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Purpose: Since 1995, the Korean Gastric Cancer Association (KGCA) has been periodically conducting nationwide surveys on patients with surgically treated gastric cancer. This study details the results of the survey conducted in 2023., Materials and Methods: The survey was conducted from March to December 2024 using a standardized case report form. Data were collected on 86 items, including patient demographics, tumor characteristics, surgical procedures, and surgical outcomes. The results of the 2023 survey were compared with those of previous surveys., Results: Data from 12,751 cases were collected from 66 institutions. The mean patient age was 64.6 years, and the proportion of patients aged ≥71 years increased from 9.1% in 1995 to 31.7% in 2023. The proportion of upper-third tumors slightly decreased to 16.8% compared to 20.9% in 2019. Early gastric cancer accounted for 63.1% of cases in 2023. Regarding operative procedures, a totally laparoscopic approach was most frequently applied (63.2%) in 2023, while robotic gastrectomy steadily increased to 9.5% from 2.1% in 2014. The most common anastomotic method was the Billroth II procedure (48.8%) after distal gastrectomy and double-tract reconstruction (51.9%) after proximal gastrectomy in 2023. However, the proportion of esophago-gastrostomy with anti-reflux procedures increased to 30.9%. The rates of post-operative mortality and overall complications were 1.0% and 15.3%, respectively., Conclusions: The results of the 2023 nationwide survey demonstrate the current status of gastric cancer treatment in Korea. This information will provide a basis for future gastric cancer research., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2025. Korean Gastric Cancer Association.)

Background/aims: Papillary adenocarcinoma is classified to differentiated-type gastric cancer and is indicated for endoscopic submucosal dissection. However, due to its rare nature, there are limited studies on it. The purpose of this study was to determine the outcome of endoscopic submucosal dissection in patients with papillary-type early gastric cancer and to find the risk factors of lymph node metastasis., Methods: Patients diagnosed with papillary-type early gastric cancer at eight medical centers, who underwent endoscopic submucosal dissection or surgical treatment, were retrospectively reviewed. The clinical results and long-term outcomes of post-endoscopic submucosal dissection were evaluated, and the risk factors of lymph node metastasis in the surgery group were analyzed., Results: One-hundred and seventy-six patients with papillary-type early gastric cancer were enrolled: 44.9% (n=79) in the surgery group and 55.1% (n=97) in the endoscopic submucosal dissection group. As a result of endoscopic submucosal dissection, the en bloc resection and curative resection rates were 91.8% and 86.6%, respectively. The procedure-related complication rate was 4.1%, and local recurrence occurred in 3.1% of patients. Submucosal invasion (odds ratio, 3.735; 95% confidence interval, 1.026 to 12.177; p=0.047) and lymphovascular invasion (odds ratio, 7.636; 95% confidence interval, 1.730 to 22.857; p=0.004) were the risk factors of lymph node metastasis in papillary-type early gastric cancer patients., Conclusions: The clinical results of endoscopic submucosal dissection in papillary-type early gastric cancer were relatively favorable, and endoscopic submucosal dissection is considered safe if appropriate indications are confirmed by considering the risk of lymph node metastasis.

Objective: This study aimed to explore socio-economic factors and medical conditions that affect regular stomach cancer (SC) screening among Korean adults., Study Design: This was a retrospective observational study., Methods: Study subjects were 5545 adults aged ≥40 years who participated in the 2007-2012 Korean National Health and Nutrition Examination Survey and were followed up to year 2017 based on data linking to the Korean National Health Insurance Service and Korean Health Insurance Review and Assessment. Socio-economic factors included sex, age, residential area, education, occupation, marital status, disability, public and private health insurance, service through local public health organizations, history of cancer except for SC, and family history of SC. Medical factors included six gastric lesions with the possibility of facilitating SC screening, including benign gastric neoplasm, chronic atrophic gastritis, gastric polyp, Helicobacter pylori infection, intestinal metaplasia, and peptic ulcers. The outcome was adherence to SC screening, which was divided into non-adherence, irregular adherence, and regular adherence., Results: After adjusting for the effects of socio-economic factors, multivariate ordinal logistic regression revealed that participants with a history of four types of gastric lesions were more likely to regularly participate in SC screening: chronic atrophic gastritis (odds ratio [OR] 1.567; 95% confidence interval [CI] = 1.276-1.923), gastric polyps (OR 1.565; 95% CI = 1.223-2.003), H. pylori infection (OR 1.637; 95% CI = 1.338-2.003), and peptic ulcer (OR 2.226; 95% CI 1.750-2.831)., Conclusions: To improve participation in SC screening, it is necessary to implement personalized strategies for individuals at risk for gastric cancer in addition to population-based strategies for vulnerable groups., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Histone deacetylase (HDAC) inhibitors diminish carcinogenesis, metastasis, and cancer cell proliferation by inducing death in cancer cells. Tissue regeneration and organ development are highly dependent on the Hippo signaling pathway. Targeting the dysregulated hippo pathway is an excellent approach for cancer treatment. According to the results of this study, the combination of panobinostat, a histone deacetylase inhibitor, and 5-fluorouracil (5-FU), a chemotherapy drug, can act synergistically to induce apoptosis in gastric cancer cells. The combination of panobinostat and 5-FU was more effective in inhibiting cell viability than either treatment alone by elevating the protein levels of cleaved PARP and cleaved caspase-9. By specifically targeting E-cadherin, vimentin, and MMP-9, the combination of panobinostat and 5-FU significantly inhibited cell migration. Additionally, panobinostat significantly increased the anticancer effects of 5-FU by activating Hippo signaling (Mst 1 and 2, Sav1, and Mob1) and inhibiting the Akt signaling pathway. As a consequence, there was a decrease in the amount of Yap protein. The combination therapy of panobinostat with 5-FU dramatically slowed the spread of gastric cancer in a xenograft animal model by deactivating the Akt pathway and supporting the Hippo pathway. Since combination treatment exhibits much higher anti-tumor potential than 5-FU alone, panobinostat effectively potentiates the anti-tumor efficacy of 5-FU. As a result, it is believed that panobinostat and 5-FU combination therapy will be useful as supplemental chemotherapy in the future., Competing Interests: Declaration of Competing Interest No conflicts of interest require disclosure., (Copyright © 2023. Published by Elsevier Inc.)

Background/aims: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the stomach. We evaluated the clinical outcomes of endoscopic treatment for gastric GISTs., Methods: This is a single center, retrospective study that enrolled 135 cases of gastric subepithelial tumors (SETs) resected by endoscopic procedures and confirmed as GISTs by histopathology from March 2005 to July 2019. The immediate and long-term clinical outcomes were analyzed retrospectively., Results: The mean patient age was 57.9 years, and the mean tumor size was 2.1 cm. Of the tumors, 43.0% were located in the body, followed by the fundus (26.7%) and cardia (17.0%). Most tumors (85.2%) were resected by endoscopic submucosal dissection, followed by endoscopic mucosal resection (6.7%), submucosal tunneling endoscopic resection (5.9%), and endoscopic full-thickness resection (2.2%). Macroperforation occurred in 4.4% and microperforation in 6.7% of the cases. The R0 resection rate was 15.6%. However, the rate of complete resection by the endoscopic view was 90.4%, of which 54.8% of cases were in the very-low-risk group, followed by the low-risk group (28.1%), intermediate-risk group (11.9%), and high-risk group (5.2%). During 36.5 months of follow-up, recurrence was found in four (3.4%) of the 118 patients who were monitored for more than 6 months (low-risk group, 1/37 [2.7%]; intermediate-risk group, 2/11 [18.2%]; high-risk group, 1/6 [16.7%])., Conclusions: Endoscopic treatment of a GIST appears to be a feasible procedure in selected cases. However, additional surgery should be considered if the pathologic results correspond to intermediate- or high-risk groups.

Background/aims: Endoscopic submucosal dissection (ESD) of gastric neoplasm involving the pyloric channel (GNPC) is technically challenging due to difficulty in precise assessment of resection margin and inadequate visualization. The aim of this study was to evaluate the effectiveness and long-term outcome of ESD for GNPC and introduce a noble technique for resection of GNPC., Methods: A total of 97 patients with GNPC underwent ESD from January 2007 to October 2017. We divided them into a conventional anterograde resection group and a retrograde resection group according to the method of procedure. We compared their clinical outcomes and investigated risk factors for postprocedural complications., Results: The en bloc resection rate was 87.6%, and complete resection rate was 83.5%. Postprocedure stenosis occurred in 16 cases (16.5%). GNPCs of the retrograde resection group were more frequently located from antrum to bulb, were significantly larger, were related to ≥75% resection of the circumference, and involved significantly longer procedure times than those in the anterograde resection group. Multivariate analysis showed that resection ≥75% of the circumference was the only significant risk factor for postprocedure stenosis., Conclusions: ESD by retrograde resection method is a novel technique to make the procedure easier, depending on the size, location, and circumference of resection.

