closure. Non-traumatic graspers were used to pull the distal cuff of peritoneal dialysis catheter out of the abdominal cavity through point B. The 5-mm trocar was removed simultaneously, and the distal cuff was fixed between bilateral rectus sheaths at the anterior midline port site preperitoneally. To prevent subsequent ascites and chemotherapy fluid extravasation, the reserved crocheted wire was knotted. From point C the subcutaneous tunnel tract was created before the peritoneal steath towards the port site lateral to the umbilicus. Satisfactory catheter irrigation and outflow were then confirmed. Chemotherapy regimen after peritoneal dialysis catheterization: all patients began intraperitoneal chemotherapy on the second day after surgery. On the 1st and 8th day of each 3-weeks cycle, paclitaxel (20 mg/m(2)) was administered through peritoneal dialysis catheter, and paclitaxel (50 mg/m(2)) was injected intravenously. Meanwhile, S-1 was orally administered twice daily at a dose of 80 mg·m(-2)·d(-1) for 14 consecutive days followed by 7-days rest. To observe the patients' intraoperative and postoperative conditions. Results: All the procedures were performed successfully without intraoperative complications or conversion to laparotomy. No 30 day postoperative complications were observed. The median operative time was 33.5 (23-38) min. The median time to first flatus was 1(1-2) days, and the median postoperative hospital stay was 3 (3-4) days, without short-term complications within 30 days postoperatively. The last follow-up was up to July 10, 2019, and the patients were followed for 4(1-6) months. No ascites extravasation was observed and no death occurred in the 6 patients. There was no catheter obstruction or peritoneal fluid extravasation during and after chemotherapy. Conclusion: Laparoscopic peritoneal dialysis catheter implantation was safe and feasible for patients with peritoneal metastasis of gastric cancer. The abdominal exploration, tumor staging and the abdominal chemotherapy device implantation can be completed simultaneously, which could simplify the surgical approach, improve the quality of life for patients and further propose a new direction for the development of abdominal chemotherapy.

Background: Emerging evidence has shown that miR-1275 plays a critical role in tumour metastasis and the progression of various types of cancer. In this study, we analysed the role and mechanism of miR-1275 in the progression and prognosis of gastric cancer (GC)., Methods: Target genes of miR-1275 were identified and verified by luciferase assay and Western blotting. The function of miR-1275 in invasion and metastasis was analysed in vitro and in vivo in nude mice. The signal pathway regulated by miR-1275 was examined by qRT-PCR, Western blotting and chromatin immunoprecipitation analyses. The expression of miR-1275and JAZF1 were measured in specimens of GC and adjacent non cancerous tissues., Results: We identified JAZF1 as a direct miR-1275 target. miR-1275 supresses migration and invasion of GC cells in vitro and in vivo, which was restored by JAZF1 overexpression. Moreover, JAZF1 was recognized as a direct regulator of Vimentin. Knocking-down miR-1275 or overexpressing JAZF1 resulted in upregulation of Vimentin but downregulation of E-cadherin. Meanwhile, we validated in 120 GC patients specimens that low miR-1275expression and high JAZF1 mRNA expression levels were closely associated with lymph node metastasis and poor prognosis. The expression of JAZF1 in protein level displayed the correlations with Vimentin but inversely with E-cadherin., Conclusions: Increased miR-1275 expression inhibited GC metastasis by regulating vimentin/E-cadherin via direct suppression of JAZF1expression, suggesting that miR-1275 is a tumour-suppressor miRNA with the potential as a prognostic biomarker or therapeutic target in GC.

Objectives: Peritoneal carcinomatosis is one of the causes of death in patients with advanced gastric cancer. We assumed that cryoablation could be applied as adjuvant therapy to control peritoneal carcinomatosis from gastric cancer., Methods: We investigated the feasibility of cryoablation technique in rabbit model using a novel cryoablation balloon probe. The cryozones were harvested 7 days after cryoablation for histological evaluation. The levels of cytokines in the peripheral blood of rabbits were also detected., Results: The results demonstrated that cryoablation could be applied in a rabbit model of peritoneal carcinomatosis from gastric cancer. Seven days after cryoablation, necrotic tumor cells could be seen the cryozones. Higher level of IFN-γ was observed. The level of IL-10 was decreased after treatment., Conclusions: The findings provided the experimental basis for the future application of cryoablation in patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Objective: Endoscopic mucosa-sparing lateral dissection (EMSLD) was developed by our group, and is used to remove gastric submucosal tumor (SMT). This study aims to evaluate the feasibility and safety of this method., Methods: This retrospective study included 25 patients who underwent EMSLDs at an endoscopy center as a national key unit in china from October 2015 to July 2016. The main data collected were the size of the gastric SMT, its location and origin, en bloc resection rate, operating time, intraoperative and postoperative complications, hospitalization expense, hospital days, and follow-up after hospital discharge., Results: The mean (SD) size of the gastric SMTs was 18.3 (5.9) mm; 96% (24/25) of the tumors originated in the muscularis propria; and 64% (16/25) and 28% (7/25) were located in the gastric fundus and gastric body, respectively. The rate of en bloc resection was 96% (24/25), and the rate of intraoperative perforations due to endoscopic full-thickness resection was 48% (12/25). All wounds and perforations were effectively closed using endoscopic clips combined with the retained mucosa. The mean operative time was 74.2 (38.0) min. Delayed bleeding and perforation were not observed., Conclusion: Endoscopic mucosa-sparing lateral dissection is safe and feasible for the removal of gastric SMTs. The wound can be effectively closed using the retained mucosa and endoscopic clips, even if perforation has occurred. EMSLD provides an alternative to the resection of gastric SMTs, especially for tumors with a risk of intraoperative perforation.

Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5β1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients., Methods: Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis., Results: The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007)., Conclusion: The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

Background: The objective of this study was to evaluate the feasibility, safety, and potential benefits of laparoscopic gastrectomy (LG) comparing with open gastrectomy (OG) in elderly population., Methods: Studies comparing LG with OG for elderly population with gastric cancer, published between January 1994 and July 2015, were identified in the PubMed, Embase, and ISI Web of Science databases. Operative outcomes (intraoperative blood loss, operative time, and the number of lymph nodes harvested) and postoperative outcomes (time to first ambulation, time to first flatus, time to first oral intake, postoperative hospital stay, postoperative morbidity) were included and analyzed. The Newcastle-Ottawa Scale was used to assess the quality of the pooled study. A funnel plot was used to evaluate the publication bias., Results: Seven studies totaling 845 patients were included in the meta-analysis. LG in comparison to OG showed less intraoperative blood loss (weighted mean difference (WMD) -127.47; 95% confidence interval (CI) -202.79 to -52.16; P < 0.01), earlier time to first ambulation (WMD -2.07; 95% CI -2.84 to -1.30; P < 0.01), first flatus (WMD -1.04; 95% CI -1.45 to -0.63; P < 0.01), and oral intake (WMD -0.94; 95% CI -1.11 to -0.77; P < 0.01), postoperative hospital stay (WMD -5.26; 95% CI -7.58 to -2.93; P < 0.01), lower overall postoperative complication rate (odd ratio (OR) 0.39; 95% CI 0.28 to 0.55; P < 0.01), less surgical complications (OR 0.47; 95% CI 0.32 to 0.69; P < 0.01), medical complication (OR 0.35; 95% CI 0.22 to 0.56; P < 0.01), incisional complication (OR 0.40; 95% CI 0.19 to 0.85; P = 0.02), and pulmonary infection (OR 0.49; 95% CI 0.26 to 0.93; P = 0.03). No significant differences were observed between LG and OG for the number of harvested lymph nodes. However, LG had longer operative times (WMD 15.73; 95% CI 6.23 to 25.23; P < 0.01)., Conclusions: LG is a feasible and safe approach for elderly patients with gastric cancer. Compared with OG, LG has less blood loss, faster postoperative recovery, and reduced postoperative morbidity.

Aims and Background: Keratinocyte growth factor (KGF) is reported to be implicated in the growth of some cancer cells. Matrix metalloproteinase 9 (MMP-9) is thought to enhance the tumor invasion and metastasis ability. This study was aimed at analyzing the relationship between KGF and MMP-9 expression and patients' clinicopathological characteristics to clarify the clinical significance of the expression of KGF and MMP-9 in gastric cancer., Methods: Tissue samples from 161 patients with primary gastric cancer were investigated using immunohistochemistry. The relationship between KGF and/or MMP-9 expression and clinicopathological characteristics was analyzed., Results: KGF expression and MMP-9 expression in gastric cancer tissue were observed in 62 cases (38.5%) and 97 cases (60.2%), respectively. MMP-9 was significantly associated with depth of invasion, lymph node metastasis and TNM stage. The prognosis of MMP-9-positive patients was significantly poorer than that of MMP-9-negative patients (p = 0.009). KGF expression was positively correlated with MMP-9 expression in gastric cancer, and the prognosis of patients with both KGF- and MMP-9-positive tumors was significantly worse than that of patients with negative tumors for either factor (p = 0.045). Expression of MMP-9 was revealed to be an independent prognostic factor (p = 0.026)., Conclusions: Coexpression of KGF and MMP-9 in gastric cancer could be a useful prognostic factor, and MMP-9 might also serve as a novel target for both prognostic prediction and therapeutics.

