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Introduction: The purpose of this study was to compare the transcriptomes of poorly cohesive carcinoma (PCC; diffuse-type) and well-differentiated tubular adenocarcinoma (WD; intestinal-type) using gastric cancer (GC) tissues and cell lines and to evaluate the prognostic role of HIV-1 Tat Interactive Protein 2 (HTATIP2). Materials and Methods: We performed next-generation sequencing with 8 GC surgical samples (5 WD and 3 PCC) and 3 GC cell lines (1 WD: MKN74, and 2 PCC: KATOIII and SNU601). Immunohistochemistry was used to validate HTATIP2 expression. We performed functional analysis by HTATIP2 overexpression (OE). Kaplan-Meier survival plots and the PrognoScan database were used for survival analysis. Results: The genes with significantly reduced expression in PCC versus WD (in both tissues and cell lines) were HTATIP2, ESRP1, GRHL2, ARHGEF16, CKAP2L, and ZNF724. According to immunohistochemical staining, the HTATIP2-OE group had significantly higher number of patients with early GC (EGC) (T1) ( P  = .024), less lymph node (LN) metastasis ( P  = .008), and low TNMA stage ( P  = .017) than HTATIP2 underexpression (UE) group. Better survival rates were confirmed in the HTATIP2 OE group by Kaplan-Meir survival and PrognoScan analysis. In vitro, HTATIP2-OE in KATO III cells caused a significant decrease in cancer cell migration and invasion. Decreased Snail and Slug expression in HTATIP2 OE cells suggested that epithelial-mesenchymal transition is involved in this process. Conclusion: HTATIP2 might be a good prognostic marker and a candidate target for GC treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Reoperation due to elective surgery complications is very mentally, physically, and economically detrimental to patients. This study investigated the potential risk factors associated with early reoperation after radical gastrectomy in gastric cancer patients and included an in-depth analysis of these risk factors., Methods: This retrospective study reviewed 1568 patients with gastric cancer. Grade 3 or greater complications were defined as severe. Any factors related to reoperation after radical gastrectomy were analyzed in patients with severe local complications., Results: Among 1537 patients undergoing radical gastrectomy, 115 (7.5%) patients had severe postoperative complications, 98 (6.38%) of whom experienced severe local complications. The most common local complication was anastomotic leakage (31, 2.02%), followed by intra-abdominal abscess (30, 1.95%), pancreatic leakage (22, 1.43%), duodenal stump leakage (18, 1.17%), intra-abdominal bleeding (12, .78%), intraluminal bleeding (8, .52%), small bowel obstruction (5, .32%), and chyle leakage (3, .19%). Of these patients, 26 (1.69%) underwent reoperation, and 6 (.39%) died. In the univariate analysis of clinical factors related to reoperation, intra-abdominal bleeding and small bowel obstruction were risk factors for reoperation, and intra-abdominal bleeding (odds ratio [OR] = 9.57, confidence interval [CI] = 2.65-40.20, P < .001) and small bowel obstruction (OR = 19.14, CI = 2.60-390.13, P = .011) were independent risk factors associated with reoperation in the multivariate analysis., Conclusion: Intra-abdominal bleeding and small bowel obstruction are independent risk factors for reoperation following radical gastrectomy. Patients with postoperative intra-abdominal bleeding and small bowel obstruction need to be warned about reoperation.

Introduction: The aim of this study was to perform a clinicopathologic analysis of PHLPP1 expression in gastric cancer patients and analyze AKT activity with chemotherapy drug treatment in cancer subtypes. Materials and Methods: Surgically resected gastric cancer tissue specimens were obtained from 309 patients who underwent gastrectomy, and PHLPP1 expression was validated by tissue microarray analysis with immunohistochemistry. We assessed whether PHLPP1 selectively dephosphorylates Ser473 of AKT in an in-vitro study. Results: We found that the PHLPP1 overexpression (OE) group showed significantly greater proportions of differentiated subtype samples and early T stage samples, lower lymph node metastasis, and lower TNM stage than the PHLPP1 underexpression (UE) group. The overall survival of the PHLPP1-OE group was significantly higher (53.39 ± 0.96 months) than that of the PHLPP1-UE group (47.82 ± 2.57 months) ( P  = .01). In vitro analysis, we found that the PHLPP1-OE group showed a significant decrease in relative AKT S-473 levels in both cell lines (MKN-74 and KATO-III). We found that treatment with chemotherapy drugs decreased the activity of Ser473 in the MKN-74 cell line with PHLPP1 OE, but it did not affect the activity of Ser473 in KATO-III cells. Conclusion: We found that patients who overexpressed PHLPP1 showed low recurrence and good prognosis. PHLPP1 was found to work by lowering the activity of AKT Ser473 in gastric cancer. Additionally, we found a clue regarding the mechanism of chemotherapeutic drug resistance in a cell line of signet ring cell origin and will uncover this mechanism in the future.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast and gastric cancers and this causes poor clinical outcomes. Although both T-DM1 and Enhertu are approved as an HER2-targeting antibody-drug conjugate (ADC), the effects of these drugs are still not satisfactory to eradicate diverse tumors expressing HER2. To address this shortfall in HER2-targeted therapeutics, an elaborate cleavable linker is created and a novel HER2-targeting ADC composed with trastuzumab and monomethyl auristatin F, which is being investigated in a phase 1 clinical trial and is referred to as LegoChem Bisciences-ADC (LCB-ADC). LCB-ADC displays a higher cytotoxic potency than T-DM1 and it also has a higher G2/M arrest ratio. In animal studies, LCB-ADC produces noticeable tumor growth inhibition compared with trastuzumab or T-DM1 in an HER2 high-expressing N87 xenograft tumor. Especially, LCB-ADC shows good efficacy in terms of suppressing tumor growth in a patient-derived xenograft (PDX) model of HER2-positive gastric cancer as well as in T-DM1-resistant models such as HER2 low-expressing HER2 low expressing JIMT-1 xenograft tumor and PDX. Collectively, the results demonstrate that LCB-ADC with the elaborate linker has a higher efficacy and greater biostability than its ADC counterparts and may successfully treat cancers that are nonresponsive to previous therapeutics., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Abstract: The impact of gastric remnant volumes (GRVs) after gastrectomy on patients' quality of life (QOL) has not yet been clarified. The aim of the present study was to compare QOL after gastrectomy between small and large gastric remnant volume patients.We prospectively collected clinical data from 78 consecutive patients who underwent distal gastrectomy with Billroth II gastrojejunostomy for gastric cancer. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach questionnaire and gastric computed tomography scans were performed. The patients were subdivided into 2 groups by remnant stomach volume (the S group ≤110 mL vs L group >110 mL).The worst scores for most items were observed at postoperative month 1 and usually improved thereafter. There was no difference in the STO22 score except for dysphagia between the S and L groups after gastrectomy (P > .05). The QOL score of dysphagia was different at postoperative 6 months (S vs L, 12.4 vs 22.8, P < .03), but there was no difference at postoperative months 1, 3, 12, 24, or 36 (P > .05).The remnant gastric volume after partial gastrectomy affects neither functional differences nor QOL after 6 months following appropriate radical surgery., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study applied network analyses to illustrate patterns of associations between cancer-related physical and psychological symptoms (CPPS) and quality of life (QOL) before and after surgery., Methods: Participants consisted of 256 gastric cancer patients admitted for curative section surgery at the surgical department in a teaching hospital in Korea between May 2016 and November 2017. Participants completed the survey, including MD Anderson Symptom Inventory, Hospital Anxiety and Depression Scale, and Functional Assessment of Cancer Therapy-Gastric Cancer before surgery (T0), 1 week after surgery (T1), and 3-6 months after surgery (T2)., Results: Three networks featured several salient connections with varying magnitudes between CPPS and QOL across all time points. Particularly, anxiety was tightly connected to emotional wellbeing (EWB) across all time points and physical wellbeing (PWB) at T1. On the other hand, depression was connected to functional wellbeing at T0 and T2, gastric cancer concerns (CS) at T1, and PWB at T2. Distress and sadness were the most central symptoms in the three networks. Other central symptoms included shortness of breath at T0, fatigue at T0 and T1, and PWB and CS at T2. Anxiety, depression, and EWB served as bridges connecting CPPS to QOL across all time points with varying degrees of importance, as did PWB at T1 and T2., Conclusions: Treating psychological distress and enhancing EWB and PWB can be high impact intervention targets throughout the cancer trajectory., (© 2021 John Wiley & Sons Ltd.)

