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Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the “gastrome”). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery. (Cancer Res 2006; 66(1): 232-41)

Exosomes secreted by living cancer cells can regulate metastasis. Exosomal miRNAs can reflect pathological conditions of the original cancer cells. Therefore, we aim to identify exosomal miRNAs as circulating biomarkers for haematogenous metastasis of gastric cancer. Pre‐treatment serum samples of eighty‐nine patients with stage II/III gastric cancer were collected. Thirty‐four of them developed haematogenous metastasis after surgery and the other fifty‐five did not. Extraction of exosomes was validated by western blot, transmission electron microscopy and nanoparticle tracking analysis. MiRNA qPCR array was performed in three matched pairs of samples. Internal control was selected from PCR array and validated in the remaining samples. Expressions of exosomal miRNAs were evaluated in the remaining samples by RT‐qPCR, as well as in gastric cancer tissue samples and cell culture medium. Expression levels of exosomal miRNAs were analysed with clinical characteristics. The results indicated thirteen up‐regulated and six down‐regulated miRNAs were found after normalization. MiR‐379‐5p and miR‐410‐3p were significantly up‐regulated in metastatic patients (P

Background Educational pedagogies were modified during the COVID-19 pandemic to minimise interruption to teaching. One approach has been the distance learning problem-based learning (PBL) tutorial utilising the online peer-to-peer platform. The aim of this study was to compare the performance of students using distance learning PBL tutorials using with that of students utilising the conventional face-to-face approach. Methods This retrospective study was conducted in a single academic institution. We compared two groups of fourth-year medical students from the same class: one group used distance learning (DL); the other, the face-to-face (FF) method. We used students’ baseline performance at the preceding block for one-to-one propensity score matching. Students utilising the PBL tutorial were given grades by their tutors according to a standardised scoring system encompassing five key areas (score range: 0–10). The main outcome was a student’s total score (i.e., the sum of the scores from the five key areas, ranging from 0 to 50). Result We matched 62 students in each group. With four tutorials, there were 490 observations, with 245 in each group. The mean total score for the DL group was 37.5 ± 4.6, which was significantly lower than that of the FF group (39.0 ± 4.4, p Conclusion Findings of this study revealed that the performance of students utilising the DL PBL tutorials was lower than that of students participating in the conventional FF approach. Further studies are needed to ascertain the underlying cause.

Purpose Medical education has been disrupted by the COVID-19 pandemic in many countries, with face-to-face lectures replaced by pre-recorded videos. However, surgical skills training cannot be replaced easily by videos, as a high level of tutor–student interaction is required. Thus, we developed a new web-based surgical skill learning session (WSSL). This case–control study evaluates the surgical skills competency of medical students taught by the WSSL. Methods This case–control study compares WSSL with face-to-face tutorials. Students were assigned randomly to one of two groups according to the teaching method. Independent blinded assessment was performed by a standardized marking scheme, modified from the Objective Structured Assessment of Technical Skills (OSATS) global rating scale. Results We recruited 62 final-year medical students into the study, with 33 randomized to the face-to-face teaching group (control group), and 29 to the WSSL group(case group) according to their student number. The baseline demographic characteristics of the two groups were comparable. The mean score at the clinical competency assessment of the control group was 4.8/5 (range 4–5) and that of the case group was 4.7/5 (range 4–5) (p = 1). There were no difficulties with program or hardware installation reported by the WSSL students. Conclusions Surgical skills performance was comparable between students who were taught by the WSSL and those taught by conventional face-to-face tutorials.

Introduction Due to the COVID‐19 outbreak, all on‐site undergraduate medical teaching activities in Hong Kong have been suspended. A new web‐based surgical skills learning (WSSL) for basic surgical skills training that were normally taught face‐to‐face was developed. Methodology Basic surgical skills were taught with normal face‐to‐face tutorial to 30 final year medical students prior to the outbreak. The same group of students were invited to join the online WSSL using Zoom. Evaluation of WSSL was performed by a standardized questionnaire. Results Thirty final year medical students (16 female, 14 male students) were recruited into the study. Median age was 23 (range 22‐24). Most of them believed that WSSL is easy to follow. When compared to face‐to‐face teaching. Most students (N = 22, 73.4%) felt that WSSL was just as difficult/easy as conventional teaching for learning instrumental knots. Students were asked to evaluate WSSL by using a Likert scale of 1 to 10 (with 10 being highly recommended). Twelve (40%) students highly recommended WSSL (Score 9 to 10), 15 students (50%) slightly recommended WSSL (Score 6‐8). Conclusion Web‐based surgical skills learning is a feasible alternative for face‐to‐face surgical skills teaching.

Human epidermal growth factor receptor 2 (HER2) dysregulation is associated with tumorigenesis in gastric/gastroesophageal junction cancer; however, the number of patients with HER2-positive disease is unclear, possibly due to differing scoring criteria/assays. Data are also lacking for early disease. We aimed to assess the HER2-positivity rate using approved testing criteria in a large, real-life multinational population. HER2-positivity was defined as an immunohistochemistry staining score of 3+, or immunohistochemistry 2+ and HER2 amplification detected by in situ hybridization. A total of 4949 patients were enrolled and results showed that 14.2% of 4920 samples with immunohistochemistry results were HER2-positive. HER2-positivity was significantly higher in males (16.1% vs. 9.6% in females), in gastroesophageal versus stomach tumors (22.1% vs. 12.9%), in biopsy versus surgical samples (18.3% vs. 13.0%), in intestinal tumor subtypes versus diffuse (21.5% vs. 4.8%) and mixed types (21.5% vs. 8.5%) (P