Tissue biopsy is often not very accurate for the diagnosis of gastric epithelial neoplasia (GEN), and the results differ notably from endoscopic resection (ER) in terms of the pathological diagnosis. The aims of this study were to evaluate the diagnostic performances of biopsy, magnifying endoscopy with narrow-band imaging (ME-NBI), and biopsy plus ME-NBI for GEN.This study retrospectively analyzed 101 cases diagnosed as GEN using ER samples. The discrepancies between biopsy and ER, as well as between biopsy plus ME-NBI and ER in the diagnosis of GEN were evaluated. Factors that contributed to such discrepancies were analyzed. The sensitivity and specificity of biopsy and ME-NBI for the diagnosis of high-grade neoplasia (HGN) were determined.The discrepancy in the pathological diagnosis between biopsy and ER was 39.6% for GEN and 54.2% for HGN. The discrepancy between biopsy combined with ME-NBI and ER was 15.9% for GEN and 10.2% for HGN. Factors that undermined the diagnostic accuracy of biopsy included the lesion size (≤10 mm, odds ratio [OR] 1; 10-20 mm, OR 0.2, 95% confidence interval [CI] 0.1-0.7; >20 mm, OR 0.5, 95% CI 0.1-2.1, P = 0.03) and the number of biopsy fragments (OR 0.6, 95% CI 0.5-0.8, P = 0.001). The sensitivity and specificity for HGN were 45.8% (33.7%-58.3%) and 100% (87.5%-100%) for biopsy, and 88.1% (77.5%-94.1%) and 92.9% (81.0%-97.5%) for ME-NBI, respectively.In conclusion, biopsy-based diagnoses for GEN should be interpreted with caution. Biopsy combined with ME-NBI can contribute to the diagnosis of GEN, which improves diagnostic consistency with pathological result of ER specimens.

Background: The objective of this study was to compare the dose distributions of RapidArc (RA), static gantry intensity-modulated radiotherapy (IMRT), and three-dimensional conformal radiotherapy (3DCRT) as adjuvant radiotherapy modalities for the treatment of gastric cancer., Methods: Fifteen patients with gastric cancer that underwent limited lymphadenectomy of perigastric lymph nodes were included in this study. Dosimetric values for a total dose of 45 Gy (1.8 Gy/day) were calculated for the RapidArc, IMRT, and 3DCRT modalities. The following parameters were compared: D99%, D1%, V95%, V107%, and conformity and homogeneity index values (CI and HI, respectively) for the planned target volume (PTV). Dose volume histogram (DVH) and dose distribution of the organs at risk (OAR), as the maximal dose to the spinal cord, V30 and V40 of the small bowel, and V20, V30 of liver and kidney were also assessed respectively., Results: RA, IMRT, and 3DCRT all achieved desirable PTV coverage. However, RA and IMRT significantly decreased D1% and V107%, and provided better CI and HI values compared with 3DCRT (P <0.05). Moreover, RA also achieved a significantly lower maximum dose for the spinal cord, liver V30, and kidney V20 compared to IMRT and 3DCRT; while the mean dose for these three organ types did not differ for the RA, IMRT, and 3DCRT plans., Conclusions: Both RA and IMRT achieved favorable PTV coverage compared to 3DCRT. In addition, RA achieved better dosimetry than IMRT and 3DCRT, and provided better protection for the spinal cord, liver, and kidneys.

We aimed to evaluate the clinical response to platinum-based chemotherapy and treatment outcome of gastric cancer patients in the present of ERCC1, ERCC2, NBN, RAD51, and XRCC3 gene polymorphisms. A number of 415 patients of gastric cancer that received platinum-based chemotherapy were enrolled in the present study. The presence of ERCC1 rs11615 and rs2298881, ERCC2 rs1799793 and rs13181, NBN rs1805794, rs709816, and RAD51 rs1801321 and XRCC3 rs1799794 were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Conditional regression analysis identified that CC genotype of ERCC1 rs11615 and AA genotype of ERCC2 rs1799793 was associated with a better response to chemotherapy in gastric cancer patients, and the odds ratio (ORs)(95% confidence interval (CI)) were 2.70(1.33-5.70) and 3.12(1.52-6.84), respectively. By the Cox analysis, the CC genotype of ERCC1 rs11615, AA genotype of ERCC2 rs1799793, and CC genotype of NBN rs1805794 were significantly associated with a longer overall survival (OS) of gastric cancer. In conclusion, our results suggest that ERCC1 rs11615, ERCC2 rs1799793, and NBN rs1805794 polymorphisms in the DNA repair pathways may influence the response to chemotherapy and OS of gastric cancer.