Introduction: There have been few studies about gene differences between patients with diffuse-type gastric cancer and those with intestinal-type gastric cancer. The aim of this study was to compare the transcriptomes of signet ring cell gastric cancer (worst prognosis in diffuse-type) and well-differentiated gastric cancer (best prognosis in intestinal-type); NUDC was identified, and its prognostic role was studied., Materials and Methods: We performed next-generation sequencing with 5 well-differentiated gastric cancers and 3 of signet ring cell gastric cancer surgical samples. We performed gene enrichment and functional annotation analysis using the Database for Annotation, Visualization and Integrated Discovery bioinformatics resources. Immunohistochemistry was used to validate NUDC expression., Results: Overall, 900 genes showed significantly higher expression, 644 genes showed lower expression in signet ring cell gastric cancer than in well-differentiated gastric cancers, and there was a large difference in adhesion, vascular development, and cell-to-cell junction components between the 2 subtypes. We performed variant analysis and found 52 variants and 30 cancer driver genes, including NUDC. We analyzed NUDC expression in gastric cancer tissue and its relationship with prognosis. Cox proportional hazard analysis identified T stage, N stage, and NUDC expression as independent risk factors for survival ( P < 0.05). The overall survival of the NUDC-positive group was significantly higher (53.2 ± 0.92 months) than that of the NUDC-negative group (44.6 ± 3.7 months) ( P = 0.001) in Kaplan-Meier survival analysis., Conclusion: We found 30 cancer driver gene candidates and found that the NUDC-positive group showed significantly better survival than the NUDC-negative group via variant analysis.

Background: Anastomotic complications such as leaks, bleeding, and stricture remain the most serious complications of surgery for gastric cancer. No perfect method exists for an accurate and reliable prevention of these complications. This study investigated the safety and efficacy of post-anastomotic intraoperative endoscopy (PAIOE) for avoidance of early anastomotic complications during gastrectomy in gastric cancer., Methods: This retrospective case-control study enrolled patients from a tertiary care, academic medical center. Routine PAIOE was performed on 319 patients undergoing gastrectomy for gastric cancer between 2015 and 2016. As controls, without PAIOE 270 patients from 2013 to 2014 were used for comparison. Early anastomotic complications and outcomes after PAIOE were determined., Results: Although there were no differences between the PAIOE and non-PAIOE group in terms of overall complication rates (20.1% vs 26.7%; P > 0.05), there were fewer complications related to anastomosis (3.4% vs 8.9%; P < 0.01) in the PAIOE group. The PAIOE group had rates of 2.5% for anastomotic leakage, 0.9% for intra-luminal bleeding, and 0% for anastomotic stenosis, while the non-PAIOE group exhibited rates of 5.6%, 2.6%, and 0.7%, respectively. Thirty-one abnormalities were detected in 26 PAIOE patients (9.71%) (20 venous bleeding, 7 mucosal tearing, 2 air leaks, 1 arterial bleeding, and 1 anastomotic stricture). All abnormalities were corrected by proper interventions (13 reinforced additional suture, 13 endoscopic hemostasis, and 2 re-anastomosis). There were no morbidities associated with PAIOE., Conclusions: PAIOE appears to be a safe and reliable procedure to evaluate the stability of gastrointestinal anastomosis for gastric cancer patients. Further data collection and a well-designed prospective study are needed to confirm the validity of PAIOE.

Background: In our previous study, transumbilical endoscopic submucosal dissection (TU-ESD) was revealed to be feasible, but delayed gastric perforation was observed in 30% of ESD sites. In this study, we aimed to verify locations at which it is feasible to perform TU-ESD in the upper gastric body and to demonstrate the safety of TU-ESD in single-basin lymph node dissection (SBLND)., Methods: In vitro, TU-ESD was performed at three lesion sites (anterior wall, AW; posterior wall, PW; and lesser curvature, LC) in each porcine stomach using an EASIE-R tray (cases = 10). In vivo, TU-ESD was performed with SBLND in 9 pigs. Seven days after the operation, the pigs were sacrificed and examined., Results: In the in vitro feasibility study, the TU-ESD time was significantly faster in the PW group (5.9 ± 2.0 min) than in the LC group (8.5 ± 1.5 min) (p < 0.05) in all 10 cases. In the in vivo survival study, TU-ESD with SBLND was successfully performed without any complications (N = 9). There were no cases of delayed perforation, and healing ulcers were found in all pigs 7 days after the operation. Ulcer size (5.2 ± 3.5 cm 2 ) was approximately 36% smaller than that observed at the ESD operation site (8.1 ± 1.9 cm 2 ) (p = 0.05). Epithelialization in the margin and healing of the gastric ulcers were confirmed by microscopy., Conclusions: TU-ESD with SBLND is a feasible and safe method. The upper posterior gastric body could be the most feasible location for performing TU-ESD, perhaps because of the difference in the subcutaneous dissection time.

Background: Recently, researchers have tried to predict patient prognosis using biomarker expression in cancer patients. The aim of this study was to develop a nomogram predicting the 5-year recurrence-free probability (RFP) of gastric cancer patients using prognostic biomarker gene expression., Methods: We enrolled 360 patients in the training data set to develop the predictive model and nomogram. We analyzed the patients' general variables and the gene expression levels of 10 prognostic biomarker candidates between the nonrecurrence and recurrence groups. We also performed external validation using 420 patients from the validation data set., Results: The final nomogram was composed of age, sex, and the expression levels of CAPZA, PPase, OCT-1, PRDX4, gamma-enolase, and c-Myc. The five-year RFPs were 89%, 75%, 54% and 32% for the patients in the low-risk, intermediate-risk, high-risk and very-high-risk groups in the development cohort, respectively. In the external validation cohort, the 5-year RFPs were 89%, 75%, 63% and 60%, respectively. The areas under the curve were 0.718 (95% CI, 0.65-0.78) and 0.640 (95% CI, 0.57-0.70) for the training and validation data sets, respectively. The RFP Kaplan-Meier curves were significantly different among the 4 groups in the training and validation data sets (p < 0.0001)., Conclusion: This newly developed nomogram using gene expression can predict the 5-year RFP for gastric cancer patients after surgical treatment. We hope that this nomogram will help in the therapeutic decision between endoscopic treatment and gastrectomy., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aims to investigate the adaptation process of the alimentary tract after distal gastrectomy and understand the impact of remnant stomach volume (RSV) on diet recovery.One year after gastrectomy, although patients' oral intake had increased, the RSV was decreased and small bowel motility was enhanced. Patients with a larger RSV showed no additional benefits regarding nutritional outcomes.We prospectively enrolled patients who underwent distal gastrectomy with Billroth II reconstruction to treat gastric cancer at a tertiary hospital cancer center between September 2009 and February 2012. Demographic data, diet questionnaires, computed tomography (CT), and contrast fluoroscopy findings were collected. Patients were divided into 2 groups according to the RSV calculated using CT gastric volume measurements (large vs small). Dietary habits and nutritional status were compared between the groups.Seventy-eight patients were enrolled. Diet volume recovered to 90% of baseline by the 36 postoperative month, and RSV was 70% of baseline at 6 months after surgery and gradually decreased over time. One year after surgery, small bowel transit time was 75% compared to the 1st postoperative month (P < .05); however, transit time in the esophagus and remnant stomach showed no change in any studied interval. Compared to patients with a small RSV, those with a large RSV showed no differences in diet volume, habits, or other nutritional benefits (P > .05).Diet recovery for distal gastrectomy patients was achieved by increased small bowel motility. The size of the remnant stomach showed no positive impact on nutritional outcomes.