Background: Progressive peritoneal fibrosis is a common complication in patients on long-term peritoneal dialysis (PD). PD-associated peritonitis is a major exacerbating factor. We investigated the anti-fibrotic properties of decorin secreted by peritoneal mesothelial cells. Methods: Dialysate decorin level in stable PD patients and those with peritonitis was measured. In vitro experiments were conducted to investigate the effect of decorin in fibrotic response in human peritoneal mesothelial cells (HPMC). Findings: Increasing PD duration was associated with a progressive decrease of dialysate decorin and CA125 levels. Dialysate decorin level correlated with CA125 level. Peritonitis episodes were associated with a massive drop of dialysate decorin, which persisted for over three months despite clinical recovery. Dialysate decorin level correlated with that of TGF-β1, but was inversely related to IL-1β and IL-8. TGF-β1, IL-1β, IL-6, IL-8, or TNF-α reduced decorin secretion in HPMC, but induced fibronectin expression. The effects were mediated in part through increased p38 MAPK and AKT/PI3K phosphorylation. Decorin abrogated the induction of fibronectin expression in mesothelial cells by PD fluids or pro-fibrotic cytokines, through decreased TGF-βRI, p38 MAPK and AKT/PI3K phosphorylation and increased glycogen synthase kinase-3β phosphorylation. Decorin gene-silencing resulted in increased fibronectin expression under these conditions. Interpretation: Our data demonstrate anti-fibrotic actions of decorin in HPMC, when these cells are subjected to the pro-fibrotic effect of peritoneal dialysate and pro-fibrotic cytokines in PD, especially during peritonitis. Keywords: Peritoneal dialysis, Peritonitis, Decorin, Inflammation, Fibrosis, Mesothelial cells

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, the development of molecular markers, especially circulating biomarkers, remains largely undone for the prognosis of GIST. We discussed the clinical-pathological characteristics of GIST and identified potential biomarkers for guidance of therapy and prognosis of GIST. Around 90% of GISTs contain mutations in KIT or PDGFRA and the remaining 10% of GISTs are wild-type. Recent studies have indicated that various DNAs and miRNAs could serve as potential biomarkers for prognosis of GIST, including KIT, PDGFRA, other DNAs (such as BRAF, SDH, SETD2 and ROR2), and microRNAs (miRNAs). The pressing need and challenges in the development of circulating prognostic biomarkers for GIST are also discussed. Although challenges remain, DNAs and miRNAs are promising circulating biomarkers for surveillance and prognosis of GIST. Advances in clarification of aberrant molecular alterations may open new avenues for exploration of reliable and robust biomarkers to improve the management of GIST.

Early surgical intervention was previously advocated in patients > 60 years with bleeding peptic ulcer presenting with haemodynamic instability or ongoing transfusion requirements. It is, however, well recognized that emergency surgical intervention with its inherent risks must be reserved for highly selected patients in whom endoscopy initially fails to control exsanquinating haemorrhage or in whom life-threatening bleeding recurs. Therapeutic endoscopy for bleeding ulcer has led to a remarkable decline in rebleeding rates, the need for emergency surgery and mortality. Octogenarians are at risk, particularly when ulcer size exceeds 2 cm. Poor surgical candidates make up two-thirds of patients with major ulcer bleeding and operation is to be avoided if at all possible. Medical therapy with proton pump inhibitor and subsequent eradication of Helicobacter pylori following endoscopic treatment has been shown to be beneficial to outcomes. Should surgery be deemed necessary, it is likely that laparoscopic techniques to control bleeding, with or without the addition of an acid-reducing procedure, will find a role in haemodynamically stable patients undergoing operation on an early elective basis.

The role of bacteria other than Helicobacter pylori (HP) in the stomach remains elusive. We characterized the gastric microbiota in individuals with different histological stages of gastric carcinogenesis and after receiving HP eradication therapy. Endoscopic gastric biopsies were obtained from subjects with HP gastritis, gastric intestinal metaplasia (IM), gastric cancer (GC) and HP negative controls. Gastric microbiota was characterized by Illumina MiSeq platform targeting the 16 S rDNA. Apart from dominant H. pylori, we observed other Proteobacteria including Haemophilus, Serratia, Neisseria and Stenotrophomonas as the major components of the human gastric microbiota. Although samples were largely converged according to the relative abundance of HP, a clear separation of GC and other samples was recovered. Whilst there was a strong inverse association between HP relative abundance and bacterial diversity, this association was weak in GC samples which tended to have lower bacterial diversity compared with other samples with similar HP levels. Eradication of HP resulted in an increase in bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to individuals without HP. In conclusion, HP colonization results in alterations of gastric microbiota and reduction in bacterial diversity, which could be restored by antibiotic treatment.

