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Background: Skeletal muscle (SM) is a key factor in cancer treatment. However, it is unclear whether pretreatment SM change affects the outcome of immune checkpoint inhibitors (ICIs) therapy in gastric cancer (GC)., Methods: Advanced GCs treated with ICIs were retrospectively investigated. SM evaluated by psoas muscle area at the third lumbar vertebra was measured on CT acquired within 1 month from the start of ICIs therapy (CT-1), and on CT acquired 2.8 ± 0.84 months before CT-1. Monthly change rate of SM (MCR-SM) was defined as the change rate of SMs between those two CTs divided by the period between those CTs (month). Monthly change rate of body weight (MCR-BW) during the same period was also calculated. They were compared with disease-specific survival (DSS) and progression-free survival (PFS). MCR-SM was compared with pretreatment markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), and liver-to-spleen CT attenuation ratio (LSR) as a marker of liver lipid metabolism., Results: This study enrolled eighty-three GC patients. MCR-SM significantly correlated with DSS and PFS (P < 0.0001, 0.001, respectively), whereas MCR-BW did not. Kaplan-Meier analyses demonstrated that higher MCR-SM (MCR-SM ≥ -0.7185%) significantly associated with better DSS and PFS (P = 0.0002, 0.03, respectively). Patients with positive MCR-SM showed significantly lower NLR, MLR, and CRP than those with negative (P = 0.01, 0.006, 0.003, respectively). MCR-SM showed a significant positive correlation with LSR (P = 0.007, R = 0.30)., Conclusions: Pretreatment SM loss, associated with high systemic inflammation and hepatic fat accumulation, related to poor outcome of ICIs therapy in GC., (© 2024. The Author(s).)

A 73-year-old woman was referred to our hospital with a chief complaint of black stools and abdominal distention. She was diagnosed with advanced gastric cancer with pyloric stenosis and multiple lymph node metastasis(cT4aN3M0, cStage Ⅲ)and was administered preoperative chemotherapy after laparoscopy and gastric jejunal bypass surgery. The surgical diagnosis was sT4aN3M0P0CY0. After surgery, 2 courses of DS therapy were administered. However, a new liver metastatic lesion was found, and XELOX therapy was selected as the second-line of treatment. Subsequently, enlarged hepatic hilar lymph nodes were found; microsatellite instability testing confirmed MSI-High cancer. Nivolumab was selected as the third- line therapy. After 15 courses, a new liver metastatic lesion appeared. Although Ram+nab-PTX therapy was chosen as the fourth-line therapy, the patient developed myelosuppression after 3 courses. Two years and 4 months after the initial treatment, the patient was considered to have achieved CR. Because drug-induced liver injury had occurred, the Ram therapy was discontinued. The patient has remained in CR for 1 year without receiving any anticancer drugs. This case suggests that for MSI-high patients with gastric cancer, the consideration of treatment strategy should be based on the molecular biological background.