Purpose: Delirium is a common neurocognitive complication in cancer. Despite this, the studies examining the trajectory of the severity of delirium symptoms and its impact on health outcome in gastric cancer is rather limited. This study examined the trajectory of delirium symptom severity (DSS) following resection surgery for gastric cancer and its prospective association with cognitive function., Methods: A three-wave prospective observational study was conducted with 242 gastric cancer patients admitted for resection surgery at a teaching hospital in South Korea from May 2016 to November 2017. DSS was assessed by the clinical staff before and 1, 2, 3, and 7 days after surgery using the Delirium Rating Scale-Revised-98. A survey including the Functional Assessment of Cancer Therapy-Cognitive Scale (FACT-Cog) and Mini-Mental State Examination (MMSE) was administered before surgery (T0), 7 days after (T1), and 3 to 6 months after surgery (T2)., Results: Out of 242 participants, 48.8% (118) completed the survey at all three time points, 43.4% (105) did so for two time points, and 7.9% (19) for one time point. No cases of full delirium were observed over four postoperative time points. Latent growth curve modeling analyses indicated that DSS declined over 3 days after surgery. Age and anesthesia time were positively associated with the initial level of DSS. A medication history for memory complaints was related to a slower recovery from delirium symptoms. While the use of propofol as an anesthetic agent was associated with lower initial DSS, it predicted a slower recovery from DSS. A higher initial DSS predicted a lower T1 MMSE score., Conclusions: Severity of postoperative delirium symptoms predicts a short-term and objective cognitive function post-surgery. Monitoring and timely treatment of postoperative delirium symptoms is needed to diminish cognitive consequences in gastric cancer patients.

Purpose: Few studies investigated roles of body mass index (BMI) on gastric cancer (GC) risk according to Helicobacter pylori infection status. This study was conducted to evaluate associations between BMI and GC risk with consideration of H. pylori infection information., Materials and Methods: We performed a case-cohort study (n=2,458) that consists of a subcohort, (n=2,193 including 67 GC incident cases) randomly selected from the Korean Multicenter Cancer Cohort (KMCC) and 265 incident GC cases outside of the subcohort. H. pylori infection was assessed using an immunoblot assay. GC risk according to BMI was evaluated by calculating hazard ratios (HRs) and their 95% confidence intervals (95% CIs) using weighted Cox hazard regression model., Results: Increased GC risk in lower BMI group (< 23 kg/m2) with marginal significance, (HR, 1.32; 95% CI, 0.98 to 1.77) compared to the reference group (BMI of 23-24.9 kg/m2) was observed. In the H. pylori non-infection, both lower (< 23 kg/m2) and higher BMI (≥ 25 kg/m2) showed non-significantly increased GC risk (HR, 10.82; 95% CI, 1.25 to 93.60 and HR, 11.33; 95% CI, 1.13 to 113.66, respectively). However, these U-shaped associations between BMI and GC risk were not observed in the group who had ever been infected by H. pylori., Conclusion: This study suggests the U-shaped associations between BMI and GC risk, especially in subjects who had never been infected by H. pylori.

Background: Gastric subepithelial tumors originating from muscularis propria (MP) are usually benign, but some have malignant potential., Aims: The aim of this study was to evaluate the utility of endoscopic enucleation for the diagnosis and treatment of MP tumors., Patients and Methods: From January 2010 to February 2018, eighty patients with gastric MP tumors underwent endoscopic enucleation at our hospital. Band ligation and resection (BLR) or endoscopic muscularis resection (EMD) was performed based on considerations of tumor size (≤ 12 mm or > 12 mm). Tumor characteristics, procedure times, complete resection rates, adverse events and recurrence were analyzed., Results: Eighty patients with 82 lesions were eligible for inclusion in this study. BLR was used to treat 41 lesions. For these lesions, mean tumor size was 9.5 mm, median procedural time was 17.6 min (range 4-52), and the endoscopic complete resection rate was 100% (41/41). Perforation was developed in four patients, and was closed by endoscopic clipping. EMD was used to treat 41 lesions. Median procedure time was 66.1 min (range 12-260) and the endoscopic complete resection rate was 85.4% (35/41). Perforation occurred in eight patients, four patients received endoscopic treatment and four underwent surgery. Tumor recurrence was not observed in any patient over follow-up (mean 26.3 months)., Conclusion: Endoscopic enucleation appears to offer an effective, relatively safe means for diagnosing and treating gastric subepithelial tumors originating from the MP, and BLR provides a straightforward, effective, and relatively safe treatment for small MP tumors (≤ 12 mm).

Background Self-expandable metallic stent (SEMS) placement is a well-established palliative treatment approach for malignant gastroduodenal obstruction. In patients with a long (>10 cm) stricture, multiple stents placed in an overlapping fashion are often required. Purpose To investigate the outcomes of overlapping SEMS placement for the palliative treatment of malignant gastroduodenal obstruction in patients with a long (>10 cm) stricture. Material and Methods The medical records of 40 patients who underwent fluoroscopic overlapping SEMS placement for malignant gastroduodenal obstruction due to a long (>10 cm) stricture were reviewed. Results The technical and clinical success rates were 100% and 65.0%, respectively. The mean length of the stricture was 17.0 ± 4.7 cm and the mean number of stents placed in each patient was 2.2 ± 0.5. Metastatic cancer (odds ratio [OR], 0.315; P = 0.018), Eastern Cooperative Oncology Group (ECOG) score ≥3 (OR, 0.018; P = 0.006), and carcinomatosis with ascites (OR, 0.025; P = 0.017) were independent predictors of poor clinical success. The rates of minor and major complications were 27.5% and 2.5%, respectively. The median stent patency and survival were 33 days (interquartile range [IQR], 19-60 days) and 35 days (IQR, 19-73 days), respectively. An ECOG score ≥3 was an independent predictor of a poor survival outcome (hazard ratio, 4.681; P < 0.001). Conclusion Overlapping SEMS placement may be safe and effective for the palliative treatment of malignant gastroduodenal obstruction in patients with a long (>10 cm) stricture.

Inflammatory fibroid polyp (IFP) is a rare benign lesion of the gastrointestinal tract. We report a case of computed tomography (CT) imaging finding of a gastric IFP with massive fibrosis. CT scans showed thickening of submucosal layer with overlying mucosal hyperenhancement in the gastric antrum. The submucosal layer showed increased enhancement on delayed phase imaging. An antrectomy with gastroduodenostomy was performed because gastric cancer was suspected, particularly signet ring cell carcinoma. The histopathological diagnosis was an IFP with massive fibrosis. The authors suggest that when the submucosal layer of the gastric wall is markedly thickened with delayed enhancement and preservation of the mucosal layer, an IFP with massive fibrosis should be considered in the differential diagnosis., Competing Interests: Conflict-of-interest statement: All the authors have no conflicts of interests to declare.