Purpose: (1) To investigate associations between single nucleotide polymorphisms (SNPs) in osteopontin (OPN) and its receptor-cluster of differentiation 44 (CD44) genes and gastric cancer susceptibility. (2) To explore the correlation of OPN and CD44 expression of gastric cancer., Methods: We detected 26 SNPs of the genes in gastric cancer patients from the Chinese Han population by Sequenom technique and performed expression of OPN in combination with CD44 in 243 tissues samples of the cases by tissue microarray and immunohistochemistry (IHC)., Results: We found that the minor alleles of OPN rs4754C>T and OPN rs9138C>A remained strongly associated with decreased gastric cancer risk (P = 1.53 × 10(-4), odds ratio (OR) 0.642, 95 % confidence interval (CI) 0.511-0.808 and P = 1.59 × 10(-4), OR 0.642, 95 %CI 0.510-0.809). OPN variant rs1126772A>G and CD44 variant rs353639A>C significantly contributed to elevated risk of gastric cancer (P = 0.042, OR 1.279, 95 % CI 1.008-1.622 and P = 0.047, OR 1.334, 95 % CI 1.003-1.772). Haplotypes of OPN and CD44 variants significantly influenced risk of gastric cancer. Clinical data indicated that rs4754 and rs9138 of OPN were significantly associated with smoking (P = 0.029, OR 0.343, 95 % CI 0.127-0.926 and P = 0.029, OR 0.343, 95 %CI 0.127-0.926) and OPN rs1126772 revealed associations with tumor-node-metastasis (TNM) stage (P = 0.025, OR 1.765, 95 % CI 1.073-2.905) and tumor differentiation (P = 0.031, OR 1.722, 95 % CI 1.049-2.825). OPN expression was observed in 133 of the 243 cases (54.7 %) by IHC and was correlated with serosa invasion (P = 0.013), TNM stage (P = 0.003) and lymph node metastasis (P = 0.002). CD44 expression was found in 92 of the 243 cases (37.9 %) and was associated with tumor size (P = 0.005) and lymph node metastasis (P = 0.023), respectively. The OPN expression displayed a positive association with CD44 (P = 0.01, r s = 0.164)., Conclusions: We found that the polymorphisms rs4754, rs9138 and rs1126772 of OPN gene and rs353639 of CD44 gene were significantly associated with gastric cancer. Our IHC data indicated that interaction of OPN and CD44 protein would promote progression and metastasis of gastric cancer.

13-acetoxysarcocrassolide (13-AC), an active compound isolated from cultured Formosa soft coral Sarcophyton crassocaule, was found to possess anti-proliferative and apoptosis-inducing activities against AGS (human gastric adenocarcinoma cells) gastric carcinoma cells. The anti-tumor effects of 13-AC were determined by MTT assay, colony formation assessment, cell wound-healing assay, TUNEL/4,6-Diamidino-2-phenylindole (DAPI) staining, Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and flow cytometry. 13-AC inhibited the growth and migration of gastric carcinoma cells in a dose-dependent manner and induced both early and late apoptosis as assessed by flow cytometer analysis. 13-AC-induced apoptosis was confirmed through observation of a change in ΔΨm, up-regulated expression levels of Bax and Bad proteins, down-regulated expression levels of Bcl-2, Bcl-xl and Mcl-1 proteins, and the activation of caspase-3, caspase-9, p38 and JNK. Furthermore, inhibition of p38 and JNK activity by pretreatment with SB03580 (a p38-specific inhibitor) and SP600125 (a JNK-specific inhibitor) led to rescue of the cell cytotoxicity of 13-AC-treated AGS cells, indicating that the p38 and the JNK pathways are also involved in the 13-AC-induced cell apoptosis. Together, these results suggest that 13-AC induces cell apoptosis against gastric cancer cells through triggering of the mitochondrial-dependent apoptotic pathway as well as activation of the p38 and JNK pathways.

The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing steroidogenic acute regulatory-related lipid transfer domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, haplotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P=0.043, odds ratio [OR]=0.805, 95% confidence intervals [95% CI]=0.643-0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P=0.021, OR=2.882, 95% CI=1.173-7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). The expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P=0.004), alcohol drinking (P<0.001), tumor location (P=0.007), histological type (P=0.005) and differentiation (P=0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The cell division cycle 20 homolog (CDC20) expression is increased in diverse human cancers and plays a vital role in tumorigenesis and progression. However, the clinical significance of CDC20 expression in gastric cancer (GC) remains largely unknown. The aim of this study was to investigate the clinicopathologic features and prognostic significance of CDC20 in GC. The CDC20 mRNA expression was measured by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) was used to detect the expression of CDC20 protein in 131 clinicopathologically characterized GC cases. The relationship between CDC20 expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between CDC20 expression and prognosis of GC patients. The relative mRNA expression of CDC20 were significantly higher in GC tumor tissues than in the corresponding noncancerous tissues (P<0.001). Simultaneously, CDC20 protein expression was positively correlated with tumor size (P=0.02), histological grade (P=0.037), lymph node involvement (P=0.009), and TNM stage (P=0.015). Furthermore, Kaplan-Meier analysis indicated that patients with high CDC20 expression had poor overall survival (P<0.001). Multivariate analysis showed that high CDC20 expression was an independent predictor of overall survival. In conclusion, our data indicated that CDC20 upregulation was associated with aggressive progression and poor prognosis in GC. CDC20 was identified for the first time as an independent marker for predicting the clinical outcome of GC patients.