Background/aim: Peripheral blood inflammatory and nutritional indices are independent prognostic factors for various cancers. However, as society's longevity and the demand for surgery in the elderly increase, it remains unclear whether these indices are valuable for patients aged ≥80 years. This study aimed to assess the utility of peripheral blood indices as prognostic markers in elderly patients with gastric cancer (GC)., Patients and Methods: This study included 103 elderly patients (aged ≥80 years) who underwent radical gastrectomy at our hospital between 2008 and 2020. Preoperative systemic inflammatory and nutritional indices, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and prognostic and nutritional index (PNI), were evaluated. Prognostic evaluation was performed using Kaplan-Meier analysis and Cox regression., Results: There were no statistically significant differences in NLR, PLR, and LMR regarding overall survival (OS) and relapse-free survival (RFS). However, patients with low PNI had a markedly worse prognosis (3-year OS: 63.9% vs. 81.2%, p=0.002; 3-year RFS: 55.3% vs. 77.6%, p=0.002). Multivariate analysis revealed that male sex and low PNI were independent predictors of OS (p=0.007p=0.003, respectively) and RFS, with only PNI showing significance (p=0.023)., Conclusion: Preoperative PNI is an independent prognostic factor for survival in elderly patients with GC who undergo radical gastrectomy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Early-stage gastric cancer (EGC) found after Helicobacter pylori (Hp) eradication is often difficult to diagnose using conventional white light (WL) endoscopy. We aimed to evaluate whether Texture and Color Enhancement Imaging (TXI), a new image-enhanced endoscopy enhances the EGC lesions after Hp eradication. We also compared diagnostic accuracy and lesion detection time between WL and TXI in trainee endoscopists. 58 EGC lesions after successful Hp eradication were enrolled. Using endoscopic images in WLI, TXI mode 1 (TXI1), and TXI mode 2 (TXI2), visibility of EGC was assessed by six expert endoscopists using a subjective score. Mean color differences (ΔE) of four matched adjacent and intra-tumoral points were examined. Using randomly allocated images, diagnostic accuracy and lesion detection time were evaluated in three trainee endoscopists. Visibility score was unchanged (Score 0) in 20.7% (12/58) and 45.6% (26/57), slightly improved (Score 1) in 60.3% (35/58) and 52.6% (30/57), obviously improved (Score 2) in 45.6% (26/58) and 1.8% (1/57), in TXI1 and TXI2 compared to WL, respectively. Mean ΔE ± SEM in TXI1 (22.90 ± 0.96), and TXI2 (15.32 ± 0.71) were higher than that in WL (1.88 ± 0.26, both P < 0.0001). TXI1 presented higher diagnostic accuracy compared to WL, in two of three trainees (94.8% vs. 74.1%, 100% vs. 89.7%, P = 0.003; < 0.005, respectively). Lesion detection time was shorter in TXI1 in two of three trainees (P = 0.006, 0.004, respectively) compared to WL. TXI improves visibility of EGC after Hp eradication that may contribute to correct diagnosis., (© 2023. The Author(s).)

Background/aim: We lack reports on the clinicopathological characteristics and prognostic value of serum sirtuin 1 (SIRT1) levels and their association with SIRT1 expression in tissues of patients with gastric cancer (GC). Thus, we investigated the pathological characteristics and prognostic values of SIRT1 tissue expression and its serum concentration in GC. Moreover, we investigated the correlation between these two factors., Materials and Methods: A total of 78 patients with GC who underwent curative gastrectomy were evaluated in this study. The expression of SIRT1 in the surgical specimens was assessed using immunohistochemistry. Serum levels of SIRT1 were measured using an enzyme-linked immunosorbent assay. The association of tissue and serum SIRT1 with the clinicopathological features and prognosis were evaluated., Results: Positive SIRT1 tissue expression was significantly related to an advanced cancer stage (p=0.017). Furthermore, a significant relationship existed between a positive SIRT1 tissue expression and poorer overall survival (OS) and relapse-free survival (RFS) (p=0.033 and p=0.033, respectively). In contrast, serum SIRT1 levels showed no significant association with clinicopathological characteristics besides age. In addition, no significant correlation was observed between tissue SIRT1 expression and serum SIRT1 concentration., Conclusion: Tissue SIRT1 expression may be a valuable novel prognostic biomarker; nonetheless, further studies are required to clarify the relationship between tissue SIRT1 expression and serum SIRT1 levels in GC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Although the usefulness of the ypStage in neoadjuvant chemotherapy for advanced gastric cancer (GC) has been reported, whether or not the ypStage is applicable to all GC patients who receive preoperative chemotherapy, including conversion surgery cases, is unclear. Therefore, this retrospective study evaluated the value of the ypTNM staging system in all advanced GC patients who received chemotherapy prior to gastrectomy., Methods: A total of 66 patients who underwent chemotherapy prior to gastrectomy for advanced GC at Chiba University Hospital from January 2008 to December 2020 were enrolled in the current study. The prognostic impact of the ypStage on the overall survival (OS) and relapse-free survival (RFS) were examined via univariate and multivariate analyses., Results: The 5-year OS rates for ypStage I, II, III, and IV were 87.5%, 64.7%, 52.9%, and 28.6%, respectively, while the 5-year RFS rates were 81.3%, 57.4%, 44.4%, and 28.6%, respectively. The univariate analysis revealed that the ypStage was significantly correlated with the OS (p = 0.037) and the ypT status and ypStage showed a significant correlation with the RFS (p = 0.043 and p = 0.021, respectively). The multivariate analysis demonstrated that only the ypStage was an independent prognostic factor for the OS and RFS (p = 0.024 and p = 0.018, respectively)., Conclusion: The ypTNM stage may be a useful tool for the risk stratification of all advanced GC patients treated with chemotherapy followed by gastrectomy, including not only neoadjuvant but also conversion surgery cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Immune checkpoint inhibitors (ICIs) are expected to improve the prognosis of gastric cancer (GC). Also, hepatic steatosis has been reported to be associated with cancer cachexia and is expected to be a cancer biomarker. The purpose of this study was to evaluate prognostic impact of hepatic steatosis in ICI therapy for GC., Methods: Unresectable or recurrent GC treated with ICIs was investigated. Using unenhanced CT, the liver-to-spleen CT attenuation ratio (LSR) was calculated as a parameter of hepatic steatosis. LSR was compared with the presence of sarcopenia and inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). These parameters were also compared with disease-specific survival (DSS) and progression-free survival (PFS). Associations of LSR with insulin-like growth factor 1 (IGF-1) and growth hormone were also evaluated., Results: A total of 70 patients were investigated. LSR of sarcopenia patients was significantly lower than that of non-sarcopenic ones (p = 0.02). LSR showed significant negative correlations with NLR, PLR, and MLR (p = 0.003, 0.03, 0.01, respectively). Lower LSR was significantly associated with a higher level of serum IGF-1 (p = 0.03). In univariate analysis, LSR was significantly correlated with DSS and PFS (both p < 0.0001), and multivariate analysis demonstrated that LSR was the independent prognostic factor for both DSS and PFS (both p = 0.01). ROC analysis demonstrated that LSR >1.263 was a good predictive marker for favorable DSS (>5.3 months) with an AUC of 0.80., Conclusion: Hepatic steatosis can be a promising prognostic biomarker for ICI therapy of GC, associated with sarcopenia and the elevation of inflammatory markers. Our data suggested that GC with steatohepatitis might be less responsive to ICI therapy., (© 2022 S. Karger AG, Basel.)