Background: Metastasis is the fatal character of cancer, leading to mortality of gastric cancer. In recent years, exosomes have been reported as extracellular vesicles secreted by cells. They contain various biological molecules including miRNAs from the original cells. Exosomal miRNAs are significant for pre-metastatic niche formation, as they can change the microenvironment and make it favorable for future metastasis. Therefore, the aim of this study was to identify dysregulated exosomal miRNAs as circulating biomarkers for prediction of metastasis of gastric cancer. Materials and Methods: Pre-treatment serum samples of 36 metastatic patients and 55 non-metastatic patients with stage II/III gastric cancer were collected. Exosomes were extracted and validated by western blot, transmission electron microscope and nanoparticle tracking analysis. MiRCURY LNATM miRNA miRNome PCR Array (containing 752 miRNAs) was performed in three pairs of serum exosomes. Each pair samples were with the same stage, race, gender and similar age. These three pairs of samples represented stage II, IIIA or IIIB gastric cancer, respectively. A panel of commonly dysregulated exosomal miRNAs was released from the PCR Array. Expressions of exosomal miRNAs were validated in the remaining 33 metastatic and 52 non-metastatic patients by RT-qPCR, as well as in gastric cancer cell culture medium and cell lines. Results: By comparing the expressions of exosomal miRNAs between the metastatic patients and matched non-metastatic ones, 13 upregulated and 6 downregulated miRNAs were released after normalization with miR-16-5p and miR-93-5p. Among these miRNAs, 7 of them were selected for further validation according to their fold changes, p-values and association with cancer development. MiR-379-5p and miR-410-3p were validated to be significantly upregulated in metastatic patients (P Conclusions: Exosomal miRNAs are dysregulated in the serum of metastatic gastric cancer patients before they are clinically diagnosed. Upregulation of serum exosomal miR-379-5p and/or miR-410-3p are promising circulating biomarkers for prediction of metastasis in stage II/III gastric cancer. Citation Format: Xin Liu, Kent-Man Chu. Exosomal miRNAs as circulating biomarkers for prediction of metastasis in stage II/III gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2765.

Patients with gastric intestinal metaplasia and dysplasia are at increased risk of gastric cancer development. We tested the feasibility of using endoscopic radiofrequency ablation for the treatment of dysplasia and metaplasia in the stomach.Patients who had histologically confirmed low-grade gastric dysplasia or IM were recruited. Endoscopic RFA was performed at 8 week-intervals for a maximum of 3 sessions. All patients were followed up by endoscopy until 12 months post-RFA. The primary outcome was the complete eradication of dysplasia or IM on follow-up. Secondary outcome was adverse events related to RFA.A total of 12 patients were recruited. Four patients had low-grade dysplasia and the remaining 8 patients had non-dysplastic IM at baseline. At one year after RFA, complete eradication of dysplasia was noted in four patients with low-grade dysplasia (100%). Gastric IM persisted in all patients with baseline metaplasia but the severity of IM improved in 6 (75%) patients. Endoscopic RFA was safe with minimal complications encountered.RFA successfully eradicated low-grade dysplasia of the stomach. Gastric IM however persisted after RFA but most patients had evidence of histological improvement on follow up.

Cigarette smoke has always been the single most preventive cause of death in the world. In 2011, over 460,000 died from cigarette smoke-related diseases in US. The detrimental effects of cigarette smoke on human beings are due to the presence of many carcinogens and other components (e.g. nicotine and tar). Nicotine is now accepted as one of the major components responsible for gastrointestinal disorders. Cigarette smoking, nicotine and a nicotine-derived nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered as risk factors for gastrointestinal cancer, however, the underlying mechanism remains largely unknown. Previous studies reported that cigarette smoke and nicotine aggravated inflammation not only in the stomach, but also in the colon. The carcinogenic actions of cigarette smoke, nicotine and NNK on gastrointestinal cancers development have been widely studied. The strong association of cyclooxygenase-2 (COX-2) with gastrointestinal diseases has been extensively studied, however, due to the unresolved cardiovascular risk, it is of great importance to develop other new anti-cancer drugs for the treatment of cancers. This current review aims to provide an overview of the effects of cigarette smoke, nicotine and NNK on gastrointestinal inflammation, and also the carcinogenic properties in cancer development (tumor growth, angiogenesis and epithelial-mesenchymal transition). In addition, current studies on nicotinic acetylcholine receptors, adrenergic receptors and miRNAs in nicotine-related cancer pathogenesis are also highlighted.

Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.

Aims Stress has been implicated in the development of cancers. Adrenaline levels are increased in response to stress. The effects of adrenaline on colon cancer are largely unknown. The aims of the study are to determine the effects of adrenaline in human colon adenocarcinoma HT-29 cells and the possible underlying mechanisms involved. Main methods The effect of adrenaline on HT-29 cell proliferation was determined by [3H] thymidine incorporation assay. Expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) were detected by Western blot. Matrix metalloproteinase-9 (MMP-9) activity and prostaglandin E2 (PGE2) release were determined by zymography and enzyme immunoassay, respectively. Key findings Adrenaline stimulated HT-29 cell proliferation. This was accompanied by the enhanced expression of COX-2 and VEGF in HT-29 cells. Adrenaline also upregulated MMP-9 activity and PGE2 release. Adrenaline stimulated HT-29 cell proliferation which was reversed by COX-2 inhibitor sc-236. COX-2 inhibitor also reverted the action of adrenaline on VEGF expression and MMP-9 activity. Further study was performed to determine the involvement of β-adrenoceptors. The stimulatory action of adrenaline on colon cancer growth was blocked by atenolol and ICI 118,551, a β1- and β2-selective antagonist, respectively. This signified the role of β-adrenoceptors in this process. In addition, both antagonists also abrogated the stimulating actions of adrenaline on COX-2, VEGF expression, MMP-9 activity and PGE2 release in HT-29 cells. Significance These results suggest that adrenaline stimulates cell proliferation of HT-29 cells via both β1- and β2-adrenoceptors by a COX-2 dependent pathway.