Background/aim: Because there are ongoing efforts to identify and develop novel drugs in the treatment of refractory gastric cancer, it is necessary to develop effective preclinical studies. Here, the preclinical efficacy of gastric tumor xenograft (GTX)-derived cell line models for the personalized treatment of gastric cancer was investigated., Materials and Methods: Anti-cancer drugs were scanned with high-throughput screening (HTS) using pre-established GTX-derived cell lines. The efficacy of a selected drug (afatinib) was re-confirmed in vivo and intracellular signaling pathways were investigated in xenograft tumor cell lysates using western blotting. Validation studies, such as cell proliferation and caspase activity assays, were also conducted in vitro with GTX-derived cell lines., Results: HTS indicated that afatinib was effective in one of the five GTX-derived cell lines (GTX-087). A xenograft mouse model was established from GTX-087, and administration of afatinib at 1 mg/20 g body weight/day per oral resulted in tumor-suppressive activity in vivo. The RAS-ERK pathway was inactivated by an increase in Bax and cleaved caspase-3 in this xenograft model. In vitro cell proliferation assay also revealed that afatinib was able to suppress the growth of the GTX-087 cell line. Caspase activity assay confirmed that afatinib had an apoptotic role on GTX-087 and showed that caspase-3/7 activity increased in a time dependent manner., Conclusion: The GTX-derived cell line model might be useful for estimating novel drug responses and could be an alternative to patient-derived xenograft animal models., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Patients who underwent curative gastrectomy for gastric cancer are regularly followed-up for the early detection of recurrence and postoperative symptom management. However, there is a lack of evidence with regard to proper surveillance intervals and diagnostic tools. This study aims to evaluate whether frequent surveillance tests have a survival benefit or improve the quality of life in patients who underwent curative resection for advanced gastric cancer., Methods and Analysis: The STOFOLUP trial is an investigator-initiated, parallel-assigned, multicentre randomised controlled trial involving 16 hospitals in the Republic of Korea. Patients (n=886) diagnosed with pathological stage II or III gastric adenocarcinoma will be randomised to either the 3-month or the 6-month group at a 1:1 ratio, stratified by trial site and tumour stage. Patients allocated to the 3-month group will undergo an abdominal CT scan every 3 months postoperatively and those allocated to the 6-month group will undergo CT every 6 months. The primary endpoint is 3-year overall survival and the secondary endpoints are quality of life, as assessed using KOrean QUality of life in Stomach cancer patients Study group-40, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the stomach cancer-specific module (STO22), and nutritional outcomes. Other survival data including data concerning 3-year disease-free survival, recurrence-free survival, gastric cancer-specific survival and postrecurrence survival will also be estimated. The first patient was enrolled on July 2021 and active patient enrolment is currently underway., Ethics and Dissemination: This study has been approved by the Institutional Review Board of eight of the participating hospitals (NCC 2021-0085, KBSMC2021-01-059, SMC 2021-01-140, KC21OEDE0082, 4-2021-0281, AJIRB-MED-INT-20-608, 2021-0515 and H-2102-093-1198). This study will be disseminated through peer-reviewed publications, national or international conferences., Trial Registration Number: NCT04740346., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.

Iridin is a natural flavonoid found in Belamcanda chinensis documented for its broad spectrum of biological activities like antioxidant, antitumor, and antiproliferative effects. In the present study, we have investigated the antitumor potential of iridin in AGS gastric cancer cells. Iridin treatment decreases AGS cell growth and promotes G2/M phase cell cycle arrest by attenuating the expression of Cdc25C, CDK1, and Cyclin B1 proteins. Iridin-treatment also triggered apoptotic cell death in AGS cells, which was verified by cleaved Caspase-3 (Cl- Caspase-3) and poly ADP-ribose polymerase (PARP) protein expression. Further apoptotic cell death was confirmed by increased apoptotic cell death fraction shown in allophycocyanin (APC)/Annexin V and propidium iodide staining. Iridin also increased the expression of extrinsic apoptotic pathway proteins like Fas, FasL, and cleaved Caspase-8 in AGS cells. On the contrary, iridin-treated AGS cells did not show variations in proteins related to an intrinsic apoptotic pathway such as Bax and Bcl-xL. Besides, Iridin showed inhibition of PI3K/AKT signaling pathways by downregulation of (p-PI3K, p-AKT) proteins in AGS cells. In conclusion, these data suggest that iridin has anticancer potential by inhibiting PI3K/AKT pathway. It could be a basis for further drug design in gastric cancer treatment.

High expression of glucose transporter family members, which augment glucose uptake and glycolytic flux, has been shown to play a pivotal role in the proliferation and survival of tumor cells, contributing to the energy supply, biosynthesis and homeostasis of cancer cells. Among the many members, solute carrier family 2 member 1 (SLC2A1) encodes a glucose transporter, GLUT1, that is critical in the metabolism of glucose, which is an energy source for cell growth that contributes to cancer progression and development. The aim of this study was to analyze the survival and genetic changes/immune profiles in patients with gastric cancer with high SLC2A1 expression and to provide treatment for improving prognosis. This study investigated the clinicopathologic parameters, the proportion of immune cells and gene sets affecting SLC2A1 expression in 279 and 415 patients with gastric cancer from the Eulji Hospital cohort and The Cancer Genome Atlas, respectively. We assessed the response to conventional chemotherapy drugs, including fluorouracil, a compound of fluoropyrimidine S-1, oxaliplatin, and all-trans-retinoic acid (ATRA), in gastric cancer cell lines with high SLC2A1 expression. High SLC2A1 expression was associated with poor prognosis, cancer cell proliferation, decreased immune cells, including CD8 T cells and B cells, and a low prognostic nutrition index, representing body nutrition-related status. In pathway network analysis, SLC2A1 was indirectly linked to the retinoic signaling pathway and negatively regulated immune cells/receptors. In the drug response analysis, the drug ATRA inhibited gastric cancer cell lines with high SLC2A1 expression. Treatment involving the use of SLC2A1 could contribute to better clinical management/research for patients with gastric cancer., Competing Interests: This study was supported by Daewon Pharmaceutical Co., Ltd. in 2018. (To Byoung Kwan Son). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background/aims: Some cases of gastric low-grade dysplasia (LGD) and high-grade dysplasia (HGD) on forceps biopsy (FB) are diagnosed as gastric cancer (GC) after endoscopic resection (ER). This study aims to evaluate the clinical outcomes of ER for gastric LGD and HGD on pretreatment FB and to identify the factors that predict pathologic upstaging to GC., Methods: Patients who underwent ER for LGD and HGD on pretreatment FB from March 2005 to February 2018 in 14 hospitals in South Korea were enrolled, and the patients' medical records were reviewed retrospectively., Results: This study included 2,150 cases of LGD and 1,534 cases of HGD diagnosed by pretreatment FB. In total, 589 of 2,150 LGDs (27.4%) were diagnosed as GC after ER. Helicobacter pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration significantly predicted GC. A total of 1,115 out of 1,534 HGDs (72.7%) were diagnosed with GC after ER. Previous history of GC, H. pylori infection, smoking history, tumor location in the lower third of the stomach, tumor size >10 mm, depressed lesion, and ulceration were significantly associated with GC. As the number of risk factors predicting GC increased in both LGD and HGD on pretreatment FB, the rate of upstaging to GC after ER increased., Conclusions: A substantial proportion of LGDs and HGDs on pretreatment FB were diagnosed as GC after ER. Accurate ER procedures such as endoscopic submucosal dissection should be recommended in cases of LGD and HGD with factors predicting pathologic upstaging to GC.