Purpose: In actual surgical research, case-matched studies are frequently conducted as an alternative to randomized controlled trials (RCTs). However, it is still unclear what differences there are between RCTs and case-matched studies in upper gastrointestinal surgery, and clarifying them is a very important clinical issue. Thus, the purpose of this study was to investigate estimated treatment effects between RCTs, case-matched studies, and cohort studies regarding laparoscopic distal gastrectomy (LDG) for advanced gastric cancer (AGC)., Methods: We searched the PubMed, Cochrane Central Register of Controlled Trials, and Web of Science databases for studies that compared LDG versus open distal gastrectomy for AGC published from the inception of the databases until July 2021. A meta-analysis was performed using the Review Manager version 5.3 software program from the Cochrane Collaboration, and six short-term outcomes and three long-term outcomes were assessed., Results: Twenty-three studies with 13698 patients were included. There was no difference in estimated treatment effects between RCTs and case-matched studies for all outcomes except for the number of retrieved lymph nodes and postoperative complications. In terms of intraoperative blood loss, postoperative hospital stay, number of retrieved lymph nodes, and recurrence, observational studies tended to overestimate the treatment effects., Conclusion: The estimated treatment effects of LDG for AGC in the case-matched study were almost the same as in the RCTs. However, to assess the true magnitude of the treatment effect, the design and actual implementation of the analysis must be critically evaluated., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 79-year-old man was detected with anemia on medical examination and underwent gastroscopy at the previous hospital. Gastroscopy revealed a 15-mm ulcerative lesion(Type 0-Ⅱc plus Ⅲ)on the greater curvature of the upper gastric body. Tumor biopsy showed well-differentiated adenocarcinoma. The patient was suspected of deep submucosal invasion due to poor stretching of the gastric wall and the ulcer depth; hence, he was transferred to our hospital for surgery. When gastroscopy was repeated, the ulcer was found to be scarred(Type 0-Ⅱc), thereby indicating the occurrence of intramucosal carcinoma; hence, endoscopic submucosal dissection was performed. The pathological finding showed 10×6 mm, tub1, pT1a, ly0, v0, pUL1, pHM0, pVM0, suggesting a curative resection. Early gastric cancer of the depressed type is known to develop a malignant cycle with repeated improvements and exacerbations of the ulcer. Diagnosing the depth of tumor invasion is particularly difficult when there is an active ulcer. For small lesions with active ulcers, repeating gastroscopy might allow for correct diagnosis and appropriate treatment.