Cigarette smoke is one of the risk factors for gastric cancer and nicotine has been reported to promote tumor growth. Deregulation ofmicroRNA (miRNA) and cyclooxygenase-2 (COX-2) expressions are hallmarks of many cancers including gastric cancer. Here, we used an miRNA array platform covering a panel of 95 human miRNAs to examine the expression profile in nicotine-treated gastric cancer cells. We found that miR-16 and miR-21 were upregulated upon nicotine stimulation, transfection with anti-miR-16 or anti-miR-21 significantly abrogated cell proliferation. In contrast, ectopic miR-16 or miR-21 expression exhibited a similar stimulatory effect on cell proliferation as nicotine. Nicotine-mediated IkappaBα degradation and nuclear factor-kappa B (NF-κB) translocation dose-dependently. Knockdown of NF-κB by short interfering RNA (siRNA) or specific inhibitor (Bay-11-7085) markedly suppressed nicotine-induced cell proliferation and upregulation of miR-16 and miR-21. Interestingly, NF-κB-binding sites were located in both miR-16 and miR-21 gene transcriptional elements and we showed that nicotine enhanced the binding of NF-κB to the promoters of miR-16 and miR-21. Furthermore, activation of COX-2/prostagiandin E 2 (PGE 2 ) signaling in response to nicotine was mediated by the action of prostaglandin E receptors (EP2 and EP4). EP2 or EP4 siRNA or antagonists impaired the nicotine-mediated NF-κB activity, upregulation of miR-16 and miR-21 and cell proliferation. Taken together, these results suggest that miR-16 and miR-21 are directly regulated by the transcription factor NF-κB and yet nicotine-promoted cell proliferation is mediated via EP2/4 receptors. Perhaps this study may shed light on the development of anticancer drugs to improve the chemosensitivity in smokers.

Background: Recent studies have suggested the eradication rate for Helicobacter pylori infection with standard amoxycillin–clarithromycin-containing triple therapy as first-line treatment have fallen below 80%. Levofloxacin-containing triple therapy was proposed as an alternative. The aim of this study is to compare the efficacy and tolerability of the standard 7-day clarithromycin-containing triple therapy against the 7-day levofloxacin-containing triple therapy, and to assess whether the classical triple therapy is still valid as empirical first-line treatment for H. pylori infection in Hong Kong. Methods: Three hundred consecutive H. pylori-positive patients were randomized to receive either 1 week of EAL (esomeprazole 20 mg b.d., amoxycillin 1 g b.d., and levofloxacin 500 mg daily) or EAC (esomeprazole 20 mg b.d., amoxycillin 1 g b.d., and clarithromycin 500 mg b.d.). H. pylori status was rechecked by 13C-urea breath test 6 weeks after treatment. Patients who failed either of the first-line eradication therapy were invited to undergo H. pylori susceptibility testing. Results: H. pylori eradication was achieved in 128 of 150 (85.3%) patients in EAL and 139 of 150 (92.7%) patients in EAC groups, respectively (p = .043), for both intention-to-treat and per-protocol analysis. More patients in the clarithromycin- than the levofloxacin-containing therapy group developed side effects from the medication (21.3% vs 13.3%, p = .060). Nine patients (six from the EAL group and three from the EAC group) who failed their corresponding eradication therapy returned for susceptibility testing. All nine isolates were highly resistant to levofloxacin (minimum inhibitory concentration or MIC > 32 μg/mL), whereas only two of the six isolates from the EAL group were resistant to clarithromycin (MIC > 0.5 μg/mL). Conclusions: The standard 7-day clarithromycin-containing triple therapy is still valid as the most effective empirical first-line eradication therapy for H. pylori infection in Hong Kong, as prevalence of primary resistance of H. pylori to amoxycillin and clarithromycin remains low. Patients who failed their empirical first-line eradication therapy should undergo H. pylori susceptibility testing to guide further treatment.

This is a review on the current status of capsule endoscopy in the assessment of patients with gastrointestinal bleeding of obscure origin after initial negative upper endoscopy and colonoscopy. Relevant information was gathered from a Medline search of the English literature, previous review and original articles, references cited in papers, and by checking the latest issues of appropriate journals. Based on the available evidence, capsule endoscopy, if done early in the course of investigation, can identify a bleeding lesion and thus direct subsequent test or treatment in about 60% of patients. Consequently, resources can potentially be saved as unnecessary investigations, blood transfusions and hospital admissions can be minimized and early implementation of definite treatments will be possible. The best candidates for capsule endoscopy are those with ongoing overt obscure bleeding or occult obscure bleeding. Large prospective studies are necessary to assess the impact of capsule endoscopy on clinical outcome.

Summary Background The efficacy of levofloxacin-based quadruple therapy in resistant Helicobacter pylori infection is not known. Aim To test the efficacy of levofloxacin-based quadruple therapy and traditional quadruple therapy in resistant H. pylori infection. Methods One hundred and two patients with resistant H. pylori infection were randomized to 1 week of either EBAL (esomeprazole 40 mg b.d., bismuth subcitrate 240 mg b.d., amoxicillin 1 g b.d. and levofloxacin 500 mg b.d.) or EBMT (esomeprazole 40 mg b.d., bismuth subcitrate 240 mg b.d., metronidazole 400 mg t.d.s. and tetracycline 500 mg q.d.s.). 13C-urea breath test was performed at week 12 to assess post-treatment H. pylori status. Results In intention-to-treat analysis H. pylori eradication was achieved in 37 of 51 (73%) subjects in EBAL and 45 of 51 (88%) subjects in EBMT groups, respectively (P = 0.046). Per-protocol eradication rates of EBAL and EMBT groups were 78% and 94%, respectively (P = 0.030). The intention-to-treat eradication rate was statistically lower for EBAL than EMBT (56% vs. 90%, P = 0.013) among those who had failed more than one course of eradication therapy. Previous levofloxacin triple therapy did not affect the efficacy of either protocol significantly. Conclusions Levofloxacin-based quadruple therapy was inferior to traditional quadruple therapy for resistant H. pylori infection.