Background/aims: This study was performed to examine the state of long interspersed nuclear element (LINE)-1 methylation level in gastric epithelial dysplasias (GEDs) and evaluate as a molecular marker for gastric carcinogenesis when it was compared with RUNX3 expression., Methods: We examined 89 patients with GEDs subcategorized by the Vienna classification - 41 category 3 (low grade) and 48 category 4 (high grade/intramucosal carcinoma) lesion. All tissue samples were evaluated for RUNX3 immunohistochemical staining and the level of LINE-1 methylation., Results: The rate of negative expression of RUNX3 in category 4 lesion was significant higher than category 3 (P<0.01). LINE-1 methylation level was statistically different between category 3 and category 4 lesion (P<0.01). Between positive and negative expression of RUNX3 in GEDs, there was a significant difference of LINE-1 methylation level (P<0.01). The area under the ROC curve (AUC) of LINE-1 methylation level for diagnosis of category 4 lesion was 0.88 (95% CI, 0.76-1.00)., Conclusions: LINE-1 methylation level was well correlated with the Vienna classification of GED and it had a close relationship with the negative expression of RUNX3 in category 4 lesion. LINE-1 methylation level could be a good candidate for a molecular marker of early gastric cancer., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Serum pepsinogen (PG) I and the PG I/PG II ratio have been used for atrophic gastritis (AG) diagnosis for decades. Low levels of PG I and/or PG I/PG II are closely related to AG and predict the risk of gastric cancer. We evaluated the performance of the chemiluminescent immunoassay-based Architect Pepsinogen I/II assay., Methods: The evaluation consisted of determination of the precision, linearity, limit of blank (LoB), limit of detection (LoD) and method comparison with Eiken and Biohit assays., Results: The total CVs were below 5% for both PG I and PG II. Acceptable linearity was observed for PG I and PG II in their respective reportable ranges. The PG I LoB was 0.317ng/mL and the PG II LoB was 0.418ng/mL, and LoDs were 0.412ng/mL and 0.497ng/mL, respectively. Correlation analysis indicated that results of the Architect assay were comparable to those of the Eiken and Biohit assays, but the three methods lead to different estimations of the cancer risk., Conclusion: The overall analytical performance of Architect Pepsinogen I/II assay is acceptable for the detection of patients with suspected AG. The categorization results of gastric cancer risk showed some difference among test methods suggesting the need for harmonization among the methods from vendors., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs.

Background: The main requirements when performing laparoscopic local resection for early mucosal tumors of the stomach are a clearly defined cancer-free margin and precise tumor localization. In this study, a novel method for precise intraoperative tumor localization and appropriate resection in a porcine model is introduced: endoscopic submucosal cutting and light transmission (ESCLT)., Methods: A total of 15 cases of laparoscopic local resection were performed in 6 pigs. The size of the target lesions was approximately 20 mm. The imaginary lesions were located in the high body anterior wall, posterior wall, lower body posterior wall, angle, and antrum anterior wall of the stomach. Mucosal marking around the lesions, mucosal precutting surrounding the marking, and submucosal cutting along the precutting line using white light endoscopy were sequentially performed. Next, an endoscopic light source was placed directly in front of the lesion. Exact oval-shaped submucosal cutting margins were identified via laparoscopy. Laparoscopic local resection was performed after the minimal distance from the stapler line to the submucosal cutting line was confirmed. The sizes of the mucosal marking, submucosal cutting line, and the entire resected mucosa and serosa were measured., Results: The procedure was completed successfully in all pigs. Local resection was completed on all of the lesions. The mean endoscopic and laparoscopic procedure times were 26.1 and 12.7 min, respectively. The mean size of the resected specimens was: (i) marking lesion, 22 × 19.5 mm; (ii) submucosal cutting line, 26.7 × 23.2 mm; (iii) entire resected mucosa, 37 × 31 mm; and (iv) entire resected serosa, 41.7 × 33.1 mm. There was no intraoperative morbidity., Conclusion: ESCLT provides a precise and useful method of intraoperative tumor localization during laparoscopic local resection of the stomach in terms of minimizing the resection of normal stomach tissue and guaranteeing adequate mucosal safety margins.

Background: Mass screening for gastric cancer (GC), particularly using endoscopy, may not be the most practical approach as a result of its high cost, lack of acceptance, and poor availability. Thus, novel markers that can be used in cost-effective diagnosis and noninvasive screening for GC are needed., Methods: A total of 154 urine samples from GC patients and healthy individuals and 30 pairs of matched tumor and normal stomach tissues were collected. Multivariate analysis was performed on urinary and tissue metabolic profiles acquired using (1)H nuclear magnetic resonance and (1)H high-resolution magic angle spinning spectroscopy, respectively. In addition, metabolic profiling of urine from GC patients after curative surgery was performed., Results: Multivariate statistical analysis showed significant separation in the urinary and tissue data of GC patients and healthy individuals. The metabolites altered in the urine of GC patients were related to amino acid and lipid metabolism, consistent with changes in GC tissue. In the external validation, the presence of GC (early or advanced) from the urine model was predicted with high accuracy, which showed much higher sensitivity than carbohydrate antigen 19-9 and carcinoembryonic antigen. Furthermore, 4-hydroxyphenylacetate, alanine, phenylacetylglycine, mannitol, glycolate, and arginine levels were significantly correlated with cancer T stage and, together with hypoxanthine level, showed a recovery tendency toward healthy controls in the postoperative samples compared to the preoperative samples., Conclusions: An urinary metabolomics approach may be useful for the effective diagnosis of GC.

Octamer transcription factor-1 (OCT-1) is a well-known transcription factor that is reportedly overexpressed in intestinal metaplasia and gastric carcinoma in the intestine. In this study, we investigated OCT-1 overexpression as a prognostic factor for gastric cancer. The association between OCT-1 overexpression (detected using immunohistochemistry) and clinicopathological features including survival was evaluated. In vitro gain-of-function approaches were utilized to assess the function of OCT-1 in malignancy. Analysis of OCT-1 expression in patients with gastric cancer with well-differentiated carcinoma as per the World Health Organization classification showed that OCT-1 overexpression was correlated with advanced tumor invasion (58.8 % of patients with advanced tumor invasion vs. 21.2 % of patients with early tumor invasion; p<0.01), lymph node metastasis (63.9 % of patients with metastasis vs. 24.1 % of those without; p=0.015), and cancer recurrence (83.3 % of patients with recurrence vs. 25.4 % of those without; p<0.01), as well as a lower survival rate (62.8 vs. 87.9 Mo; p<0.01). However, there were no significant differences in the levels of OCT-1 expression in gastric cancer patients with other carcinoma types (p>0.05). Furthermore, we found that the proliferation rate of OCT-1-overexpressing MKN-45 cells was higher than that of the control cells. OCT-1 overexpression may be a marker for poor prognosis in patients with well-differentiated gastric adenocarcinoma.

Background: In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials., Methods: FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed., Results: The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (P<0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P=0.0073) and UK (OS: 0.45 vs 1.9 years, P<0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P=0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour., Conclusion: A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive.

Background: The aim of this study was to use immunohistochemistry (IHC) and silver in situ hybridization (SISH) to evaluate alterations in EGFR and HER2 in gastric cancer in order to determine the relationship with prognosis in gastric cancer patients following curative resection., Patients and Methods: In this study, we analyzed EGFR and HER-2 status by IHC and SISH in 254 stage I-III gastric cancer patients who underwent curative surgery., Results: Thirteen cases (2.48 %) showed EGFR alteration by IHC or SISH. EGFR alteration was associated with older age (P = 0.021), intestinal type (P = 0.040) and higher stage disease (P < 0.001). The patients with operable state gastric cancer who had EGFR alteration had an unfavorable prognosis, and multivariate analysis confirmed that EGFR alteration was an independent unfavorable prognostic factor. Twenty-seven cases (10.6 %) showed HER-2 alteration by IHC or SISH. HER-2 alteration was associated with older age (P = 0.006), well or moderately differentiated histology (P < 0.001) and intestinal type (P = 0.002)., Conclusion: HER-2 alteration is not an independent prognostic factor for curatively resectable gastric cancer. We observed EGFR alteration in a subset of cases with operable state gastric cancer and determined that it was associated with an unfavorable prognosis.