Two patients underwent hemodialysis. Case 1 with stage IV gastric cancer was treated with reduced doses of capecitabine (1,000 mg/m 2 /day, days 1 to 14) and oxaliplatin (65 mg/m 2 , day 1). Although grade 1 thrombocytopenia occurred in the first cycle, grade 3 thrombocytopenia developed in the second cycle because of increasing dosage. After the dosage was reduced, chemotherapy was continued safely. Case 2 with stage IA gastroesophageal cancer was treated with radiotherapy followed by chemotherapy. Treatment with the same dose of CapeOX therapy as in case 1 resulted in no severe toxicity. We conclude that a half-dose of the CapeOX regimen is safe for gastric cancer patients undergoing hemodialysis.

Background: This study investigated the prognostic value of preoperative serum C-reactive protein(CRP)level in patients with gastric cancer(GC)., Methods: This retrospective study examined 446GC patients undergoing curative gastrectomy. The associations between preoperative CRP level and postoperative long-term outcomes were examined by univariate and multivariate analyses., Results: The patients were divided into high(n=147)or low(n=299)CRP groups based on an optimal cut- off CRP value of 0.13mg/dL according to the ROC curve analysis. High CRP levels were significantly associated with other clinical factors such as older age(B65 years), high BMI(B25 kg/m2), poor performance status(PS), and advanced cT and cN+. In the survival analyses using only the clinical factors, high CRP levels were significantly associated with worse 5-year overall and cancer-specific survivals. The multivariate analysis for 5-year overall survival identified preoperative CRP to be an independent factor(HR: 1.95, 95%CI: 1.15-3.36, p=0.0129), as well as PS, tumor location, and cT., Conclusion: Preoperative CRP level could be a useful prognostic indicator in patients with GC undergoing curative gastrectomy.

Background: The presence of comorbidities in cancer patients may influence treatment decisions and prognoses. This study aimed to examine the impact of comorbidities on overall survival in Japanese patients diagnosed with major solid tumors., Methods: To obtain patient-level information on clinical conditions and vital status, we performed a record linkage of population-based cancer registry data from Osaka Prefecture, Japan and administrative data produced under the Diagnosis Procedure Combination (DPC) system. The study population comprised patients who received a primary diagnosis of gastric, colorectal, or lung cancer between 2010 and 2012 at any of five cancer centers. We employed the Charlson Comorbidity Index (CCI) score to quantify the impact of comorbidities on survival. The association between CCI score and survival for each cancer site was analyzed using Cox proportional hazards regression models for all-cause mortality, after adjusting for patient sex, age at cancer diagnosis, and cancer stage., Results: A total of 2,609 patients with a median follow-up duration of 1,372 days were analyzed. The most frequent CCI score among the patients was 0 (77.7%), followed by 2 (14.3%). After adjusting for the covariates, we detected a significant association between CCI score and all-cause mortality. The hazard ratios per one-point increase in CCI score were 1.12 (95% confidence interval [CI], 1.02-1.23), 1.20 (95% CI, 1.08-1.34), and 1.14 (95% CI, 1.04-1.24) for gastric, colorectal, and lung cancer, respectively., Conclusions: Comorbidities have a negative prognostic impact on overall survival in cancer patients, and should be assessed as risk factors for mortality when reporting outcomes.