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

Scutellarein (SCU), a flavone that belongs to the flavonoid family and abundantly present in Scutellaria baicalensis a flowering plant in the family Lamiaceae, has been reported to exhibit anticancer effects in several cancer cell lines including gastric cancer (GC). Although our previous study documented the mechanisms of Scutellarein‑induced cytotoxic effects, the literature shows that the proteomic changes that are associated with the cellular response to SCU have been poorly understood. To avoid adverse side‑effects and significant toxicity of chemotherapy in patients who react poorly, biomarkers anticipating therapeutic responses are imperative. In the present study, we utilized a comparative proteomic analysis to identify proteins associated with Scutellarein (SCU)‑induced cell death in GC cells (AGS and SNU484), by integrating two‑dimensional gel electrophoresis (2‑DE), mass spectrometry (MS), and bioinformatics to analyze the proteins. Proteomic analysis between SCU‑treated and DMSO (control) samples successfully identified 41 (AGS) and 31 (SNU484) proteins by MALDI‑TOF/MS analysis and protein database search. Comparative proteomics analysis between AGS and SNU484 cells treated with SCU revealed a total of 7 protein identities commonly expressed and western blot analysis validated a subset of identified critical proteins, which were consistent with those of the 2‑DE outcome. Molecular docking studies also confirmed the binding affinity of SCU towards these critical proteins. Phosphatidylinositol 4,5‑bisphosphate 3‑kinase catalytic subunit β isoform (PIK3CB) protein expression was accompanied by a distinct group of cellular functions, including cell growth, and proliferation. Cancerous inhibitor of protein phosphatase 2A (CIP2A), is one of the oncogenic molecules that have been shown to promote tumor growth and resistance to apoptosis and senescence‑inducing therapies. In the present study, both PIK3CB and CIP2A proteins were downregulated in SCU‑treated cells, which boosts our previous results of SCU to induce apoptosis and inhibits GC cell growth by regulating these critical proteins. The comparative proteomic analysis has yielded candidate biomarkers of response to SCU treatment in GC cell models and further validation of these biomarkers will help the future clinical development of SCU as a novel therapeutic drug.

Apigetrin is a flavonoid glycoside phytonutrient derived from fruits and vegetables that is well known for a variety of biological activities such as antioxidant and anti-inflammatory activities. In the current study, we determined the effect of apigetrin on AGS gastric cancer cell. Apigetrin reduced cancer cell proliferation and induced G2/M phase cell cycle arrest by regulating cyclin B1, cdc25c and cdk1 protein expression in AGS cell. Apigetrin treatment caused apoptotic cell death in AGS cells, characterized by the accumulation of apoptosis portion, cleavage of caspase-3 and poly ADP-ribose polymerase (PARP). Apigetrin-treated cells increased the expression of extrinsic apoptosis pathway proteins and mRNA. However, intrinsic apoptosis pathway related proteins were not altered. In addition, AGS cells treated with apigetrin increased autophagic cell death, featured by the formation of autophagic vacuole and acidic vesicular organelles. Autophagy marker proteins, such as LC3B-II and beclin-1, were increased, and p62, an autophagy flux marker protein, was also increased by endoplasmic reticulum stress. Also, the phosphorylation of PI3K/AKT/mTOR pathway proteins and its downstream targets in apigetrin-treated AGS cells was identified to be decreased. Taken together, these data suggest that apigetrin-treated AGS cells induced G2/M phase cell cycle arrest, extrinsic apoptosis and autophagic cell death through PI3K/AKT/mTOR pathway, which can lead to the inhibition of gastric cancer development. Thus, our findings strongly indicate that apigetrin is a basic natural derived compound that could be used as a nutrient source with potential anticancer activities against gastric cancer., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Gastric cancer is the common type of malignancy positioned at second in mortality rate causing burden worldwide with increasing treatment options. Prunetin (PRU) is an O-methylated flavonoid that belongs to the group of isoflavone executing beneficial activities. In the present study, we investigated the anti-proliferative and cell death effect of the compound PRU in AGS gastric cancer cell line. The in vitro cytotoxic potential of PRU was evaluated and significant proliferation was observed. We identified that the mechanism of cell death was due to necroptosis through double staining and was confirmed by co-treatment with inhibitor necrostatin (Nec-1). We further elucidated the mechanism of action of necroptosis via receptor interacting protein kinase 3 (RIPK3) protein expression and it has been attributed by ROS generation through JNK activation. Furthermore, through computational analysis by molecular docking and dynamics simulation, the efficiency of compound prunetin against RIPK3 binding was validated. In addition, we also briefed the pharmacokinetic properties of the compound by in silico ADMET analysis.

Background: The indications for endoscopic dissection have been expanded to improve the quality of life of patients with early gastric cancer (EGC). This study aimed to develop a nomogram to predict the status of lymph node metastasis with the aim of avoiding unnecessary gastrectomies., Methods: We reviewed the clinicopathological data of 10 579 patients who underwent curative resection for EGC. The nomogram was developed by multivariate analysis and was evaluated by external validation. Overall, disease-free and recurrence-free survival were compared between the gastrectomy group of 6641 patients and the endoscopic dissection group of 999 patients to show the efficacy of the nomogram., Results: Multivariate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion, and histologic differentiation were all significant prognostic factors for lymph node metastasis. The nomogram had good discriminatory performance, with a concordance index of 0.846. This was supported by the external validation point of 0.813. For patients with low risk of lymph node metastasis on the nomogram (≤ 3 % of the provisional value in this study), the endoscopic dissection and gastrectomy groups had comparable rates of overall ( P  = 0.32), disease-free ( P  = 0.47), and recurrence-free ( P  = 0.09) survival., Conclusions: We developed and validated a nomogram that predicts the risk of lymph node metastasis in EGC based on a large database. This precision nomogram is useful to avoid unnecessary gastrectomy after endoscopic dissection, which may ultimately improve the quality of life of patients with EGC., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Autophagy is a process of active programmed cell death, where a dying cell induces autophagosomes and subsequently regulated by degradative machinery. The aim of this study was to investigate the mechanism behind induction of autophagic cell death by Naringin flavonoid in AGS cancer cells. Growth inhibition of AGS cells showed downregulation of PI3K/Akt/mTOR signaling by Naringin treatment. Transmission electron microscopy observation showed swollen mitochondria and lysosome near peri-nuclear zone fused with autophagic vacuoles. Rapamycin pre-treatment with Naringin showed significant decrease in mTOR phosphorylation and increase in LC3B activation in AGS cells. Decrease in mTOR phosphorylation is associated with lysosomal function activation was observed by time-dependent treatment of Naringin. Induction of lysosomal membrane permeabilization (LMP) was observed by LAMP1 activation leading lysosomal cell death by releasing Cathepsin D from lysosomal lumen to cytosol. Naringin treated AGS cells showed up-regulating BH3 domain Bad, down-regulating Bcl-xL, and Bad phosphorylation and significant mitochondrial fluorescence intensity expression. Significant localization of mitochondria and LC3B activation was examined by person coefficient correlation. Activation of ERK1/2-p38 MAPKs and production of intracellular ROS has been observed over Naringin treatment. It has also been elucidated that pre-treatment with NAC inhibited mitochondria-LC3B colocalization, where ROS acted as upstream of ERK1/2-p38 MAPKs activation. Lysosomal cell death involvement has been evaluated by BAF A1 pre-treatment, inhibiting LAMP1, Cathepsin D, ROS, and blocking autophagolysosome in AGS cell death. Taken together, these findings show that, Naringin induced autophagy cell death involves LMP mediated lysosomal damage and BH3 protein Bad activation in AGS cancer cells.

Objective: The predictive value of mismatch repair protein deficiency (MMRD) for chemoradiotherapeutic outcome has rarely been reported in gastric cancer. This study investigated the clinical significance of MMRD as a prognostic factor for tumor recurrence, and as a predictor of response to adjuvant chemoradiotherapy in advanced gastric cancer patients., Methods: Between 1995 and 2008, tissue specimens of 881 patients who underwent radical gastrectomy for stage II and III gastric cancer were analyzed. MMRD was assessed using immunohistochemical stains for MLH1, PMS2, MSH2, and MSH6. Patients were divided into two groups according to adjuvant treatment: a 5-fluorouracil/leucovorin (FL) adjuvant chemoradiotherapy group and a surgery alone group. Disease-free survival (DFS) was compared between the two groups correlated to MMRD. Risk factors for tumor recurrence were analyzed using multivariate analysis., Results: Of the 881 gastric cancer patients, 88 (10.0%) exhibited MMRD and 398 (45.2%) patients received adjuvant FL chemoradiotherapy. The multivariate analysis revealed that MMRD was a good independent prognostic factor (hazard ratio, 0.572; 95% confidence interval, 0.370-0.883; P = 0.012). For stage III gastric cancer displaying mismatch repair protein proficiency (MMRP), adjuvant FL chemoradiotherapy after surgery resulted in better DFS than surgery alone (P = 0.001). Among the stage II gastric cancer patients, adjuvant FL chemoradiotherapy did not show survival benefit, regardless of MMRD., Conclusion: MMRD is a good independent prognostic factor in advanced gastric cancer. Adjuvant FL chemoradiotherapy was beneficial in patients with stage III gastric cancer with MMRP but not in those with MMRD., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Combination laparoscopic lymph node (LN) dissection and endoscopic resection is a promising treatment for early gastric cancer. However, LN dissection could cause nerve injury and deterioration of motility in the preserved stomach. This experimental study aims to evaluate changes in gastric motility after tailored perigastric regional lymph node dissection without gastrectomy., Materials and Methods: We identified four most frequently involved LN combinations considering tumor location from retrospective reviews of 4697 gastrectomy patients. We randomly assigned 55 dogs to five groups: control (laparotomy only) and four experimental groups with LN dissection without gastrectomy: group 1 (LNs 3, 7, and 8), group 2 (LNs 3, 4, and 6), group 3 (LNs 1, 3, and 7), and group 4 (LNs 3, 4, and 11). Gastric emptying time (GET) was measured using barium-impregnated polyethylene spheres. GET 50 and GET 75 were the time points when 50% and 75% of the markers, respectively, had emptied from the stomach., Results: On postoperative days (PODs) 2 and 3, GET 50, GET 75, and proportion of GET 50 <4 h in groups 1 and 2 were comparable with controls. However, group 3 showed delayed GET 50 and GET 75 , and groups 3 and 4 demonstrated significantly smaller proportions of GET 50 <4 h compared with controls on PODs 2 and 3. This effect resolved by POD 6 and there were no significant differences in GET 50, GET 75, or proportion of GET 50 <4 h between the groups., Conclusions: Tailored perigastric LN resection without gastrectomy was feasible and acceptable in terms of postoperative motility in the preserved stomach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family ( RASSF1 ), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