C4.4A, a metastasis-associated gene, encodes a glycolipid-anchored membrane protein which is overexpressed in several human malignancies. However, there are few data available on C4.4A expression and its relationship with progression in gastric cancer. Our study was designed to explore the expression of C4.4A in gastric cancer and to correlate it with clinical outcome. C4.4A expression was studied by quantitative real-time RT-PCR and immunohistochemistry for assessment of correlations with clinicopathological factors. C4.4A mRNA expression was significantly up-regulated in gastric cancer as compared with noncancerous tissue (p<0.05)., being observed in 107 (88.4%) of the 121 gastric cancer cases by immunohistochemistry. We found that the expression of C4.4A mRNA was correlated with size of the tumor, depth of invasion, lymph node metastasis, distant metastasis and TNM stage. Moreover, patients with overexpression of C4.4A has a significantly worse survival (p<0.05). Further multivariable analysis indicated that the expression of C4.4A was an independent prognostic indicator for gastric cancer (p<0.05). In conclusion, overexpression of C4.4A correlates with metastatic potential of gastric cancer and C4.4A could be a novel independent prognostic marker for predicting outcome.

MPS-1 (metallopanstimulin-1), also known as ribosomal protein S27, was overexpressed in gastric cancer cells. However, how MPS-1 contributes to gastric carcinogenesis has not been well characterized. Here, we show that high expression of MPS-1 was observed in gastric cancer tissues and associated with gastric cancer cell metastasis. Alteration of MPS-1 expression regulates invasion and migration of gastric cancer cells both in vitro and in vivo. Furthermore, by using Signal-Net and cluster analyses of microarray data we identified integrin β4 (ITGB4) as a downstream target of MPS-1 that mediates its effects on cell metastasis. Knockdown of MPS-1 expression in gastric cancer cells led to significant reduction of ITGB4 expression at both the RNA and protein levels. Mechanically, we found that overexpression of ITGB4 in MPS-1 knockdown cells largely recovers the ability of invasion and migration. Conversely, knockdown of ITGB4 partially reduced cell invading/migrating ability induced by MPS-1 overexpression. Moreover, MPS-1 and ITGB4 expressions are positively correlated in gastric cancer cell lines and tissues. Finally, the survival analyses show that the expression of MPS-1 and ITGB4 is associated with poor outcomes in gastric cancer patients. Collectively, our findings suggest that MPS-1 regulates cell invasiveness and migration partially through ITGB4 and that MPS-1/ITGB4 signaling axis may serve as therapeutic targets in the treatment of gastric cancer.

Objective: To explore the molecular mechanism of miR-124 suppressing the proliferation and invasion of gastric cancer cells., Methods: SPHK1 3'UTR-luciferase vector was constructed and luciferase reporter gene assay was employed to examine the effect of miR-124 on luciferase activity. Human gastric cancer MGC-803 cells were transfected with miR-124 mimics, and then Western blot was performed to detect the expression of SPHK1 protein., Results: Luciferase reporter vector system confirmed that SPHK1 was a target gene of miR-124. Western blot showed that the expression of SPHK1 protein was inhibited by miR-124. After transfection of miR-124 mimics or SPHK1 siRNA for 12 h, 24 h and 48 h, respectively, MTT assay showed that the A values of the three groups were significantly different (P < 0.05), and it was in a time-dependent manner. After transfection of miR-124 mimics or SPHK1 siRNA for 24 h, transwell invasion assay showed that the number of transmembrane cells was 54.6 ± 8.3 in the SPHK1 siRNA group and 47.8 ± 6.6 in the miR-124 mimics group, both were significantly lower than 100.6 ± 11.3 of the control group (P < 0.05), indicating that SPHK1 siRNA can slow down the invasion of MGC-803 cells., Conclusion: miR-124 can suppress the cell proliferation and invasion by targeting SPHK1 in gastric carcinoma.

This study aims to investigate the expression and significance of KPNA2 in human gastric adenocarcinoma progression and prognosis. Using immunohistochemistry and real-time reverse transcriptase polymerase chain reaction assay, we identified abnormally elevated expression of KPNA2 in gastric adenocarcinoma tissues compared to paired normal stomach mucosa tissues in 30 patients (p < 0.05). In order to investigate the correlations between KPNA2 and the clinicopathological features of gastric adenocarcinoma, the expression of KPNA2 in 142 patients with gastric adenocarcinoma was detected by immunohistochemistry, and the results showed that overexpression of KPNA2 was associated with the size of tumor (p < 0.001), histological grade (p < 0.001), lymph node involvement (p = 0.001), and tumor node metastasis stage (p < 0.001). Kaplan-Meier survival analysis showed that patients with high KPNA2 expression showed a significantly shorter overall survival time compared with patients with low KPNA2 expression. Multivariate analysis suggested that KPNA2 expression might be an independent prognostic indicator (p < 0.001) for the survival of patients with gastric adenocarcinoma. In conclusion, overexpression of KPNA2 is closely related to progression of gastric adenocarcinoma and might be regarded as an independent predictor of poor prognosis for gastric adenocarcinoma.