Objectives To review the short-term outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong. Design Historical cohort study. Setting All Hospital Authority hospitals in Hong Kong. Patients This was a multicentre retrospective study of all patients who underwent endoscopic resection of superficial upper gastro-intestinal lesions between January 2010 and June 2013 in all government-funded hospitals in Hong Kong. Main outcome measures Indication of the procedures, peri-procedural and procedural parameters, oncological outcomes, morbidity, and mortality. Results During the study period, 187 lesions in 168 patients were resected. Endoscopic mucosal resection was performed in 34 (18.2%) lesions and endoscopic submucosal dissection in 153 (81.8%) lesions. The mean size of the lesions was 2.6 (standard deviation, 1.8) cm. The 30-day morbidity rate was 14.4%, and perforations and severe bleeding occurred in 4.3% and 3.2% of the patients, respectively. Among patients who had dysplasia or carcinoma, R0 resection was achieved in 78% and the piecemeal resection rate was 11.8%. Lateral margin involvement was 14% and vertical margin involvement was 8%. Local recurrence occurred in 9% of patients and 15% had residual disease. The 2-year overall survival rate and disease-specific survival rate was 90.6% and 100%, respectively. Conclusion Endoscopic mucosal resection and endoscopic submucosal dissection were introduced in low-to-moderate-volume hospitals with acceptable morbidity rates. The short-term survival was excellent. However, other oncological outcomes were higher than those observed in high-volume centres and more secondary procedures were required.

It was reported that circulating microRNAs could be applied as non-invasive biomarkers for cancer monitoring. The purpose of this study was to identify plasma miRNA that may serve as a novel biomarker for gastric cancer and to evaluate its clinical application. MicroRNA profiles were generated from plasma samples of 5 patients with gastric cancer (GC) versus 5 healthy controls (HC). MicroRNA-940 (miR-940) was one of the most downregulated miRNAs with fold change of 0.164. It was revealed that the expression of miR-940 was downregulated in both the initial set (N = 30, P

We previously reported that nicotine promoted gastric cancer cell growth via upregulation of cyclooxygenase 2 (COX-2). In the present study, we further investigated whether beta-adrenoceptors, protein kinase C (PKC), and extracellular signal-regulated kinase-1/2 (ERK1/2) were involved in the modulation of COX-2 expression and cell proliferation by nicotine in AGS, a human gastric adenocarcinoma cell line. Results showed that nicotine dose dependently increased the phosphorylation of EKR1/2 and the expression of AP-1 subunits c-fos and c-jun. In this connection, the ERK1/2 inhibitor U0126 abrogated the upregulation of AP-1 and COX-2 as well as cell proliferation induced by nicotine. Moreover, nicotine induced the translocation of PKC-betaI from cytosol to membrane and increased the total levels of PKC expression. Inhibition of PKC by staurosporine attenuated nicotine-induced ERK1/2 phosphorylation and COX-2 expression. Furthermore, atenolol and ICI 118,551, a beta1- and beta2-adrenoceptor antagonist, respectively, reversed the stimulatory action of nicotine on the expression of PKC, ERK1/2 phosphorylation, and COX-2 together with cell proliferation. Collectively, these results suggest that nicotine stimulates gastric cancer cell growth through the activation of beta-adrenoceptors and the downstream PKC-betaI/ERK1/2/COX-2 pathway.

Background & Aims: The role of clopidogrel in patients at risk for gastrointestinal complications is uncertain, although it has been recommended for patients who have gastrointestinal intolerance to aspirin. We tested the hypothesis that clopidogrel is as effective as esomeprazole and aspirin in preventing recurrences of ulcer complications. Methods: This was a prospective, double-blind, randomized, controlled study of 170 patients who developed ulcer bleeding after the use of low-dose aspirin between November 2002 and January 2005. After healing of ulcers and eradication of Helicobacter pylori, if present, patients were assigned randomly to treatment with esomeprazole 20 mg/day and aspirin 100 mg/day (n = 86) or clopidogrel 75 mg/day (n = 84) for 52 weeks. The primary end point was recurrent ulcer complications. Results: During a median follow-up period of 52 weeks, no patient in the esomeprazole group, as compared with 9 patients in the clopidogrel group, developed recurrent ulcer complications. The cumulative incidences of recurrent ulcer complications were 0% in patients receiving esomeprazole and aspirin and 13.6% in patients receiving clopidogrel (absolute difference, 13.6%; 95% confidence interval for the difference, 6.3–20.9; log-rank test, P = .0019). Conclusions: The combination of esomeprazole and aspirin is superior to clopidogrel in preventing ulcer complications in patients who have a past history of aspirin-related peptic ulcer bleeding.