Background: The aim of this study was to develop a prediction model for the presence and location of lymph node metastasis (LNM) in early gastric cancer., Method: We reviewed medical records of 4 929 patients who underwent radical gastrectomy for early gastric cancer. Variables of age, sex, lymphatic invasion, depth of invasion, location, gross type, differentiation, and tumor size were analyzed. Logistic regression analysis was used to determine independent predictors of LNM at each LN station., Result: Overall incidence of LNM was 9.1% (448/4 929 patients). For the presence of LNM, risk factors of age, sex, lymphatic invasion, depth of invasion, anatomical part, gross ulceration, size, and tumor differentiation were significantly associated with LNM. The area under the curve (AUC) for predicting LNM after validation was 0.834 for the test set. For the location of LNM, age, sex, lymphatic invasion, depth of invasion, anatomical part, circumferential portion, gross type, differentiation, and tumor size were significantly associated with LNM. The AUC of each LN station was favorable with the test set., Conclusion: Predicting the location of metastatic LNs appeared to be possible in patients with early gastric cancer., (© 2019 Wiley Periodicals, Inc.)

Introduction: Signet ring cell carcinoma (SRC) is a poorly differentiated cancer of the stomach. Recent studies imply that early gastric SRC can be well managed by endoscopic resection. Unfortunately, unlike differentiated cancers, the endoscopic features of early gastric SRC have not been well studied. This study evaluated the endoscopic features of early gastric SRC, as well as the risk factors for submucosal (SM) invasion., Method: The medical records of patients from 7 tertiary hospitals (Daejeon and Chungcheong province) were reviewed to examine endoscopic findings and clinical data. These patients underwent surgery or endoscopic resection between January 2011 and December 2016 and were divided into 2 groups (derivation group and validation group) in order to develop and validate an endoscopic scoring system for SM invasion., Results: In total, 331 patients (129 in the derivation group and 202 in the validation group) were enrolled in this study. In the derivation group, the risk factors for SM invasion, namely, fold convergence, nodular mucosal change, and deep depression, were identified by logistic regression analysis (ORs 3.4, 5.9, and 6.0, p < 0.05). A depth-prediction score was created by assigning 1 point for fold convergence and 2 points for other factors. When validation lesions of 0.5 point or more were diagnosed as SM invasion, the sensitivity and specificity were 76.8-78.6% and 61.6-74.7% respectively., Conclusion: Fold convergence, nodular mucosal change, and deep depression are risk factors for SM invasion in early gastric SRC. Our depth-prediction scoring system may be useful for differentiating SM cancers., (© 2018 S. Karger AG, Basel.)

Proteomic analysis serves as an important biological tool for identifying biological events. Novel biomarkers of a specific disease such as cancer may be identified using these promising techniques. The aim of the present study was to investigate the effect of tangeretin and to identify potential biomarkers in AGS gastric cancer cells using a proteomics approach. The results of the present study revealed that tangeretin inhibited AGS cell viability dose‑dependently with a half‑maximal inhibitory concentration of 100 µM. Two‑dimensional gel electrophoresis was performed to determine the potential biomarker between control and tangeretin (100 µM)‑treated AGS cells. A total of 16 proteins was identified from 36 significant protein spots using matrix‑assisted laser‑desorption/ionization time‑of‑flight‑mass spectrometry using peptide fingerprinting. The bioinformatics tools Protein ANalysis THrough Evolutionary Relationships (PANTHER) and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to identify the functional properties and association of the proteins obtained. Using western blot analysis, the regulatory pattern of four selected proteins, protein kinase Cε, mitogen‑activated protein kinase 4, phosphoinositide 4‑kinase and poly(ADP‑ribose) polymerase 14, were successfully verified in replicate sample sets. These selected proteins are primarily involved in apoptosis signaling, angiogenesis, cell cycle regulation, receptor kinase binding, intracellular cytoplasmic and nuclear alterations. Therefore, aim of the present study was to identify potential diagnostic biomarkers from the functional categories of altered protein expression in tangeretin‑inhibited AGS gastric cancer cell viability.

Gastric cancer (GC) patients usually receive surgical treatment. Postoperative therapeutic options such as anticancer adjuvant therapies (AT) based on prognostic prediction models would provide patient-specific treatment to decrease postsurgical morbidity and mortality rates. Relevant prognostic factors in resected GC patient's serum may improve therapeutic measures in a non-invasive manner. In order to develop a GC prognostic model, we designed a retrospective study. In this study, serum samples were collected from 227 patients at a 4-week recovery period after D2 lymph node dissection, and 103 cancer-related serum proteins were analyzed by multiple reaction monitoring mass spectrometry. Using the quantitative values of the serum proteins, we developed SEPROGADIC (SErum PROtein-based GAstric cancer preDICtor) prognostic model consisting of 6 to 14 serum proteins depending on detailed purposes of the model, prognosis prediction and proper AT selection. SEPROGADIC could clearly classify patients with good or bad prognosis at each TNM stage (1b, 2, 3 and 4) and identify a patient subgroup who would benefit from CCRT (combined chemoradiation therapy) rather than CTX (chemotherapy), or vice versa. Our study demonstrated that serum proteins could serve as prognostic factors along with clinical stage information in patients with resected gastric cancer, thus allowing patient-tailored postsurgical treatment.

Pectolinarigenin (PEC), a natural flavonoid that is present in citrus fruits, has been reported to exhibit antitumor effects in several cancers. Though the mechanism of PEC-induced cytotoxicity effects has been documented, the proteomic changes that are associated with the cellular response to this flavonoid are poorly understood in gastric cancer cells. In this study, a comparative proteomic analysis was performed to identify proteins associated with PEC-induced cell death in two human gastric cancer cell lines: AGS and MKN-28. Two-dimensional gel electrophoresis (2-DE) revealed a total of 29 and 56 protein spots with significant alteration were screened in AGS and MKN-28 cells respectively. In total, 13 (AGS) and 39 (MKN28) proteins were successfully identified by mass spectrometry from the differential spots and they are known to be involved in signal transduction, apoptosis, transcription and translation, cell structural organization, and metabolism, as is consistent with multiple effects of PEC on tumor cells. Notably, novel target proteins like Probable ATP-dependent RNA helicase DDX4 (DDX4) and E3 ubiquitin-protein ligase LRSAM1 (LRSAM1) along with the commonly differential expressed proteins on both the cell lines that are treated with PEC were confirmed by immunoblotting. The DDX4 accelerates cell cycle progression by abrogating the G2 checkpoint when overexpressed in cancer cells, while the aberrant expression of LRSAM1 may be involved in the cancer pathology. Thus, proteomic analysis provides vital information about target proteins that are important for PEC-induced cell death in gastric cancer cells., Competing Interests: We declare that there are no conflicts of interest.