F-actin capping protein α1 subunit (CAPZA1) was previously identified in a proteomic analysis of human gastric cancer clinical specimens and selected for further study. The association between CAPZA1 overexpression, detected by immunohistochemistry, and clinicopathological features including survival were evaluated. In vitro gain-of-function and loss-of-function approaches were utilized to assess the function of CPAZA1 in malignancy. Univariate analysis revealed that poorly differentiated disease, according to the World Health Organization (WHO) classification, advanced T stage, positive lymph nodes, high TNM stage, D2 lymph node dissection, adjuvant chemotherapy and CAPZA1 underexpression were significantly associated with cancer-related death (p<0.05); however, only high TNM stage remained significantly associated by multivariate analysis (p<0.01). CAPZA1 overexpression was associated with well differentiated histology, smaller tumor size, lower T stage, absence of lymph node metastasis, lower TNM stage, lower recurrence rate and longer survival time, compared to CAPZA1 underexpression. In vitro, forced expression of CAPZA1 caused a significant decrease in gastric cancer cell migration and invasion, whereas CAPZA1 depletion had the opposite effect. The present study suggests that CAPZA1 could be a marker of good prognosis in gastric cancer and shows that CAPZA1 is associated with decreased cancer cell migration and invasion.

Background: Microsatellite instability (MSI) is a form of genetic instability characterized by new alleles not present in the normal genotype. This mutation occurs by altered DNA mismatch repair (MMR) genes. Studies of limited numbers of patients have reported conflicting results regarding the association of the MSI phenotype with gastric cancer. This study aims to evaluate the clinical significance of mismatch repair genes in gastric cancer., Materials and Methods: We studied 156 gastric cancer patients who underwent gastrectomy from March 2010 to February 2011 in our hospital. Mismatch repair status was determined by the immunohistochemical analysis of human MutL Homolog 1 (hMLH1) and human MutS Homolog 2 (hMSH2) expression., Results: Seventeen (10.9%) cases did not express hMLH1 but all cases expressed hMSH2. In univariate analyses, the expression of hMLH1 was associated with age, nodal status, and Lauren's classification. In multivariate analyses, there was no statistically significant association between the loss of hMLH1 expression and selected clinical parameters., Conclusion: The expression of hMLH1 was associated with age, nodal status, and Lauren's classification. Our results suggest that MMR gene abnormalities play an important role in the tumorigenesis of patients demonstrating gastric cancer.

Objective: Sonic hedgehog is produced in gastric epithelial cells and plays a crucial role in parietal cell function and the regulation of gastric epithelial cell differentiation. Emerging evidence suggests that the sonic hedgehog pathway is not only involved in the development of cancers but also in their progression and aggressiveness., Methods: To assess its prognostic value in gastric cancer, sonic hedgehog protein expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising 319 human gastric cancer specimens. Cytoplasmic sonic hedgehog expression was scored from 0 to 4, reflecting the percentage of sonic hedgehog-positive cells., Results: Specimens were classified into two groups according to their sonic hedgehog score: those with a score ranging from 0 to 3 were considered low expressers and those with a score of 4 were considered overexpressers. The sonic hedgehog overexpression group included more patients with early gastric cancer than the low sonic hedgehog expression group (25.9 vs. 74.1%, P=0.000). Sonic hedgehog expression was lower in patients with lymph node metastasis than in patients without lymph node metastasis (31.4 vs. 68.4%, P=0.02). Similarly, patients with a lower TNM stage showed significantly higher sonic hedgehog expression. In addition, the survival time of patients with sonic hedgehog overexpression was significantly prolonged (69.27±1.39 months) compared with that of patients with low sonic hedgehog expression (61.23±2.04 months, log-rank test, P=0.03)., Conclusions: These results indicate that sonic hedgehog overexpression may be a marker of good prognosis in gastric cancer.

Background: Patients with mucinous gastric carcinoma (MGC) usually have a poor prognosis, largely due to the advanced stage of disease. In this study, we evaluated the effects of c-MYC amplification on tumor stage and disease-specific survival of 128 patients with MGC and compared the results with those of 302 patients with non-mucinous gastric carcinoma (non-MGC)., Patients and Methods: Two-color fluorescence in situ hybridization (FISH) for c-MYC was performed on 430 GC samples. Real-time quantitative polymerase chain reaction (q-PCR) analysis for c-MYC was also performed after tumor microdissection., Results: c-MYC amplification was found in 10.2% of MGCs and 6.0% of non-MGCs. c-MYC amplification was more frequently found in MGCs of higher tumor stage than in MGCs of lower stage (p=0.038). c-MYC amplification in MGC was correlated with greater invasion depth (p=0.007). The mean survival time of patients with c-MYC amplification was shorter than that of patients without c-MYC amplification in MGC. Real-time q-PCR results showed that the calculated c-MYC/GAPDH ratios were higher in c-MYC-amplified MGC than in c-MYC-non-amplified MGC., Conclusion: This study showed that c-MYC amplification in MGC is highly correlated with advanced stage and deeply invasive MGC. This suggests that c-MYC amplification in MGC could be a possible genetic alteration contributing to the frequent presentation of advanced-stage MGC.

Fibroblast growth factor receptor 2 is a member of receptor tyrosine kinase family, and fibroblast growth factor receptor 2 gene amplification or missense mutation has been observed in various human cancers, including gastric carcinoma. Recent studies have shown that anti-fibroblast growth factor receptor 2 agents inhibit tumor progression in various human cancers, such as endometrial carcinoma and gastric carcinoma, which remains one of the most frequent causes of cancer-related death worldwide. We considered that knowledge of the status of fibroblast growth factor receptor 2 gene amplification in gastric carcinoma might aid in targeted cancer therapy. In this study, fibroblast growth factor receptor 2 amplification status was evaluated by fluorescence in situ hybridization in 313 surgically resected gastric carcinoma tissues, and the results were validated by quantitative real-time polymerase chain reaction. In addition, potential associations between clinicopathologic parameters and the presence of fibroblast growth factor receptor 2 amplification were investigated, and survival analysis was performed. Of the 313 cases, 14 (4.5%) showed fibroblast growth factor receptor 2 amplification by fluorescence in situ hybridization. Fibroblast growth factor receptor 2 amplification was found to be associated with a higher pT stage (P = .023), higher pN stage (P = .038), and distant metastasis (P = .009) and to be significantly associated with lower cancer-specific survival by univariate analysis (P = .012). Gastric carcinoma with fibroblast growth factor receptor 2 amplification was found to be associated with advanced disease and a poor prognosis. We believe that the determination of fibroblast growth factor receptor 2 amplification status could allow the identification of a subset of cancers sensitive to targeted fibroblast growth factor receptor 2 inhibitor-based therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Gastric cancer (GC) is the fourth most common cancer worldwide. In spite of the mortality incidence associated with GC, no reliable prognostic biomarkers are currently available for this malignancy. The sulfatases (or SULFs), SULF1 and SULF2, play a critical role in the pathogenesis of a variety of human cancers. We sought to evaluate the potential of SULFs as biomarkers for GC. Thirty pairs of GC and corresponding normal tissues were analysed for the expression and methylation status of SULFs. Furthermore, the functional role of SULF overexpression was investigated in GC cell lines and tumour xenograft animal models. Lastly, we validated the expression of SULF1 protein in a large cohort of 450 GC patients. GC tissues showed conspicuously higher expression of SULF1 (p = 0.0002) and SULF2 (p = 0.001) compared to normal mucosa, which was correlated with its promoter hypomethylation. Furthermore, high expression of SULFs caused marked acceleration in the growth of xenograft tumours in nude mice. The expression of SULF1 protein significantly correlated with higher recurrence rates (p = 0.0002) and worse overall survival (p < 0.0001) in GC patients. Multivariate analysis revealed that SULF1 is an independent prognostic (p = 0.0123) and lymph node metastasis predictive factor (p = 0.0003) in patients with GC. We provide novel evidence that hypomethylation of promoter CpG islands within SULF genes imparts them with oncogenic potential in GC. Moreover, our data suggest that SULF1 may serve as a promising biomarker for patients with GC., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: This study aimed at examining the association of gene silencing and promoter methylation of glutathione peroxidase 1 (GPX1) and glutathione peroxidase 3 (GPX3) in gastric cancer cells and determined the clinical significance of GPX1 and GPX3 expression loss in gastric cancer tissue., Materials and Methods: Analysis of mRNA expression was carried out by reverse transcription-polymerase chain reaction (RT-PCR). Methylation of the GPX1 promoter region was analyzed by bisulfite sequencing, and that of the GPX3 promoter region was analyzed by methylation-specific PCR (MSP). Tissue microarray-based immunohistochemistry of GPX1 and GPX3 in 1,163 resected gastric cancer specimens was performed to assess the associations with clinicopathological parameters., Results: Reduced GPX1 and GPX3 mRNA expression was associated with promoter methylation in gastric cancer cell lines. A correlation between DNA promoter methylation and loss of GPX1 expression was noted in 16 gastric cancer tissue samples (p=0.005). Loss of GPX1 and GPX3 proteins was found in 24.4% and 30.8% of gastric cancer tissues. Loss of GPX1 expression was significantly associated with advanced gastric cancer (p=0.039) and lymphatic invasion (p=0.010); loss of GPX3 expression was associated with advanced gastric cancer (p<0.001) and lymph node metastasis (p<0.001). Kaplan-Meier analysis showed that low expression of GPX1 was associated with poor cancer-specific survival (p=0.010)., Conclusion: Data from this study implicate aberrant hypermethylation of promoter regions of GPX1 and GPX3 as a mechanism for down-regulation of GPX1 and GPX3 mRNA expression in gastric cancer cells. Loss of GPX1 expression was associated with aggressiveness and poor survival in patients with gastric cancer.