Background: Both serum IL-6 levels and CpG island methylation have been shown to have prognostic significance in gastric cancer, it was suggested that an important link existed between IL-6 and methylation of cancers. Aim: To investigate the prognostic value of IL-6 serum level and the association between serum IL-6 levels and CpG island methylation at p16, DAPK, MGMT and E-cadherin in patients with gastric cancer. Patients and Methods: Methylation status was assessed by MSP in 75 surgical specimens of gastric adenocarcinoma. IL-6 serum levels were measured by chemiluminescent enzyme immunoassay (CLEIA). Results: Methylation of p16, DAPK, MGMT, and E-cadherin were present in 53, 48, 32, and 59% of patients. Patients with tumors methylated at p16 and DAPK had lower serum levels of IL-6 compared to unmethylated tumors (1.8 vs. 4.8 pg/ml, p = 0.01 for p16; 1.5 vs. 6.2 pg/ml, p = 0.0001 for DAPK). But there was no difference with MGMT and E-cadherin methylation status. Serum IL-6 levels were also associated with TNM stage (p = 0.001), depth of tumor invasion (p = 0.002), lymphatic invasion (p = 0.01), vascular invasion (p = 0.008), metastasis (p = 0.002) and signet cell histology (p = 0.001). Conclusion: IL-6 is of prognostic value for patients of gastric cancer. Low serum IL-6 levels were associated with p16 or DAPK gene methylation in patients with gastric cancer.

Background & Aims: Epstein–Barr virus (EBV) infection has been associated with some cases of gastric cancer. Methods: We studied a case of early onset gastric adenocarcinoma after nonmyeloablative hematopoietic stem cell transplantation for myeloma in a 56-year-old man. Results: The development of gastric adenocarcinoma was preceded by severe graft-versus-host disease (GVHD) necessitating strong immunosuppression, which resulted in an intense reactivation of EBV infection. Three sequential gastric biopsy examinations performed at 100, 130, and 150 days after hematopoietic stem cell transplantation showed gastritis, dysplasia, and adenocarcinoma, respectively. There was no evidence of Helicobacter pylori infection. Quantitative polymerase chain reaction for circulating EBV showed a surge of EBV DNA peaking at the time of gastritis, followed by a gradual decrease afterward with adequate control of GVHD and tailing of immunosuppression. In situ hybridization for EBV-encoded early small RNA showed absence of EBV in the gastritis specimen, but the presence of EBV in the dysplastic and carcinoma specimens. Aberrant promoter methylation of E-cadherin was observed only in the carcinoma specimens, showing that infection with EBV preceded E-cadherin methylation. Conclusions: Mucosal damage caused by GVHD, immunosuppression, and EBV reactivation combined to lead to EBV infection of the gastric cells and initiation of carcinogenesis, suggesting this case to be a genuine EBV-related opportunistic malignancy post-transplantation. An interesting proposition is that this case also might reflect a compacted timeline of events in EBV-related gastric cancers developing in immunocompetent patients.

Purpose Selective cyclooxygenase-2 (COX-2) inhibitors cause significantly fewer peptic ulcers than conventional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at low risk or high risk for peptic ulcers. On the other hand, proton pump inhibitor co-therapy has also been shown to be effective in preventing relapse of peptic ulcers in high-risk patients using nonselective NSAIDs. We compared the efficacy of a selective COX-2 inhibitor with that of proton pump inhibitor co-therapy in the reduction in the incidence of ulcer relapse in patients with a history of NSAID-related peptic ulcers. Materials and methods For this study, we recruited 224 patients who developed ulcer complications after NSAID use. We excluded patients who required concomitant aspirin treatment and who had renal impairment. After healing of ulcers and eradication of Helicobacter pylori , patients were randomly assigned to treatment with celecoxib 200 mg daily (n = 120) or naproxen 750 mg daily and lansoprazole 30 mg daily (n = 122) for 24 weeks. The primary endpoint was recurrent ulcer complications. Results During a median follow-up of 24 weeks, 4 (3.7%, 95% confidence interval [CI] 0.0%-7.3%) patients in the celecoxib group, compared with 7 patients (6.3%, 95% CI 1.6%-11.1%) in the lansoprazole group, developed recurrent ulcer complications (absolute difference −2.6%; 95% CI for the difference −9.1%-3.7%). Celecoxib was statistically non-inferior to lansoprazole co-therapy in the prevention of recurrent ulcer complications. Concomitant illness (hazard ratio 4.72, 95% CI 1.24-18.18) and age 65 years or more (hazard ratio 18.52, 95% CI 2.26-142.86) were independent risk factors for ulcer recurrences. Significantly more patients receiving celecoxib (15.0%, 95% CI 9.7-22.5) developed dyspepsia than patients receiving lansoprazole (5.7%, 95% CI 2.8-11.4. P = .02). Conclusions Celecoxib was as effective as lansoprazole co-therapy in the prevention of recurrences of ulcer complications in subjects with a history of NSAID-related complicated peptic ulcers. However, celecoxib, similar to lansoprazole co-therapy, was still associated with a significant proportion of ulcer complication recurrences. In addition, more patients receiving celecoxib developed dyspepsia than patients receiving lansoprazole and naproxen.

BACKGROUND Currently, to the authors' knowledge, there is no serum marker to predict disease recurrence after patients undergo curative resection for gastric carcinoma. Previous reports have indicated that serum levels of soluble E-cadherin had prognostic value in these patients. The objective of the current study was to determine whether soluble E-cadherin levels could predict disease recurrence in patients with gastric carcinoma who underwent curative surgery. METHODS Sixty-nine patients who underwent curative surgery for gastric carcinoma after December 1997 were followed prospectively. Venous blood samples were collected preoperatively, 1 month after surgery, and every 3 months thereafter. The blood samples were assayed for soluble E-cadherin and for carcinoembryonic antigen (CEA) using commercial enzyme-linked immunosorbent assay kits. Receiver operating characteristic (ROC) curves were used to define a cut-off level of E-cadherin for the optimal sensitivity and specificity for predicting disease recurrence. RESULTS The median follow-up was 21 months for patients with recurrent disease (n = 17 patients) and 36 months for patients without recurrent disease (n = 52 patients; P = 0.007). The optimal cut-off level of E-cadherin was 10,000 ng/mL. The sensitivity for predicting prediction disease recurrence using this cut-off level at 3 months and at 6 months postsurgery was 47% and 59% respectively, which was significantly better compared with the sensitivity of CEA using the conventional cut-off level (6% at 3 months postsurgery and 6% at 6 months postsurgery; P = 0.004 and P < 0.0001, respectively). The median time between the elevated E-cadherin level and documented disease recurrence was 13 months (range, 3–20 months), compared with 4 months (range, 1–20 months) for CEA. CONCLUSIONS Serum soluble E-cadherin was a good marker for predicting disease recurrence in the first 3–6 months after surgery, with a median of 13 months before clinical recurrence. The use of this marker may allow time for vigilant surveillance and consideration of adjuvant therapy. Cancer 2005. © 2005 American Cancer Society.