Background: Biomarkers are needed for noninvasive early detection of gastric cancer (GC). We investigated salivary extracellular RNA (exRNA) biomarkers as potential clinical evaluation tools for GC., Methods: Unstimulated whole saliva samples were prospectively collected from 294 individuals (163 GC and 131 non-GC patients) who underwent endoscopic evaluation at the Samsung Medical Center in Korea. Salivary transcriptomes of 63 GC and 31 non-GC patients were profiled, and mRNA biomarker candidates were verified with reverse transcription quantitative real-time PCR (RT-qPCR). In parallel, microRNA (miRNA) biomarkers were profiled and verified with saliva samples from 10 GC and 10 non-GC patients. Candidate biomarkers were validated with RT-qPCR in an independent cohort of 100/100 saliva samples from GC and non-GC patients. Validated individual markers were configured into a best performance panel., Results: We identified 30 mRNA and 15 miRNA candidates whose expression pattern associated with the presence of GC. Among them, 12 mRNA and 6 miRNA candidates were verified with the discovery cohort by RT-qPCR and further validated with the independent cohort (n = 200). The configured biomarker panel consisted of 3 mRNAs ( SPINK7 , PPL , and SEMA4B ) and 2 miRNAs ( MIR140-5p and MIR301a ), which were all significantly down-regulated in the GC group, and yielded an area under the ROC curve (AUC) of 0.81 (95% CI, 0.72-0.89). When combined with demographic factors, the AUC of the biomarker panel reached 0.87 (95% CI, 0.80-0.93)., Conclusions: We have discovered and validated a panel of salivary exRNA biomarkers with credible clinical performance for the detection of GC. Our study demonstrates the potential utility of salivary exRNA biomarkers in screening and risk assessment for GC., (© 2018 American Association for Clinical Chemistry.)

Pectolinarigenin (PEC), a natural flavonoid present in Cirsium chanroenicum and in some species of Citrus fruits, has various pharmacological benefits such as anti-inflammatory and anti-cancer activities. In the present study, we investigated the anti-cancer mechanism of PEC induced cell death caused by autophagy and apoptosis in AGS and MKN28 human gastric cancer cells. The PEC treatment significantly inhibited the AGS and MKN28 cell growth in a dose-dependent manner. Further, PEC significantly elevated sub-G1 phase in AGS cells and G2/M phase cell cycle arrest in both AGS and MKN28 cells. Apoptosis was confirmed by Annexin V and Hoechst 33342 fluorescent staining. Moreover, Immunoblotting results revealed that PEC treatment down-regulated the inhibitor of apoptosis protein (IAP) family protein XIAP that leads to the activation of caspase-3 thereby cleavage of PARP (poly-ADP-ribose polymerase) in both AGS and MKN28 cells in a dose-dependent manner. The autophagy-inducing effect was indicated by the increased formation of acidic vesicular organelles (AVOs) and increased protein levels of LC3-II conversion in both AGS and MKN28 cells. PEC shows the down regulation of PI3K/AKT/mTOR pathway which is a major regulator of autophagic and apoptotic cell death in cancer cells that leads to the down-regulation of p-4EBP1, p-p70S6K, and p-eIF4E in PEC treated cells when compared with the untreated cells. In conclusion, PEC treatment might have anti-cancer effect by down-regulation of PI3K/AKT/mTOR pathway leading to G2/M phase cell cycle arrest, autophagic and apoptotic cell death in human gastric cancer cells. Further studies of PEC treatment can support to develop as a potential alternative therapeutic agent for human gastric carcinoma.

Background: Limited studies exist comparing clinical outcomes by adjuvant treatment for pT1N1 gastric cancer. This study compared the disease-free survival (DFS) of patients with pT1N1 gastric cancer according to the type of adjuvant treatment-surgery alone, chemotherapy (CTx), and chemoradiotherapy (CCRTx)-and evaluated risk factors for tumor recurrence., Methods: Between 1995 and 2015, 738 patients underwent radical gastrectomy for pT1N1 gastric cancer and were divided into three groups: surgery alone (n = 355), CTx (n = 214), and CCRTx (n = 169). Chronological changes in adjuvant treatment type and chemotherapeutic regimens were evaluated and DFS was compared. Risk factors for tumor recurrence were analyzed., Results: The proportion of patients who underwent surgery alone was more than 50% until 2001, and the proportion of those who had either CTx or CCRTx was more than 50% from 2002 to 2011, after which the proportion who underwent surgery alone increased again. The main chemotherapeutic agent was 5-fluorouracil with leucovorin. The 5-year DFS was 96.5% in the surgery-alone group, 96.0% in the CTx group, and 95.8% in the CCRTx group (no significant difference). The various chemotherapeutic regimens did not show differences in DFS. In univariate and multivariate analyses, adjuvant CTx and CCRTx showed no beneficial effect with regard to tumor recurrence., Conclusions: Because adjuvant CTx and CCRTx did not show any benefit with regard to tumor recurrence, these treatment strategies might be unnecessary for pT1N1 gastric cancer after gastrectomy. Further studies are necessary to reveal pT1N1 gastric cancer patient subgroups who might benefit from adjuvant treatments.

Purpose: The purpose of this study was to estimate surgical outcomes of elderly patients older than 80 years who received laparoscopic or open gastrectomy for gastric cancer and to identify risk factors for postoperative complications., Methods: Two hundred forty-two elderly patients older than 80 years underwent gastric cancer surgery between January 2010 and December 2016 in three tertiary hospitals. They were divided into two groups: laparoscopic gastrectomy (N = 59) and open gastrectomy (N = 183). The surgical outcomes and risk factors for postoperative complication were evaluated., Results: Among the elderly patients, 24.4% showed an ASA score of 3 or 4, and 20.7% showed a Charlson comorbidity index (CCI) score of 2 or more. 46.3% of patients had hypertension and 15.3% had diabetes. The laparoscopic gastrectomy group showed similar operation time, less intraoperative blood loss, and faster postoperative gastrointestinal recovery compared to the open gastrectomy group. The incidence of postoperative complications was 30.1% in the open group and 22.0% in the laparoscopic group (P = 0.249). One patient died for pulmonary complication in the open gastrectomy group. In multivariate analysis, older age, male, higher CCI score, and open approach were found to be correlated with increased risk for postoperative complications., Conclusions: Although elderly patients over 80 years had a high incidence of comorbidity, gastric cancer surgery can be safely performed. The laparoscopic approach might be feasible for open surgery in improving quality of life in these patients, given a faster postoperative intestinal recovery period, with similar risk for postoperative complications.

Purpose: Gastric cancer shows a male predominance that might be explained by protective effects from estrogens in females. Two Lauren classification histological subtypes, intestinal and diffuse, have distinct carcinogeneses. The purpose of this study was to estimate the effects of sex hormone on female gastric cancer according to Lauren classification., Materials and Methods: We reviewed medical records for and administered questionnaires, surveying reproductive and hormonal factors, to 758 patients who underwent gastrectomy for gastric cancer at Samsung Medical Center from May 2012 to November 2014. Clinicopathological characteristics were compared between females and males. The incidence of intestinal-type gastric cancer was compared between females subgroups, consist of premenopausal women and three groups of postmenopausal women (five-year intervals after menopause), and males. The association between reproductive factors and intestinal-type gastric cancer was analyzed by multivariate models for the female group., Results: In total, 227 females (29.9%) and 531 males (70.9%) were included in the analysis. Undifferentiated adenocarcinoma and diffuse-type histology were more frequent in female patients than male patients. While 221 (41.6%) male patients had intestinal-type gastric cancer, no premenopausal female patient had this type of gastric cancer. The incidence of intestinal-type gastric cancer increased with time after menopause, and was similar to males after 10 years from menopause. Parity was associated with an increased risk of intestinal-type gastric cancer in menopausal women., Conclusion: These findings support that female sex hormones might be protective against intestinal-type gastric cancer., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018)