Single-nucleotide polymorphisms (SNPs) of adiponectin (ADIPOQ), adiponectin receptor 1 (ADIPOR1) and ADIPOR2 genes contribute to the risk and progression of cancers. Here, we investigated the associations between variants of these three genes and the risk of gastric cancer. We genotyped six ADIPOQ SNPs, nine ADIPOR1 SNPs and six ADIPOR2 SNPs using the Sequenom technique in a hospital-based case-control study of patients with gastric cancer and cancer-free controls in the Chinese Han population. We found associations of certain variants with location of gastric cancer. Rs16861205 with the minor allele A in ADIPOQ, rs10773989 with the minor allele C and rs1044471 with the minor allele T in ADIPOR2 presented significant associations with a decreased risk of cardia cancer (P = 0.024, OR 0.605, 95 % CI 0.390-0.938; P = 0.015, OR 0.699, 95 % CI 0.522-0.935; and P = 0.022, OR = 0.703, 95 % CI 0.519-0.951, respectively). ADIPOQ rs16861205 with minor allele A displayed an association with an increased risk of body cancer (P = 0.010, OR 1.821, 95 % CI 1.148-2.890). Further stratified analysis of the patients indicated that there were significant correlations for rs1342387A/G (P = 0.027) and rs16861205A/G (P = 0.000) with tumor location; rs16850799A/G (P = 0.004) and rs2058033C/A (P = 0.003) with invasion depth; rs16850799A/G (P = 0.019) with the tumor-node-metastasis stage; rs16850799A/G (P = 0.016), rs1501299A/C (P = 0.005) and rs1063538C/T (P = 0.017) with alcohol consumption; rs11612414A/G (P = 0.040) and rs12733285T/C (P = 0.005) with salted food; rs1063538C/T (P = 0.043) with family history of gastric cancer; and rs11612414A/G (P = 0.029) with gender. Adiponectin expression significantly correlated with gender (P = 0.014), alcohol consumption (P = 0.037), family history (P = 0.019) and invasion depth of primary tumor (P = 0.024). Our data suggested that variants of ADIPOQ may be genetic markers conferring susceptibility to gastric cancer subtypes. These findings need to be validated in a larger panel of samples from distinct populations.

We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association.

Methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with DNA methylation, an epigenetic feature frequently found in gastric cancer. We conducted a case-control study to explore the association of MTHFR C677T polymorphisms with gastric cancer risk and its relation with the DNA methylation of COX-2, MGMT, and hMLH1 genes. Genotyping of P16, MGMT and HMLH1 was determined by methylation-specific PCR after sodium bisulfate modification of DNA, and genotyping of MTHFR C677T was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. Folate intake was calculated with the aid of a questionnaire. Compared with the MTHFR 677CC genotype, the TT genotype was significantly associated with 2.08 fold risk of gastric cancer when adjusting for potential risk factors. Individuals who had an intake of folate above 310 μg/day showed protective effects against gastric cancer risk. The effect of MTHFR C677T polymorphisms on the risk of gastric cancer was modified by folate intake and methylation status of MGMT (P for interaction <0.05).

Human Hox genes (Homeobox) have crucial roles in development and differentiation, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrant expression of Hoxc6 gene has been reported in several tumor tissues and cancer cell lines. The prognostic significance of Hoxc6 in gastric cancer remains largely unknown.This study was aimed to investigate the clinical significance of Hoxc6 in gastric cancer.Total RNA of paired tissue samples (n=25) and a tissue microarray containing 161 paired tissues from patients with gastric cancers at different stages were collected. Quantitative real-time PCR and immunochemistry assay were carried out to investigate the expression of Hoxc6. Hoxc6 mRNA was increased in gastric cancer tissues ( 16 of 25) compared with the adjacent normal mucosa (P<0.05). Immunohistochemical detection showed that expression of Hoxc6 was associated with the depth of tumor invasion (P<0.05). Patients with higher expression levels of Hoxc6 had a shorter overall survival rate (P<0.05).Hoxc6 might contribute to the progression of gastric carcinogenesis and may be a significant predictor of poor survival in patients with gastric cancer after curative operations.