Background: The aim of this study was to compare gene copy number (GCN) and protein expression of MET and to evaluate their prognostic roles in gastric carcinomas., Methods: MET protein expression and gene amplification (GA) status were determined by immunohistochemistry (IHC) and silver in-situ hybridisation (SISH), respectively, in a large series of gastric carcinoma., Results: Protein overexpression was observed in 104 of 438 cases, with IHC 2+ in 94 and IHC 3+ in 10, and high polysomy of chromosome 7 and GA were found in 61 and 13 of 381, respectively. Direct comparison revealed a significant correlation between high level of protein expression and increased GCN. All cases with GA showed protein overexpression. Furthermore, all with IHC 3+ showed GA except 1, even which could be categorised as GA according to the ASCO/CAP guideline for human epidermal growth factor receptor 2 assessment. IHC 3+ and GA were significantly associated with poor prognosis., Conclusion: MET IHC reflects well on GA, and therefore, it could be a primary screening test for patient selection for anti-MET therapy if GA is a major determinant of drug responsiveness. Also, the prognostic role of MET indicates that anti-MET therapy is a very promising modality in adjuvant treatment for gastric cancer.

Background: Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer., Methods: The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers., Results: MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis., Conclusions: The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.

We used an ecological approach to determine the correlation between vegetable, fruit and salt intakes, refrigerator use, and gastric cancer mortality in Korean population. Information on fruit and vegetable intakes per capita from the National Health and Nutrition Survey, death certificate data from the National Statistical office, refrigerator per household data from Korean Statistical Information Service, and salt/sodium intake data from a cross-sectional survey were utilized. Correlation coefficients were calculated between vegetable and fruit intakes, refrigerator per household, and gastric cancer mortality and between salt and sodium intakes, and gastric cancer mortality and incidence in the four areas. With 5, 10, and 15 years lag time, refrigerator usage and fruit intake were negatively associated with gastric cancer mortality (p < 0.01), but vegetable intake was not associated with gastric cancer mortality. When estimates of salt/sodium intake evaluated by 24-h urine collection in four areas of Korea were compared to the gastric cancer mortality and incidence in these regions, positive correlation was shown between salt/sodium intake, and gastric cancer incidence and mortality. Negative associations between refrigerator use, fruit intake, and gastric cancer mortality and positive associations between salt/sodium intake and gastric cancer mortality and incidence were suggested.

Signaling of the Toll-like receptor (TLR) is closely associated with tumor development and progression processes including cell proliferation, angiogenesis, metastasis, and immunosuppression. In this study, we examined the expression of TLR5 in gastric cancer cells and its function in cell proliferation. RT-PCR revealed that the TLR5 gene was expressed in all gastric cancer cell lines examined, SNU638, SNU601, SNU216, and AGS. The TLR5 agonist, flagellin, induced IL-8 production and NF-κB activation in the gastric cancer cell lines. In addition, flagellin enhanced the proliferation of all gastric cancer cells examined, whereas LPS did not affect that of SNU638 cells. Blockade of TLR5 using an antibody, restored the proliferation of SNU638 cells enhanced by flagellin, indicating that TLR5 is essential for cell proliferation by flagellin. Flagellin also led to phosphorylation of ERK in SNU638 cells. The ERK inhibitor, PD98059, restored the proliferation ability of SNU638 cells enhanced by flagellin, suggesting that ERK may play an important role in the proliferation of gastric cancer cells. These findings suggest that TLR5 may play an important role in tumor progression of gastric cancer via the regulation of cell proliferation.

Background: Although natural orifice extraction is now widely performed, there have been no reports of this procedure following subtotal gastrectomy for gastric cancer. This report describes trans-vaginal specimen extraction in four patients with early gastric cancer., Methods: The clinical data of four patients with early gastric cancer were reviewed. Totally laparoscopic subtotal gastrectomy and D1 + β lymph node dissection was performed using five trocars and a conventional procedure. Posterior colpotomy was performed by an experienced gynecologist, who retrieved the specimens in a retrieval bag via the trans-vaginal route. The colpotomy site was repaired immediately following specimen removal. Reconstruction was performed using the intracorporeal Billroth II method and an endo-GIA 60., Results: Totally laparoscopic subtotal gastrectomy and trans-vaginal specimen extraction was successfully accomplished in all patients without intraoperative complications., Conclusions: The present technique may be a safe and feasible operative procedure for some limited groups of elderly female patients with early gastric cancer.

Background: The risk of recurrence after laparoscopy-assisted radical gastrectomy (LAG) was investigated., Materials and Methods: Clinical data of 398 consecutive patients who underwent radical gastrectomy with R0 resection for gastric cancer at Gyeongsang National University Hospital between January 2005 and December 2007 were reviewed retrospectively., Results: Of the patients, 65.4% (n = 261) and 34.6% (n = 138) underwent LAG and open radical gastrectomy (OG), respectively. Of the LAG cases, 73.2% (n = 192), 10.7% (n = 28), 12.6% (n = 33), and 3.1% (n = 8) had stage I, II, III, and IV gastric cancer, respectively. All patients were followed up for a mean of 36.8 ± 13.7 months, and 14.6% (n = 58) had recurrence during the follow-up period. Univariate analysis revealed that tumor size, tumor-node-metastasis (TNM) stage, method of approach (LAG versus OG), and operation type were associated significantly with recurrence. Multivariate analysis revealed that only high TNM stage was significantly associated with recurrence (P = 0.00). While patients who underwent OG had higher incidence of recurrence than patients who underwent LAG, OG was not significantly associated with recurrence on multivariate analysis (P = 0.06)., Conclusions: LAG and OG did not differ significantly in terms of recurrence, even when used in advanced gastric cancer cases. Multivariate analysis revealed that high TNM stage was significantly associated with recurrence. Thus, LAG appears to be a safe and feasible procedure that has the potential to be an alternative to open surgery, even for advanced gastric cancer.