Background/aim: Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-ĸB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis., Materials and Methods: The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-ĸB in tumors was examined by western blotting., Results: Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-ĸB expression, but a similar trend was not noted for AMPK., Conclusion: Metformin may be a useful drug for the treatment of GC with peritoneal metastasis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is the standard gastric cancer screening method in Japan. Atrophic gastritis and enlarged gastric folds are considered the two major features of Helicobacter pylori-induced chronic gastritis, but the clinical meaning of evaluating them by UGI-XR has not been elucidated., Methods: We analyzed healthy UGI-XR examinees without a history of gastrectomy, previous Helicobacter pylori eradication and usage of gastric acid suppressants., Results and Conclusions: Of the 6433 subjects, 1936 (30.1 %) had atrophic gastritis and 1253 (19.5 %) had enlarged gastric folds. During the 3-year prospective observational follow-up, gastric cancer developed in seven subjects, six of whom (85.7 %) had atrophic gastritis with H. pylori infection and five of whom (71.4 %) had enlarged gastric folds with H. pylori infection. The Kaplan-Meier method with log-rank testing revealed that both UGI-XR-based atrophic gastritis (p = 0.0011) and enlarged gastric folds (p = 0.0003) are significant predictors for future gastric cancer incidence.

CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47(hi) gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47(lo) , and CD44(hi) CD47(hi) cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection., Methods: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep-sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice)., Results: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers., Conclusions: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Case: An 82-year-old man died because of squamous cell carcinoma of the right lung with metastasis to the left femoral bone. At the age of 75 years, he was admitted to our hospital because of hematemesis. Widespread type 3 gastric cancer was detected in the lesser curvature. Computed tomography(CT)showed multiple liver metastases. Preoperative chemotherapy with TS-1/cisplatin(CDDP)was administered. TS-1 was orally administered at 80mg/body/day and CDDP was administered by intravenous infusion at 20mg/body/day every week for 3 weeks and this was followed by a drug-free 2-week period as the first course. After the fourth course, gastrectomy was performed for the primary lesion and radiofrequency ablation(RFA)was performed for the liver metastases. The patient survived for more than 7 years with a complete response (CR)and died thereafter because of squamous cell carcinoma of the lung.

Endoscopic submucosal dissection (ESD) utilizes electrical coagulation, which can cause burns, fibrosis and adhesion of the stomach and surrounding tissue; these complications might increase the surgical difficulties for subsequent laparoscopy-assisted gastrectomy (LAG) and the risk of complications. However, scarce data are available on the influence of previous ESD on LAG. The purpose of this study was to evaluate the feasibility and safety of LAG following incomplete ESD in patients with early gastric cancer. Ninety-seven patients who underwent LAG were analyzed retrospectively; 17 patients had undergone ESD previously and the remaining 80 patients had no history of ESD. Clinicopathological data and surgical outcomes were compared between the two groups. No differences were observed in surgical outcomes of LAG after ESD in terms of operation time, intraoperative blood loss, total number of harvested lymph nodes, time until start of flatus, and postoperative hospital stay. These results were not influenced by tumor location and operative procedures. In conclusion, in terms of surgical outcomes, LAG is a safe and feasible procedure for the treatment of early gastric cancer regardless of previous endoscopic treatment. LAG may be the first-choice radical treatment after incomplete ESD for early gastric cancer.

H. pylori-induced gastritis plays important roles in gastric cacrcinogenesis and cancer development is characterized by accumulation of various gene aberrations. Activation-induced cytidine deaminase (AID) is exclusively expressed in B lymphocytes and is essential for diversification of immunoglobulin genes. H. pylori-positive human gastritis mucosa ectopically express AID. H. pylori infection to gastric cells in vitro induced AID in association with induction of various gene mutations and deletions. H. pylori-induced AID is mediated by NFkappaB. Furthermore, AID gene introduction into gastric mucosal cells accelerated p53 gene mutations, and inhibition of AID using siRNA significantly reduced H. pylori-induced p53 gene mutations. Thus, H. pylori infection induces ectopic AID expression in the gastric mucosal cells via NFkappaB activation, resulting in various gene mutations and aberrations in the gastric mucosal cells leading to gastric cancer development.