The ribosomal protein S27 (metallopanstimulin-1, MPS-1) has been reported to be a multifunctional protein, with increased expression in a number of cancers. We reported previously that MPS-1 was highly expressed in human gastric cancer. Knockdown of MPS-1 led to spontaneous apoptosis and repressed proliferation of human gastric cancer cells in vitro and in vivo. However, how does MPS-1 regulate these processes is unclear. Here we performed microarray and pathway analyses to investigate possible pathways involved in MPS-1 knockdown-induced apoptosis in gastric cancer cells. Our results showed that knockdown of MPS-1 inhibited NF-κB activity by reducing phosphorylation of p65 at Ser536 and IκBα at Ser32, inhibiting NF-κB nuclear translocation, and down-regulating its DNA binding activity. Furthermore, data-mining the Gene-Regulatory-Network revealed that growth arrest DNA damage inducible gene 45β (Gadd45β), a direct NF-κB target gene, played a critical role in MPS-1 knockdown-induced apoptosis. Over-expression of Gadd45β inhibited MPS-1 knockdown-induced apoptosis via inhibition of JNK phosphorylation. Taken together, these data revealed a novel pathway, the MPS-1/NF-κB/Gadd45β signal pathway, played an important role in MPS-1 knockdown-induced apoptosis of gastric cancer cells. This study sheds new light on the role of MPS-1/NF-κB in apoptosis and the possible use of MPS-1 targeting strategy in the treatment of gastric cancer., (Copyright © 2011 UICC.)

Aim: We conducted a prospective study in an Chinese population to detect the association between GSTM, GSTT and GSTP gene polymorphisms and survival of gastric cancer., Methods: A prospective follow-up study with 317 gastric cancer patients was conducted between January 2003 and January 2005. GSTM1, GSTT1 and GSTP1 genotyping was performed using ABI TaqMan Gene Expression assays., Results: Of 317 patients, 5 were lost to follow-up due to migration, while the remaining 302 patients completed the study. The median follow-up time was 34.2 months (range: 2 to 60 months), during which a total of 120 (39.1%) died of gastric cancer. The GSTT1-null genotype showed a significant increased risk of death from gastric cancer, with an HR (95% CI) of 1.59 (1.04-3.58). Moreover, we found individuals carrying null-GSTM1 and null-GSTT1 had a moderate higher risk of death from gastric cancer, with an HR of 1.92 (1.05-3.65)., Conclusion: This study reported the carriage of null GSTT1 and null GSTM1 might be linked to the higher death risk from gastric cancer in Chinese population.

Aim: To prepare PHF10 antibody and check the expression of PHF10 protein in the tissues of gastric cancer and adjacent tissue., Methods: His-tagged PHF10 was expressed in E.coli BL21. Rabbit PHF10 polyclonal antiserum was generated by injecting the purified recombinant His-tagged PHF10 inclusion body as the antigen, and further separated by affinity purification. To confirm the specificity of the PHF10 antibody, transiently expressed Flag-PHF10 fusion protein was analyzed by immunoblotting with anti-flag monoclonal antibody control. The produced antibody Was used to check the expression of PHF10 protein in gastric cancer and adjacent tissues by Western blot., Results: Antibodies specifically binding to PHF10 could be obtained by immunization, and expression of PHF10 was significantly higher in gastric cancerous tissues comparing with adjacent normal tissues and GES-1 shows more PHF10 expression than gastric cancer cell lines with the generated antibody., Conclusion: The specific anti-PHF10 antibody is obtained and it could be used to detect the expression of PHF10 protein in gastric cancer cell lines and tissues, in which PHF10 is unregulated in gastric cancer.