Gastric adenocarcinoma is one of the most common cancers in Asian countries including China. Although its incidence rates in the West are lower than that in Asia, gastric cancer is still a major health problem worldwide, being second only to lung cancers in the number of deaths it causes. Helicobacter pylori infection has been identified as the major pathogen, but the detailed pathogenesis of gastric carcinoma remains elusive. Due to the lack of suitable and specific biomarkers for early detection, most cases of the disease are diagnosed at late stages and the survival rate is low. In this study, we used a proteomic approach to globally analyze the protein profiles of paired surgical specimens of primary gastric adenocarcinoma and nontumor mucosa aiming at identifying specific disease-associated proteins as potential clinical biomarkers and for carcinogenetic study. Compared to nontumor tissues, multiple protein alterations were found in tumor tissues. Some of these alterations involve variations in the expression of cytoskeleton proteins, including an increase in cytokeratin 8 and tropomyosin isoform and a decrease in cytokeratin 20. Co-up-regulations of heat-shock proteins and glycolytic enzymes were observed in tumor tissues, indicating self-protective efforts of cells and the growing energy requirement during malignant transformation. Diverse regulations also occurred with proteins involved in cell proliferation and differentiation, such as GMP reductase 2 and creatine kinase B, and proteins bearing potential tumor suppressor activities, including prohibitin and selenium binding protein 1. More interestingly, a human stomach-specific protein, 18 kDa antrum mucosa protein, was found to be dramatically under-expressed in cancer tissues, implicating a possible special pathological role for this protein in gastric carcinogenesis. Further comprehensive evaluation by globally considering the altered factors may result in the discovery of a biomarker index for effective assessment of the disease and may provide in-depth information for better understanding the pathogenesis of gastric cancer.

Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.

SUMMARY. Conventional pleural cavity drainage after esophagectomy involves one to two large-bore drainage tubes connected to underwater bottles. The purpose of this study is to evaluate the use of a small mobile vacuum drainage system. Out of 173 patients who underwent transthoracic esophagectomy, 167 (97%) had the vacuum drain successfully placed at the end of the operation. Of those, use of the vacuum drain was uneventful for 131 until its removal (78%). Air leaks necessitating connection to underwater drainage occurred in 34 patients (20%), but in 26 of them this was only temporary. Overall success was therefore achieved in 157 patients (94%). Median in-situ placement of the vacuum drain was 4 days, and 85% of patients had their drains removed by the seventh postoperative day. The presence of lung adhesions significantly increased the need for underwater drainage. Postoperative outcomes were no different from a historical cohort with conventional underwater drainage. No drain-related complications were reported. The vacuum drain is an alternative to the conventional, large-bore, chest tube system after transthoracic esophagectomy.

Gastric cancer remains the second leading cause of cancer deaths worldwide. Patients usually present late with local invasion or metastatic diseases. The present study investigated the expression level of liver-intestine cadherin (LI-cadherin) by RT-PCR and its correlation with clinicopathological data in 71 pairs of tumor and non-cancerous gastric mucosa. Protein expression level of LI-cadherin was determined by Western blotting and immunohistochemistry. The mRNA of LI-cadherin was highly expressed in tumor as compared to non-cancerous mucosa. Lymph node metastasis was significantly associated with the expression of LI-cadherin (p=0.038). On multivariate analysis, T staging and LI-cadherin expression were found to be independent factors associated with lymph node metastasis.

Cigarette smoke has been shown to cause gastric cancer. Overexpression of cyclooxygenase-2 (COX-2) is a common characteristic in gastric malignancy. The present study aimed to explore the correlation between cigarette smoke and COX-2 in the promotion of tumorigenesis in human gastric cancer cells (AGS). We further studied the action of COX-2 on other proto-oncogenes on gastric tumor growth. Results showed that chloroform extract (CE) and ethanol extract (EE) from cigarette smoke dose-dependently stimulated gastric cancer cell proliferation, which was accompanied with an activation of ornithine decarboxylase (ODC) activity, COX-2, and c-myc expressions. Both antisense of c-myc and alpha-difluoromethylornithine (DFMO, specific ODC inhibitor) inhibited cell proliferation without affecting COX-2 expression in response to cigarette smoke extracts (CSE). However, selective COX-2 inhibitor (SC-236) not only blocked the proliferative activity but also the ODC activity and c-myc protein expression by CSE in gastric cancer cells. Further, supplementation of exogenous prostaglandin (PG) E(2) reversed all the inhibitory actions of SC-236. Our results underline the importance of COX-2 in the cancer-promoting effect of CSE and its modulation on its downstream growth-related genes, such as c-myc and ODC in cancer cell proliferation. These results reveal that CSE-induced gastric carcinogenesis is via the COX-2/c-myc/ODC and PGE(2)-dependent pathway. Hence, selective COX-2 inhibitor could be an effective therapeutic agent for gastric cancer in smokers.