Background: The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types., Methods: The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q)., Results: Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%)., Conclusions: The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis.

Background: The transitional-CpG sites between weakly methylated genes and densely methylated retroelements are overmethylated in the gastric mucosa infected with Helicobacter pylori (H. pylori) and they are undermethylated in the gastric cancers depending on the level of loss of heterozygosity (LOH) events. This study delineated the transitional-CpG methylation patterns of CpG-island-containing and -lacking genes in view of the retroelements., Methods: The transitional-CpG sites of eight CpG-island-containing genes and six CpG-island-lacking genes were semi-quantitatively examined by performing radioisotope-labelling methylation-specific PCR under stringent conditions. The level of LOH in the gastric cancers was estimated using the 40 microsatellite markers on eight cancer-associated chromosomes. Each gene was scored as overmethylated or undermethylated based on an intermediate level of transitional-CpG methylation common in the H. pylori-negative gastric mucosa., Results: The eight CpG-island genes examined were overmethylated depending on the proximity to the nearest retroelement in the H. pylori-positive gastric mucosa. The six CpG-island-lacking genes were similarly methylated in the H. pylori-positive and -negative gastric mucosa. In the gastric cancers, long transitional-CpG segments of the CpG-island genes distant from the retroelements remained overmethylated, whereas the overmethylation of short transitional-CpG segments close to the retroelements was not significant. Both the CpG-island-containing and -lacking genes tended to be decreasingly methylated in a LOH-level-dependent manner., Conclusions: The overmethylated genes under the influence of retroelement methylation in the H. pylori-infected stomach are demethylated in the gastric cancers influenced by LOH.

P-cadherin is a member of the cadherin family and is expressed in several solid tumors. This molecule was recently highlighted with the development of a new targeted compound being studied in a clinical trial on solid tumors. In the present study, we examined the protein and messenger RNA (mRNA) expression status of P-cadherin and its promoter methylation in gastric carcinoma cell lines and tissues. Of the 10 cell lines, 4 were found to express P-cadherin protein and mRNA, and the P-cadherin gene was found to be hypomethylated in its promoter region in these cell lines. Nonneoplastic gastric mucosal tissues from gastric carcinoma patients were negative for P-cadherin protein evaluated by immunohistochemistry and Western blotting and had a methylated P-cadherin promoter region. In carcinoma tissues, 70.8% (749/1058) of cases showed P-cadherin protein expression, and P-cadherin positive cases had a well or moderately differentiated histology according to the World Health Organization classification, intestinal-type histology by Lauren classification, and an earlier pT class. Furthermore, patients with P-cadherin expressing tumors had a favorable prognosis by univariate and multivariate survival analyses. In addition, P-cadherin protein expression was found to be significantly correlated with promoter hypomethylation. In summary, P-cadherin is silenced in nonneoplastic gastric mucosa, and P-cadherin expressing tumors constitute a subset of gastric carcinoma with intestinal-type histology and a favorable prognosis. In addition, our findings suggest that P-cadherin promoter methylation underlies the regulation of its expression. These findings may aid patient selection and the interpretation of P-cadherin targeted therapy and clinical trial results., (Copyright 2010 Elsevier Inc. All rights reserved.)

Annexins (ANXs) are a family of calcium and phospholipid binding proteins that have been implicated in diverse important biological and physiological process. ANX A10 (ANXA10) is a member of this family, though little is known about its functions. In the present study, array based comparative genomic hybridization (CGH) was used to screen DNA copy number change in gastric cancer cell lines and the results obtained were compared with oligonucleotide microarray data. DNA loss of the ANXA10 locus in chromosome 4q33 was found in several gastric cancer cell lines by array based CGH and these cell lines showed decreased ANXA10 expression by oligonucleotide microarray analysis. Functional analysis using siRNA and full-length cDNA transfection in gastric cancer cell lines demonstrated that ANXA10 regulates gastric cancer cell proliferation. Of the 585 primary gastric carcinoma tissues examined, ANXA10 expression at the protein level was found to be reduced in 289 (49.4%) cases. Quantitative real-time PCR analysis validated loss of DNA at the ANXA10 locus in gastric carcinomas with reduced ANXA10 expression. By univariate survival analysis, lack of ANXA10 expression was associated with poor survival (p = 0.016). These results suggest that ANXA10 inactivation by chromosomal deletion may play a role during gastric cancer progression.

Purpose: SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients., Experimental Design: We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray., Results: Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival., Conclusion: This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.

Metastasis is a multi-step process involving many biomolecular changes and DNA methylation is one such molecular change. Although differences in DNA methylation have been reported in matched primary and metastatic mammary carcinoma, no such differences have been reported in gastric carcinoma. Accordingly, to investigate whether DNA methylation profiles in metastatic gastric carcinoma differ from those of their primary counterparts, we investigated the DNA methylation of eleven genes, ADAM23, CDH1, FHIT, FLNC, GSTP1, ITGA4, LOX, RUNX3, THBS1, TIMP3, and UCHL1 in 74 matched human primary gastric carcinomas, lymph node metastases, non-neoplastic gastric mucosal, and uninvolved lymph node tissues by utilizing methylation-specific PCR. Seven of these genes (ADAM23, FLNC, ITGA4, LOX, RUNX3, TIMP3, and UCHL1) showed cancer-specific methylation, and three (CDH1, FHIT, and THBS1) showed cancer-unrelated methylation. GSTP1 was rarely methylated in any tissue type. Of the seven genes that showed cancer-specific methylation, FLNC was more frequently methylated in metastatic gastric carcinomas than in their primary counterparts (p=0.004). In addition, the average number of methylated genes in metastatic tumors was greater than that in primary tumors (p=0.004). The high-methylation group (cases with three or more genes methylated in primary tumors) was found to contain more women (p=0.031) and diffuse type tumors by Lauren classification (p=0.022). DNA methylation profiles were not found to affect prognosis. We suggest that promoter methylation of FLNC may be involved in the lymph node metastasis of gastric carcinoma and that the DNA methylation statuses of metastatic tumors should be considered in node-positive gastric carcinoma.

To identify novel methylation-silenced genes in gastric cancer, we carried out a genome-wide search for genes that are up-regulated after treatment with the demethylating agent, 5-aza-2'-deoxycytidine (5Aza-dC). When three gastric cancer cell lines (SNU-1,-601, and -719) were treated with 5Aza-dC, 143 genes were found to be upregulated by twofold or more using oligonucleotide microarrays. Six of these genes, i.e. TFPI2, GPX3, GPX1, IGFBP6, IRF7 and DMRT1, showed promoter hypermethylation in one or more gastric cancer cell lines, but were unmethylated in normal gastric mucosa by bisulphite sequencing and methylation-specific PCR analysis. The following percentages of these genes were found to be aberrantly methylated in gastric cancer samples; TFPI2 (80.9%), GPX3 (30.1%), DMRT1 (46.9%), GPX1 (16.7%), IGFBP6 (22.6%) and IRF7 (32.1%). Interestingly, the survival of patients possessing methylated alleles of TFPI2 (123/152, 80.9%) was poorer than that of patients with unmethylated alleles (p=0.023). Multivariate analysis confirmed that TFPI2 methylation is a significant and independent prognostic factor in gastric carcinoma. Furthermore, altered TFPI2 expression, as demonstrated by immunohistochemistry in 566 consecutive gastric cancer tissues, was found to be significantly associated with sex (p=0.003), WHO classification (p<0.001), and a mixed subtype by Lauren's classification (p<0.001). Thus, the present study identified several novel genes, which were methylated in gastric cancer and among them, methylation of TFPI2 was an unfavourable prognostic marker.