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is a viral protein expressed in all EBV-infected cells that induces malignant transformation. EBNA1 is reported to contribute to tumor progression through an increase in reactive oxygen species via nicotinamide adenine dinucleotide phosphate oxidase. However, the underlying molecular mechanism of EBNA1-induced ROS accumulation in gastric cancer is poorly understood. Here, we demonstrated that miR34a regulation by EBNA1 determined cell fate in EBV-infected gastric cancer cells. ROS content and NOX2 expression were higher in EBNA1-expressing SNU719 cells than in EBNA1-nonexpressing SNU638 cells. Downregulation of NOX2 using siRNA technology in SNU719 cells decreased cell viability and ROS content. Regulation of EBNA1 expression in EBV-associated gastric cancers modulated NOX2 expression, ROS content and cell viability. We also showed that upregulation of NOX2 by EBNA1 was mediated by downregulating miRNA34a. Finally, overexpression of miR34a in EBNA1-expressing SNU719 cells induced typical apoptosis, suggesting that reactivation of miR34a in EBNA1-expressing gastric cancer cells could be a strategy for treatment of EBV-infected gastric cancer cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: It remains unclear whether selection of treatment modality affects the survival of patients with malignant gastric outlet obstruction (GOO). We compared the effect of gastrojejunostomy (GJ) and endoscopic self-expandable metallic stent (SEMS) placement on the long-term outcomes of patients with malignant GOO caused by unresectable gastric cancer., Method: We conducted a retrospective study of gastric cancer patients undergoing GJ or endoscopic SEMS placement for the palliation of malignant GOO. To reduce the effect of selection bias, we performed a propensity score-matching analysis between two groups., Results: In a propensity-matched analysis (45 and 99 in GJ and SEMS groups, respectively), clinical success rates were comparable between the GJ and SEMS groups (95.6 and 96.0%), while the SEMS group showed significantly shorter hospital stays than the GJ group. The GJ group showed a significantly longer reintervention period and overall survival (393 and 129 days) compared to the SEMS group. In multivariate Cox regression analysis, GJ, low ECOG scale (good performance status), and additional chemo- or radiation therapy were identified as independent favorable predictors of overall survival. GJ was also identified as an independent protective predictor against reintervention., Conclusion: We found that palliative GJ was significantly associated with longer overall survival and lower risk of reintervention than SEMS placement in patients with malignant GOO caused by unresectable gastric cancer. Given very limited expected survival in selected patients with unresectable gastric cancer and more favorable short-term outcomes in cases of SEMS placement, individualized approach might be required in treatment decision between palliative GJ and SEMS placement.

Gastric cancer remains the second most common cancer in Korea; however, its mortality has decreased due to earlier diagnosis. In Korea, screening endoscopy has been performed nationwide since 1999. The aim of this study was to elucidate the benefit of screening endoscopy on actual survival in gastric cancer patients and to determine the optimal interval of screening endoscopy.We analyzed 1651 patients diagnosed with gastric adenocarcinoma who underwent surgical treatment between June 2008 and December 2014. Patients were divided into 4 groups according to the interval of screening endoscopy prior to their gastric cancer diagnosis. (Group I = within 1 year, Group II = >1 but <2 years, Group III = more than 2 years, Group IV = no prior endoscopic examination). Patient demographics, clinicopathologic characteristics, and postoperative surgical outcomes including overall survival were compared.The 5-year gastric cancer-specific survival rates of groups I and II were significantly higher than groups III and IV (90.9% vs 85.4%, P = 0.002, respectively). Multivariate analysis showed that screening interval was an independent factor for the diagnosis of advanced gastric cancer. The risk of advanced gastric cancer decreased in group I (odds ratio: 0.515, 95% confidence interval [CI] 0.369-0.719; P < 0.001) and group II (odds ratio: 0.678, 95% CI 0.517-0.889, P = 0.005).Screening endoscopy was helpful in increasing the survival of gastric cancer patients. A 2-year endoscopic screening interval is suitable to detect early-stage gastric cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: The aim of this study was to compare surgical outcomes of patients with gastric cancer undergoing reduced port totally laparoscopic-assisted total gastrectomy (duet TLTG) with those of patients undergoing conventional laparoscopic-assisted total gastrectomy (LATG)., Materials and Methods: Between January 2013 and 2015, 54 patients with gastric cancer underwent LATG at the Samsung Medical Center. Duet TLTG using 3 ports was performed in 30 patients, and conventional LATG using 5 ports was performed in 24 patients. Either extracorporeal or intracorporeal anastomosis was used for esophagojejunostomy. Surgical outcomes were compared between the operation methods., Results: The operating time was similar for duet TLTG and conventional LATG [222 min (range, 163 to 287 min) vs. 233 min (range, 170 to 310 min), respectively; P=0.807]. Blood loss during surgery was also similar between duet TLTG and conventional LATG groups [100 mL (range, 50 to 400 mL) vs. 175 mL (range, 50 to 400 mL), respectively; P=0.249]. The median number of nodes dissected [duet TLTG vs. conventional LATG, 47 (20 to 67) vs. 41 (22 to 70), P=0.338] was not different between groups. Pain scores were 3.9, 3.3, and 2.9, and 3.9, 3.4, and 2.8, at postoperative days 1, 3, and 5, respectively, in the duet TLTG and the conventional LATG groups (P=0.857, 0.659, and 0.427, respectively). Overall complication rates in the duet TLTG and conventional LATG groups were not significantly different (36.7% vs. 16.7%, P=0.103)., Conclusions: Duet TLTG is an acceptable procedure with quality of lymph node dissection, including the number of dissected lymph nodes and morbidity.

Objective: The aim of the study was to develop a reliable and easy-to-use risk-scoring system (RSS) to predict lymph-node metastasis (LNM) and determine the feasibility of endoscopic submucosal dissection for mucosa-confined signet ring cell carcinomas (SRCs)., Background: Fewer LNM and better survival rates have been reported for early gastric SRCs compared with other undifferentiated early gastric cancers (EGCs)., Methods: Data from 1544 patients with mucosa-confined SRCs were reviewed. Stepwise logistic regression analysis determined the independent predictors of LNM. Risk scores were based on the final predictive factors for LNM, and performance was internally validated using a split-sample approach. External validation was also performed in an independent dataset (n = 208) to assess the discriminatory power of the RSS., Results: The overall LNM incidence was 3.8% (57/1544). Three risk factors (tumor size ≥1.7 cm, tumors of elevated type, and lymphatic-vascular involvement) were significantly associated with LNM. These factors were incorporated into the RSS, and were assigned scores ranging from 0 to 4. The area under the receiver-operating characteristic curve for predicting LNM after internal and external validation was 0.68 (95% confidence interval, 0.0793-0.2865) and 0.686 (95% confidence interval, 0.618-0.748), respectively. A score of 2 points was the optimal cut-off value for LNM prediction, and the overall diagnostic accuracy was 96%. LNM were found in 2.9% and 23.8% of the low and high-risk groups of the RSS, respectively., Conclusions: A RSS may help to predict LNM and evaluate endoscopic submucosal dissection feasibility in patients with intramucosal SRC.

Background: Laparoscopy-assisted distal gastrectomy (LADG) is a treatment method for patients with early gastric cancer; however, single- or reduced-port LADG for these patients has been rarely reported., Objective: To compare surgical outcomes of patients with gastric cancer undergoing single-port totally laparoscopic distal gastrectomy (TLDG) to those of patients undergoing reduced-port (three ports) TLDG., Methods: This retrospective study included 94 patients with early gastric cancer who underwent single-port or reduced-port TLDG at Samsung Medical Center between May 2014 and December 2014. Surgical outcomes were compared between operation methods., Results: There are more female patients (54.2 vs. 19.6 %, p = 0.001) and less obese patients (21.1 ± 2.1 vs. 24.6 ± 3.2 kg/m(2), p = 0.001) in the single-port TLDG group. There were no significant differences in blood loss during surgery, the number of dissected lymph nodes, and the pain score at postoperative first day between two groups. The variance in operation time for the reduced-port TLDG was significantly greater than that for single-port TLDG (p = 0.01). Complication rates in the single-port and reduced-TLDG groups were similar (20.8 vs. 21.7 %, p = 1.000). No postoperative deaths occurred in either group., Conclusions: Single-port TLDG might be considered as a treatment option for a limited subset, such as females or less obese patients with early gastric cancer.

The brain-derived neurotrophic factor (BDNF) activates its receptor, tropomyosin receptor kinase B (TrkB; also called NTRK2) that has been shown to promote the malignant progression of several cancers. In this study, we investigated the clinical and biological significance of the BDNF/TrkB axis in the progression of human gastric cancer. The increased co-expression of the BDNF/TrkB axis was significantly correlated with bone metastatic properties in advanced gastric cancers. BDNF acting via TrkB receptors increased the levels of long pentraxin 3 (PTX3) that was related to bone metastatic status of gastric cancer by enhancing gastric cancer-osteoblastic niche interactions. In bone metastatic gastric cancer, PTX3 knockdown using small interfering RNA significantly inhibited BDNF-induced interactions of cancer cells with osteoblasts. Moreover, BDNF-derived PTX3 induction supported subsequent osteoclastogenesis, and this effect was significantly reversed by PTX3 silencing. These findings suggest that a functional interaction between BDNF/TrkB and PTX3 enhances the osteolysis of bone metastatic gastric cancer, thereby providing potential prognostic factors for the development of bone metastasis of gastric cancer.