Cytogenetic analyses of four squamous cell carcinomas (SCC) of the esophagus showed complex numerical and structural abnormalities. Chromosomal bands or regions preferentially involved were 11q13, 8q10, 21q10, 3p10 approximately p11, 1p11 approximately q11, 5p11 approximately q11, and 14p11 approximately q11. For the first time, to our knowledge, recurrent aberrations were identified in esophageal SCC, including homogeneous staining region (hsr), isochromosomes i(3q) and i(21q), and ring chromosome. Losses of chromosomal material dominated over gains. Recurrent imbalances included under-representation of 4p13 approximately pter, 5q14 approximately qter, 9p22 approximately pter, 10p, 11p13 approximately pter, 12p13 approximately pter, 17p10 approximately pter, 18p11 approximately pter, 21p, and 22p, as well as over-representation of 1q25 approximately qter, 3q, 7q, and 8q. Interestingly, hsr at different chromosomal regions occurred in three of four cases. With the application of fluorescence in situ hybridization (FISH) and multicolor combined binary ratio labeling-FISH with specific DNA probes, it could be shown that in two cases the hsr was derived from chromosome 11 material and that the amplicon included CCND1. Our results, together with previous molecular genetic findings, indicate that CCND1might be a prime target in 11q13 amplification, and that amplification of this gene might be crucial in the tumorigenesis of esophageal SCC. These observed chromosomal aberrations and imbalances thus provide important information for further molecular genetic investigation of esophageal SCC.

Summary Aim : To study whether prophylaxis with lansoprazole could prevent relapse of ulcers after eradication of Helicobacter pylori in patients with NSAID-related peptic ulcers. Methods : Patients who presented with peptic ulcers and were found to be infected with H. pylori while receiving NSAIDs were recruited into the study. They received, twice daily, lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg for 1 week, followed by lansoprazole 30 mg daily for 4 weeks. Patients with healed ulcers and H. pylori eradicated were given naproxen 750 mg daily, and randomly assigned to receive lansoprazole 30 mg daily or no treatment for 8 weeks. The primary endpoint was the cumulative recurrence of symptomatic and complicated ulcers. Results : At the end of the 8-week treatment period, significantly fewer patients (1/22, 4.5%, 95% confidence interval [CI] 0–23) in the lansoprazole group compared with the group that received H. pylori eradication alone (9/21, 42.9%, 95% CI 22–66) developed recurrence of symptomatic and complicated ulcers (log rank test P = 0.0025). Conclusions : Lansoprazole significantly reduced the cumulative relapse of symptomatic and complicated ulcers in patients requiring NSAIDs after eradication of H. pylori.

Purpose: To evaluate whether pretherapeutic serum soluble E-cadherin is an independent factor predicting long-term survival in gastric cancer. Gastric cancer remains the second leading cause of cancer-related deaths in the world, but a satisfactory tumor marker is currently unavailable for gastric cancer. Soluble E-cadherin has recently been found to have prognostic value in gastric cancer. Patients and Methods: One hundred sixteen patients with histologically proven gastric adenocarcinoma were included in the trial. Pretherapeutic serum was collected, and soluble E-cadherin was assayed using a commercially available enzyme-linked immunosorbent assay kit. The patients were followed up prospectively at the outpatient clinic. Results: There were 75 men and 41 women, with a mean (± SD) age of 66 ± 14 years. Forty-eight percent of tumors were located in the gastric antrum. The median survival time was 11 months. The mean pretherapeutic value of soluble E-cadherin was 9,159 ng/mL (range, 6,002 to 10,025 ng/mL), and the mean pretherapeutic level of carcinoembryonic antigen was 11 ng/mL (range, 0.3 to 4,895 ng/mL). On multivariate analysis, soluble E-cadherin is an independent factor predicting long-term survival. Ninety percent of patients with a serum level of E-cadherin greater than 10,000 ng/mL had a survival time of less than 3 years (P = .009). Conclusion: Soluble E-cadherin is a potentially valuable pretherapeutic prognostic factor in patients with gastric cancer.

Morphine pretreatment protects against stress-induced gastric ulceration, however, the exact mechanism is still undefined. Interestingly, the effect of morphine on ulcer healing has not been investigated. In this report, we would like to study these effects in a defined stress ulcer model and to delineate a new implication for morphine to promote stress ulcer healing in rats. Our study showed that cold-restraint stress for 3 h induced hemorrhagic lesions and increased myeloperoxidase activity in the gastric mucosa. Stress also reduced the dimension of layer of periodic acid-Schiff reagent-stained cells in the gastric mucosa by about 50%. Morphine pretreatment (2 or 8 mg/kg, given intraperitoneally) at the time of stress dose-dependently reversed stress-induced gastric ulceration, increase of myeloperoxidase activity and reduction of thickness of mucus-stained cells in the gastric mucosa. Morphine treatment after stress (given at the end of a 3-h stress and also at 3 h thereafter) increased ulcer healing by reducing the ulcer size measured 24 h later. Such action was blocked by naloxone (8 mg/kg) given intraperitoneally 15 min before morphine treatment. Morphine also increased the number of cell proliferation and dimension of layer of cells stained for mucus but not the number of microvessels in the gastric mucosa. Moreover, the number of apoptotic cells was less evidenced in the morphine-treated rats. This study reports for the first time that morphine not only prevents stress ulceration but also promotes healing of stress ulcer through a defined mechanism.