This study investigated the factors affecting the length of the minilaparotomy incision (LOMI) in laparoscopy-assisted distal gastrectomy with Billroth I reconstruction. By using abdominal computed tomography scans, we measured the thickness of the rectus muscle (TRM), the thickness of the abdominal wall (TAW), and the distance from the gastroduodenal artery to the skin (GDAS) in 80 patients with early gastric cancer who had undergone surgery. There were positive correlations between the LOMI and body mass index (BMI), TRM, and TAW, and the LOMI increased significantly in patients with BMI > or =25 kg/m2, TAW > or =2.1 cm, and TRM > or =1.0 cm. These observations suggest that patients with two or more of the following clinical factors, BMI > or =25 kg/m2, TAW > or =2.1 cm, and TRM > or =1.0 cm, may require surgical procedures other than laparoscopy-assisted Billroth I, such as total laparoscopic intracorporeal Billroth I, Billroth II, or uncut Roux-en-Y reconstruction.

Background: Detection of tumor-associated genetic alterations in plasma of cancer patients has recently been suggested to be an accurate method for detecting early or recurrent cancer., Methods: We performed quantitative real-time PCR for MYC and GAPDH in tissue and plasma samples of 57 patients with gastric cancer and in plasma of 79 cancer-free individuals. We also performed two-color MYC fluorescence in situ hybridization (FISH) in tissue from the 57 patients with gastric cancer., Results: The tissue MYC/GAPDH ratio by real-time PCR was significantly correlated with MYC status by FISH (p<0.001). The mean ratio of plasma MYC/GAPDH was 5.226+/-3.578 (range: 1.25-18.35) in gastric cancer patients, and 2.436+/-0.881 (range: 1.00-5.00) in the healthy volunteers (p<0.001). We used receiver-operating characteristics (ROC) curve analysis to select two optimal plasma MYC/GAPDH cut-offs of 2.725 and 5.225. The sensitivity and specificity were 75.4% and 76.9% at 2.725, 38.6% and 100% at 5.225, respectively. The plasma MYC/GAPDH ratio from cancer patients was significantly correlated with the tissue MYC/GAPDH ratio (p=0.009), and tissue MYC status by FISH (p=0.024)., Conclusions: These findings suggest that the plasma MYC/GAPDH ratio, as determined by real-time PCR, may be an alternative non-invasive approach for detecting gastric cancer.

Ca2+ and Mg2+ have a fundamental role in many cellular processes and ion channels are involved in normal physiologic processes and in the pathology of various diseases. The aim here was to show that the presence and potential role of transient receptor potential melastatin 7 (TRPM7) channels in the growth and survival of AGS cells, the most common human gastric adenocarcinoma cell line. The patch-clamp technique for whole-cell recording was used in AGS cells. TRPM7-specific small interfering RNAs were used for specific inhibition of TRPM7. Whole-cell voltage-clamp recordings revealed the TRPM7-like currents that activated spontaneously following loss of intracellular Mg2+. The current had a non-linear current-voltage relationship with the characteristic steep outward rectification associated with TRPM7 channels. Reverse transcription-polymerase chain reaction, western blotting, and immunoreactivity all showed abundant expression of TRPM7 messenger RNA and protein in AGS cells. Transfection of AGS cells with TRPM7 siRNA significantly reduced the expression of TRPM7 mRNA and protein as well as the amplitude of the TRPM7-like currents. Furthermore, we found that Mg2+ is critical for the growth and survival in AGS cells. Blockade of TRPM7 channels by La3+ and 2-APB or suppression of TRPM7 expression by siRNA inhibited the growth and survival of these cells. Human gastric adenocarcinoma cells express TRPM7 channel whose presence is essential for cell survival. The protein is a likely potential target for the pharmacological treatment of gastric cancer.

Background: This retrospective study determined whether extracorporeal esophagojejunostomy after laparoscopy-assisted total gastrectomy (LATG) for gastric cancer can be considered minimally invasive surgery, compared to the conventional open total gastrectomy (OTG)., Patients and Methods: This retrospective study involved 60 patients seen between January 2004 and July 2006. Twenty-seven patients underwent LATG, and 33 patients had OTG. The surgical procedure included the use of five ports with an upper vertical midline incision. In all patients, reconstruction was performed by using a Roux-en-Y esophagojejunostomy through the minilaparotomy site. In all cases, the jejunojejunostomy was performed extracorporeally as the conventional method. In OTG, a Roux-en-Y esophagojejunostomy was performed with an upper midline incision., Results: The mean number of retrieved lymph nodes was smaller and the mean operating time was longer in the LATG group. The postoperative hospital course was similar in both groups. In the LATG group, the mean length of the minilaparotomy incision was 8.0+/-1.2 cm (maximum length, 11 cm), and a direct relationship was observed between the distance from the xiphoid process to the esophageal hiatus (DisXE) and the minilaparotomy incision length (Spearman's correlation of rank coefficient: 0.386; P=0.046)., Conclusions: With the concept of minimal invasiveness, if the patient's DisXE exceeds 9 cm, the length of the minilaparotomy incision in laparoscopic surgery could be disadvantageous. Nevertheless, we consider LATG the treatment of choice for early gastric cancer. If the patient's DisXE exceeds 9 cm, we consider intracorporeal anastomosis with the laparoscopic total gastrectomy. The type of esophagojejunostomy may be determined preoperatively by using three-dimensional abdominal computed tomography.

Changes in bone and mineral metabolism that occur after gastrectomy have long been recognized. Gastrectomy has been identified as a risk factor for decreased bone mass and the increased fracture incidence. Previous investigations concerning postgastrectomy bone disease have been observational studies. No prospective studies have been reported that quantify the amount of bone loss after gastrectomy within the same patients. This study investigated 46 patients undergoing gastrectomy for gastric adenocarcinoma and analyzed 36 patients (58.1+/-10.8 years, 24 men and 12 women) who had dual energy X-ray absorptiometry (DXA) performed before and 1 year after gastrectomy. Systemic adjuvant chemotherapy was administered to 14 patients. Blood was sampled from all patients to determine serum calcium, phosphorous, and bone turnover marker levels before gastrectomy and at 1, 3, 6 and 12 months after surgery and for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels before and 12 months after surgery. The mean bone loss in the lumbar spine, total hip, femoral neck, and trochanter, which was calculated as the percentage change from the baseline to the level measured at 12 months, was 5.7% (P<0.01), 5.4% (P<0.01), 6.6% (P<0.01) and 8.7% (P<0.01), respectively. Bone loss was generally greater in the group receiving chemotherapy. The serum calcium and phosphorous levels were not changed significantly and remained within the normal range throughout the observation period. After gastrectomy, the level of ICTP increased and reached a peak at 1 and 3 months, and progressively declined to baseline by 12 months. The osteocalcin levels were not coupled to an increase before 6 months. The level of 25-hydroxyvitamin D at 12 months postgastrectomy was not significantly changed compared to the baseline, however, the PTH levels increased by a mean of 63.6% at 12 months compared to the baseline (P<0.01). Significant correlations were found between the percent change in the BMD at the lumbar spine and total hip and the percentage change for the PTH level from their baselines to 12 months. The changes in the BMD at total hip, femoral neck, and trochanter also correlated to the change in body weight at 12 months. The data obtained by this study provides evidence that profound bone loss occurs in the setting of a bone remodeling imbalance during the early postgastrectomy period and allows the speculation that the gastrectomy related bone loss may be partially due to an overproduction of PTH.

The most common metastatic sites of gastric cancer are liver, lung, bone and adrenal gland. However, skin metastases from gastric cancer are relatively rare. We herein report a case of advanced gastric cancer with perianal skin metastasis in a 70-year-old male. On admission, patient presented with epigastric pain. Endoscopy and abdominal CT scan demonstrated the stage IV gastric cancer. He had one painless nodule on perianal skin area, biopsy of that lesion showed a feature of poorly differentiated adenocarcinoma clinically from the stomach. We suspected that the perianal lesion was originated from gastric cancer.