Objective: To compare the postoperative quality of life of vagus nerve preserving distal gastrectomy (VPG) vs conventional distal gastrectomy (CG) in patients with early-stage gastric cancer., Design: Randomized controlled clinical trial., Setting: Large tertiary comprehensive cancer center in Korea., Participants: One hundred sixty-three patients with early gastric cancer 18 years of age or older expected to undergo curative gastric resection., Intervention: Patients were randomized 1:1 to VPG (n = 85) or CG (n = 78)., Main Outcome Measures: European Organization for Research and Treatment of Cancer (EORTC) gastric module (STO22)., Results: Patients assigned to VPG showed less diarrhea 3 and 12 months after surgery (P = 0.040 and 0.048, respectively) and less appetite loss at 12 months (P = 0.011) compared with those assigned to CG. In both groups, fatigue, anxiety, eating restriction, and body image deteriorated at 3 months after surgery and did not regain baseline levels 12 months after surgery. There were no significant differences between the 2 groups in cancer recurrence and death over 5 years of follow-up., Conclusions: Early gastric cancer patients undergoing VPG reported significantly less diarrhea and appetite loss at 12 months postsurgery compared with those undergoing CG, with no differences in long-term clinical outcomes. VPG may improve the quality of life after gastrectomy in early gastric cancer patients compared with CG.

Background and Aims: Endoscopic resection for mucosal gastric cancer (MGC) is highly recommended in the absence of lymph node metastasis (LNM). We aimed to clarify the risk factors for LNM in MGC and to investigate the association of LNM with the indication criteria for endoscopic submucosal dissection (ESD)., Methods: A retrospective cohort study was performed on 3951 patients with MGC who underwent radical gastrectomy at the Samsung Medical Center in Seoul, Republic of Korea, between September 1994 and September 2010., Results: Of the patients with MGC, 101 (2.60%) were positive for LNM. Multivariate analysis, followed by univariate analysis, revealed the following risk factors for LNM in MGC: large tumor size, undifferentiated tumor type, lymphatic invasion, perineural invasion, and associated ulceration in the tumor (hazard ratio 1.25, 7.49, 20.65, 23.45, and 4.07, respectively). Patients without LNM had significantly increased survival and/or recurrence-free survival rates than patients with LNM (188.4/209.8 months vs 169.5/188.0 months; P = .029/.004, respectively). Only 3 of 1065 patients (0.3%) who met the absolute indication criteria for ESD had LNM. Of those who met the expanded indication criteria for ESD, 11 of 2678 patients (0.4%) had LNM. LNM also was found in 2 patients who had a differentiated tumor <0.5 cm without ulceration., Conclusion: The risk for LNM was very low when patients with MGC met the absolute and/or expanded criteria for endoscopic resection, which meant the indication criteria for ESD was safe and acceptable. However, although the risk for LNM is very low, it should not be considered negligible in endoscopic resection., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Single-port laparoscopic surgery for patients with early gastric cancer has been rarely reported. Our aim was to introduce techniques of the single-port totally laparoscopic distal gastrectomy (TLDG) in patients with early gastric cancer., Methods: This procedure was performed using only one 3-3.5 cm skin incision on the umbilicus. One 12 mm and two 10 mm ports were used, and the flexible scope was used during the operation. Partial omentectomy with D1 + β or more lymph node dissection was performed. Bowel continuity was restored by intracorporeal gastroduodenostomy using two linear staplers., Results: A total of 30 patients underwent single-port TLDG from June to August 2014. Median age of patients was 55 years (range 33-77) and median body mass index of patients was 21.2 kg/m(2) (range 15.7-26.1). Sixteen of 30 patients (53.3 %) were female. Operating times were 122.6 min, and blood losses during operations were 103.2 ml on average. The median length of postoperative hospital stay was 7 days, and the median number of dissected lymph nodes was 40 (range 16-67). No patients had dissected lymph nodes <15. The rate of complications was 20 % (6/30 patients), and no patients had an incisional hernia. Two patients experienced ileus (6.7 %), another two patients experienced delayed gastric emptying (6.7 %), and one patient suffered from small bowel obstruction. There were no postoperative mortalities., Conclusions: The single-port TLDG for patients with early gastric cancer is feasible in very selected patients and in specialized gastric cancer centers with experience in multi-trocar laparoscopy and single-port laparoscopic surgery.

Background: Despite the close link between cigarette smoking and the development of gastric cancer, little is known about the effects of cigarette smoking on surgical outcomes after gastric cancer surgery. The aim of this study was to investigate whether preoperative smoking status and the duration of smoking cessation were associated with short-term surgical consequences in gastric cancer surgery., Methods: Among 1,489 consecutive patients, 1,335 patients who underwent curative radical gastrectomy at the Samsung Medical Center between January and December 2009 were included in the present study. The smoking status was determined using questionnaires before surgery. Smokers were divided into four groups according to the duration of smoking cessation preoperatively (<2, 2-4, 4-8, and >8 weeks). The primary endpoint was postoperative complications (wound, lung, leakage, and bleeding); secondary endpoints were 3-year recurrence-free survival (RFS) and overall survival (OS)., Results: Five hundred twenty-two patients (39.1 %) were smokers. Smokers had a significantly higher overall incidence of postoperative complications than nonsmokers (12.3 vs. 5.2 %, P < 0.001, respectively), especially in impaired wound healing, pulmonary problems, and leakage. Smokers also had more severe complications than nonsmokers. After adjusting for other risk factors, the odds ratio (95 % CI) for the development of postoperative complications in the subgroups who stopped smoking <2 weeks, 2-4, 4-8, and >8 weeks preoperatively were 3.35 (1.92-5.83), 0.99 (0.22-4.38), 2.18 (1.00-4.76), and 1.32 (0.70-2.48), respectively, compared with the nonsmokers. There were no significant differences in 3-year RFS (P = 0.884) and OS (P = 0.258) between smokers and nonsmokers., Conclusions: Preoperative smoking cessation for at least 2 weeks will help to reduce the incidence of postoperative complications in gastric cancer surgery.

Patients with advanced gastric cancer (AGC) can be treated with multiple lines of chemotherapy. Although several randomized trials have demonstrated the benefit of second-line chemotherapy compared with best supportive care, there is no evidence that further lines of chemotherapy will result in substantial prolongation of survival. Despite this, the practice of offering chemotherapy beyond second-line agents to AGC patients is not uncommon if their performance status is well-preserved and they are willing to receive subsequent active treatments. The choice of chemotherapeutic agents depends on the patient's prior regimens. However, there are important controversial issues in the salvage setting of AGC, including a subset of patients who may benefit from chemotherapy, that still remain unanswered. This report reviews the available evidence regarding the impact of third- and subsequent lines of chemotherapy on survival and quality of life in patients with AGC.

Background: Laparoscopic-assisted distal gastrectomy (LADG) is a treatment method for patients with early gastric cancer; however, single or reduced port LADG has been rarely reported. This study aimed to compare surgical outcomes of patients with gastric cancer undergoing reduced port totally laparoscopic distal gastrectomy (duet TLDG) to those of patients undergoing conventional LADG., Methods: This retrospective study included 202 patients with early gastric cancer who underwent duet TLDG (102 patients) or conventional LADG (100 patients) at Samsung Medical Center between October 2013 and April 2014., Results: Operating time was shorter for duet TLDG than for conventional LADG (mean ± SD 121.1 ± 19.3 min vs. 153.0 ± 38.1 min, P < 0.001). Blood loss during surgery was similar between duet TLDG and conventional LADG groups (91.4 ± 68.4 mL vs. 85.4 ± 59.8 mL, P = 0.506). Complication rates in the duet TLDG and conventional LADG groups were similar (15.7 % vs. 10.0 %, P = 0.294). The quality of lymph node dissection, including the median number of nodes dissected (median [range] duet TLDG vs. conventional LADG, 36 [17-76] vs. 34 [15-64], P = 0.570) and number of dissected nodes in each lymph node station, did not differ between groups. The median postoperative hospital stay was similar (7 [7-23] days vs. 7 [6-9], P = 0.423). Pain scores were 3.6, 3.2, and 2.8, and 3.7, 3.1, and 2.6, at postoperative days 1, 3, and 5, respectively, in the duet TLDG and conventional LADG groups (P = 0.408, 0.250, and 0.130)., Conclusions: Reduced port duet TLDG for early gastric cancer is feasible in terms of patient safety and quality of lymph node dissection.