Integrins play an important role in tumor metastasis induced by vascular endothelial growth factor (VEGF). However, in the case of gastric cancer, the precise role of VEGF in regulating integrin alphavbeta6 is unclear. In this study, we found that most of the alphavbeta6 integrin-positive gastric cancer tissues were also VEGF-positive. Furthermore, when gastric carcinoma cells were exposed to VEGF, expression of alphavbeta6 integrin was up-regulated and the extracellular signal-related kinase (ERK) pathway was activated. When integrin alphavbeta6 was blocked either with beta6 siRNA or anti-alphavbeta6 antibody, the migration of tumor cells normally induced by VEGF, as well as the activation of ERK, were markedly inhibited. Blocking the ERK signaling pathway significantly inhibited cell mobility. Taken together, the data suggest that VEGF is critical to the invasive process in human gastric cancer and that this occurs via up-regulation of integrin alphavbeta6 expression and activation of ERK., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: To explore the impact of anti-cancer bioactive peptide-S (ACBP-S) on cell proliferation, cell cycle and apoptosis in human stomach cancer cell line MGC-803 cells., Methods: (1) The cultured MGC-803 cells were treated with ACBP-S at various concentrations for 24, 48, 72 h, respectively. The inhibition rate of proliferation of MGC-803 cells were evaluated by MTT assay. Cell apoptosis was observed by transmission electron microscopy. Cell cycle and apoptosis were analyzed by flow cytometry (FCM). RT-PCR was used to assay the changes of p27 mRNA expression. Immunocytochemistry was used to detect the changes of expression of p27, PCNA, Bax, Bcl-2 proteins, respectively. (2) a nude mouse xenograft model with gastric carcinoma cell was established. ACPB-S was administered into the tail vein of the mice in a dose of 7 microg, every other day, and the mice were killed after two weeks. The tumors were taken off for further analysis., Results: (1) ACBP-S at concentrations of 5.0, 10.0 and 15.0 microg/ml inhibit the growth of MGC-803 cells in a concentration- and time-dependent manner. The concentration of ACBP-S at 20.0 microg/ml showed an inhibition rate of (86.6 + 0.1)%. Typical apoptotic changes were observed under the transmission electron microscope. The result of FCM in the range of 5.0 and 20.0 microg/ml for 24 h showed higher early apoptosis rates, (5.7 +/- 0.2)% and (13.9 +/- 0.6)%, respectively, with s significant difference compared with that of the control group (P < 0.05). The ratio of G0/G1 was significantly increased with the increase of incubation time at 20 microg/ml. RT-PCR showed that the expression of p27 mRNA in MGC-803 cells was markedly increased after ACBP-S treatment. (2) After ACBP-S administration the tumor growth in nude mice was inhibited by 34.2%. More apoptotic and necrotic cells were observed in the mice of treatment group by histological examination with HE staining. The immunocytochemistry demonstrated that the expression of Bax protein was significantly increased and Bcl-2 and PCNA protein expressions were significantly decreased after ACBP-S treatment., Conclusion: ACBP-S has marked inhibiting effect upon the growth of MGC-803 cells inducing more apoptosis. The anti-cancer mechanism is probably related with its regulatory effects on cell cycle and apoptosis in the tumor cells.

Diallyl disulfide (DADS) is a major constituent of garlic. Previously, we found that DADS both inhibited proliferation in human gastric cancer cells in vitro and in vivo, and induced G2/M arrest. In this study, we investigated whether this differentiation effect was induced by DADS in human gastric cancer MGC803 cells, and whether it was related to an alteration in ERK activity. The results showed that the growth of MGC803 cells was inhibited by DADS. Cells treated with DADS displayed a lower nucleocytoplasmic ratio and tended to form gland and intercellular conjunction structures. The ConA-mediated cell agglutination ratio and cells' ALP specific activity decreased. In MGC803 cells, dye transfer was limited to a few cells neighbouring the dye-injected cell and to a depth of 1-2 layers beneath the scrape site. However, after treatment with DADS, the LY (Lucifer Yellow) was transferred to several cells immediately neighbouring the microinjected cell and to a depth of 2-4 cell layers from the scrape site. This indicated that DADS induced differentiation in MGC803 cells. Western blot analysis revealed that although DADS did not influence the quantity of ERK1/2 protein expressed, it did decrease its phosphorylation in a concentration-dependent manner, compared with the controls. At 30 mg x L(-1), DADS inhibited the activation of ERK1/2 in 15-30 min. These results suggested that the DADS-induced differentiation of MGC803 cells involved an alteration of the ERK1/2 signaling pathway.

Objectives: To study the changes of duodenal ulcer, gastric ulcer, gastric cancer and Helicobacter pylori (Hp) infectious status, according to the clinical data of endoscopy in our hospital during the past 25 years., Methods: The patients with duodenal ulcer, gastric ulcer and gastric cancer diagnosed by endoscopy and pathology had been selected, 104 987 general endoscope cases during the period from Jan. 1980 to Dec. 2004. The general cases were divided into 8 age groups as follows: 10-< 20 years old, 20-< 30 years old, 30-< 40 years old, 40-< 50 years old, 50-< 60 years old, 60-< 70 years old, 70-< 80 years old and > or = 80 years old., Results: The average detected rate of duodenal ulcer, gastric ulcer, and gastric cancer are 13.03%, 4.19% and 1.68% respectively. The detected rate of gastric ulcer was decreased after 1996. The detected rate of duodenal ulcer was decreased after 1999. The gastric cancer detected rate fluctuate between 1.02% and 2.36%. The average ages of duodenal ulcer, gastric ulcer and gastric cancer are 41.8, 50.7 and 59.4 respectively. The tendency of average age shows ascendant. In all patients, the detected rate of Hp showed slightly descendent after 1999., Conclusions: The diagnostic age of duodenal ulcer, gastric ulcer and gastric cancer shows ascendant tendency; The detected rates of duodenal ulcer, gastric ulcer show descendent tendency; There is no apparent change in the detected rate of gastric cancer. The Hp detected rate shows descendent tendency slightly.