Background: Chronic inflammation characterized by the recruitment and activation of macrophages has been implicated in the development of gastric cancer., Materials and Methods: Expression of the long form of pentraxin-3 (PTX3) in gastric cancer cells was examined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. The migratory capacity of gastric cancer cells and chemotaxis of macrophages by PTX3 were assessed by wound-healing and transwell assays. PTX3 silencing using small interfering RNA (siRNA) was performed to confirm PTX3-mediated effects., Results: We demonstrated that PTX3 expression was elevated in human advanced gastric cancer tissues with increased infiltration of CD11b+ macrophages. Tumor necrosis factor-alpha increased PTX3 expression via nuclear factor-kappa B activation in human gastric cancer cells. PTX3 promoted the tumor cell migratory potential, the recruitment of macrophages and their subsequent binding to gastric cancer cells. These effects were suppressed by PTX3 knockdown using siRNA., Conclusion: Our findings suggest that gastric cancer-derived PTX3 promotes macrophage recruitment, which may contribute to gastric cancer-related inflammation., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Gastric cancer is the fourth most common cancer and is one of the leading causes of cancer-related mortality worldwide. Forkhead box M1 (FOXM1) is overexpressed in gastric cancer, suggesting that it is important in gastric cancer oncogenesis. However, no studies have investigated the role of 3,3'-diindolylmethane (DIM), a component of cruciferous vegetables, in the regulation of FOXM1 and its signaling pathway in gastric cancer. Here, we report for the first time that DIM effectively downregulated Akt/FOXM1 in gastric cancer cells. Combination treatment with DIM and paclitaxel significantly and dose-dependently inhibited the proliferation of SNU638 cells when compared to treatment with DIM or paclitaxel alone. Colony formation of SNU638 cells was significantly attenuated by treatment with DIM and paclitaxel, and DIM potentiated the inhibition of colony formation in SNU638 cells by paclitaxel when compared to treatment with a single agent. Treatment with DIM plus paclitaxel substantially increased apoptosis as indicated by increased levels of cleaved polyADP-ribose polymerase (PARP) and cleaved caspase-9 protein. DIM dose-dependently sensitized gastric cancer cells through downregulation of FOXM1 and potentiated the effects of paclitaxel. FOXM1 effector genes such as CDK4, p53 and cyclin D1 were downregulated in gastric cancer cells by combination treatment with DIM and paclitaxel. In addition, DIM significantly and dose-dependently inhibited phosphorylation of Akt and potentiated paclitaxel-induced inhibition of Akt function in gastric cancer cells. Therefore, our results indicate that DIM effectively potentiates the efficacy of chemotherapeutic agents such as paclitaxel by downregulation of the Akt/FOXM1 signaling cascade in gastric cancer cells. Our findings suggest that DIM enhances the therapeutic efficacy of paclitaxel in gastric cancer and is a potential clinical anticancer agent for the prevention and/or treatment of gastric cancer.

Background: Reduced-port laparoscopic surgery for patients with early gastric cancer has been rarely reported. The aim of this study was to introduce techniques of the reduced-port laparoscopy-assisted distal gastrectomy (duet LADG) in patients with early gastric cancer., Methods: Duet LADG was performed by two persons, an operator and a scopist. Three 10 mm ports were used on the umbilicus and both sides of the lower abdomen. The same laparoscopic instruments were used for duet LADG as for conventional LADG. After the liver was retracted with a 1-0 nylon suture, partial omentectomy with D1 + β or more lymph node dissection was made. After distal subtotal resection of the stomach, bowel continuity was restored by intracorporeal gastrojejunostomy using two linear staplers. A specimen was removed through the umbilical incision after the extension., Results: A total of 30 consecutive patients underwent duet LADG from October to December 2013. The median age of the patients was 51 years (range 29-75 years), and their median body mass index was 23.2 kg/m(2) (range 18.5-29.6 kg/m(2)). Sixteen (53.3%) of 30 patients were female. Operating times for patients who received duet LADG were 121.2 ± 17.7 min. Blood loss during operations averaged 82 ml. The median number of dissected lymph nodes was 35 (range 24-66). There was no patient with fewer than 15 dissected lymph nodes. The rate of complications in patients who underwent duet LADG was 16.7% (5 of 30 patients). Two patients (6.7%) experienced ileus, and another 2 (6.7 %) patients experienced small bowel obstruction. One patient had pneumonia. There was no postoperative mortality., Conclusions: Duet LADG for patients with early gastric cancer is feasible without the need for additional ports, any special devices, or an assistant.

Goals: To evaluate the prevalence of functional dyspepsia (FD) and its risk factors., Background: FD is a common disorder, but its negative influences greatly affect the quality of life. The predictive factors of FD are still ambiguous., Study: A total of 3399 participants underwent screening gastroscopy at one of 7 nationwide health care centers in Korea and who completed a questionnaire. Atrophic gastritis was defined by gastroscopy. Serologic Helicobacter pylori immunoglobulin G antibody was measured by enzyme-linked immunosorbent assay., Results: Of the 3399 participants who did not have organic diseases, 694 (20.4%) had dyspeptic symptoms such as epigastric pain/soreness or postprandial discomfort. Among the 694 participants, atrophic gastritis and positive H. pylori serology were found in 282 (40.6%) and 422 (60.8%), respectively; these proportions were not different from the remaining asymptomatic subjects. Multivariate analysis showed that having relatives with gastric cancer [odds ratio (OR), 1.35; 95% confidence interval (CI), 1.01-1.81], education below college (OR, 1.32; 95% CI, 1.06-1.64), and high-salt diet (OR, 1.33; 95% CI, 1.05-1.68) were associated with FD symptoms., Conclusions: FD symptoms were frequently found in the health check-up subjects. Relatives of gastric cancer, education below college, and high-salt diet were risk factors of FD, suggesting that FD is a multifactorial disease.

Mucins reportedly play numerous key roles in carcinogenesis, including in tumor invasion, regulation of differentiation and tumor cell proliferation. We investigated the effect of Muc5AC, a secreted mucin, on the invasiveness/migratory capability of gastric cancer cells and the prognostic significance of Muc5AC in gastric cancer patients. The clinicopathological and prognostic significance of Muc5AC expression was validated using immunohistochemical analysis in 412 gastric cancer patients. Differential gene expression was investigated using complementary DNA microarray analysis of 48 fresh tumor tissue samples. Silencing of Muc5AC by using a small hairpin RNA-containing lentivirus increased the invasion and migration of SNU216 and AGS cells as well as Akt phosphorylation and the expression of vascular endothelial growth factor and matrix metalloproteinase-7, which were blocked by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Loss of Muc5AC expression was significantly associated with tumor progression (advanced T stage; p = 0.004), lymph node metastases (p = 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p = 0.027). Lower MUC5AC expression was identified as an independent poor prognostic factor in diffuse-type gastric cancer by using the Cox regression proportional hazard model (hazard ratio, 2.39; p = 0.043). Complementary DNA microarray analysis revealed 86 differentially expressed genes, including genes related to metastasis and invasion, in gastric cancer tissues with high (≥25%) and low (<25%) Muc5AC expression levels. Low Muc5AC expression increased the invasion and migration of gastric cancer cells and could be a useful biomarker of poor prognosis in gastric cancer., (© 2013 UICC.)

Recent studies have revealed that 3,3-diindolylmethane (DIM) has antitumor effects in both in vivo and in vitro tumor models. However, the biological function of DIM in human gastric cancer cells is unknown. Genetic and biological studies have confirmed the importance of the novel Hippo tumor-suppressor pathway in regulating cell proliferation, apoptosis, organ size and tumorigenesis in mammals. Thus, the purpose of this study was to investigate the cytotoxic effects of DIM in human gastric cancer cells and to elucidate whether DIM induces cell death by activating the Hippo signaling pathway. Two human gastric cancer cell lines (SNU-1 and SNU-484) were used to investigate the DIM response. DIM significantly inhibited the proliferation of human gastric cancer cells in a dose-dependent manner. The percentage of G1 phase cells increased 24 h following DIM treatment. DIM reduced CDK2, CDK4, CDK6 and cyclin D1 protein levels, while increasing p53 protein levels. DIM induced the levels of cleaved poly(ADP-ribose) polymerase, cleaved-caspase-9, and diminished pro-caspase-3 protein production. In addition, DIM increased pLATS1, Mob1, pMob1, pYAP and Ras association domain family 1 (RASSF1) protein levels and reduced Yap protein production levels. DIM stimulated the binding of RASSF1 with the Mst1/2-LATS1-Mob1 complex, promoting an active Hippo signaling pathway and favoring YAP phosphorylation (pYAP) that inactivates cell proliferation. Furthermore, DIM inhibited the growth of human gastric tumors in a xenograft mouse model. These results indicate that DIM suppresses the growth of gastric cancer cells by activating the Hippo signaling pathway.