Background: Recently, novel intracorporeal esophagojejunostomy using a linear stapler after laparoscopic total gastrectomy (LTG) was reported and termed as the overlap method. In this study, we evaluated the feasibility and safety of the overlap method for esophagojejunostomy or esophagogastrostomy after LTG or laparoscopic proximal gastrectomy (LPG), respectively., Methods: Twenty-five patients underwent anastomosis using a linear stapler during esophagojejunostomy and esophagogastrostomy after LTG and LPG, respectively. Clinicopathological data and surgical outcomes were evaluated., Results: The average surgical duration for LTG was 236.8 min compared with 224.1 min for LPG. Postoperative complications were observed in four patients (16.0%); these included a wound infection, an intestinal obstruction, an afferent loop syndrome, and a reflux symptom. The average postoperative hospital stay of the patients was 12.5 days. There was no case of conversion to open surgery, anastomotic leakage or stenosis, or mortality., Conclusions: The overlap method for esophagojejunostomy or esophagogastrostomy after LTG or LPG is safe and feasible and does not require an additional minilaparotomy, which may result in less pain and favorable cosmetic outcomes.

The purpose of this study was to evaluate the merits of the sentinel node (SN)-navigated reduced gastrectomy (SNRG) procedure. The subjects (sT1N0) were divided into the SNRG group (n=34) and the GL group, that consisted of patients which underwent gastrectomy according to the Japanese Gastric Cancer Association guidelines (n=33). We compared the area of the resected stomach and evaluated their body weight changes, and the results of a questionnaire survey about postoperative symptoms, and nutritional effects by blood tests administered at postoperative months (POM) 3, 6 and 12. The median area of the resected stomach was 104 cm2 in the SNRG group vs. 192 cm2 in the GL group. The body weight loss ratio was -5.9±5.8 vs. -9.3±4.1% at POM 3, and the henoglobin (g/dl) change rate was -1.1±7.9 vs. -6.4±6.5% at POM 12 in the SNRG and GL groups, respectively. There were no significant differences regarding the passage of food, reflux, the incidence of dumping syndrome, digestive and excretory function, or general condition and the satisfaction levels of the patients. In conclusion, SNRG has some advantages over GL in terms of postoperative disorders for at least one year after surgery, and is the recommended choice of a surgical procedure for early gastric cancer.

The standard regimen of S-1 and cisplatin is not adaptable for patients with gastric cancer with an ingestion inability. A 74- year-old man was revealed to have unresectable gastric cancer with severe pyloric stenosis(cT4, cN3, cH1, cP0, cStage IV). He was treated with systemic chemotherapy using modified docetaxel, cisplatin and 5-fluorouracil(mDCF). He had manageable neutropenia(grade 3 and 4)during his treatment. CT findings after 3 courses showed reduced primary tumor and metastatic lesions. A curative operation was performed based on the effective response with downstaging. Palliative surgery was considered before receiving chemotherapy. mDCF therapy is one of the recommended options for gastric cancer with an ingestion inability.

Background: In order to improve a patient's quality of life after total gastrectomy, jejunal pouch reconstruction has been employed. However, little information exists regarding the optimal size of the jejunal pouch after total gastrectomy., Methods: The study was designed as a single-center randomized trial in which the results of double-tract reconstruction with pouches of two different sizes were compared, i.e., short and long pouch double tract (SPDT and LPDT, respectively). We conducted a clinical assessment with standard questionnaire after surgery. The amount of residual food in the jejunal pouch was determined by endoscopy., Results: No demographic differences were noted between the two groups. The eating capacity per meal was higher in the SPDT group than in the LPDT group. The postoperative weight loss 24 months after surgery was lower in SPDT group than that in the LPDT group. Although the incidence of early dumping symptoms was higher in the SPDT group, no difference was noted in the other postprandial abdominal symptoms between the two groups., Conclusions: We conclude that the optimal pouch should be relatively short, as a short pouch improves the eating capacity per meal and the weight loss ratio to the preoperative value.

Background & Aims: The DNA/RNA editing enzyme activation-induced cytidine deaminase (AID) is mutagenic and has been implicated in human tumorigenesis. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of AID and somatic gene mutations. We investigated whether AID induces genetic aberrations at specific chromosomal loci that encode tumor-related proteins in gastric epithelial cells., Methods: Human gastric epithelial cell lines that express activated AID and gastric cells from AID transgenic mice were examined for DNA copy number changes and nucleotide alterations. Copy number aberrations in stomach cells of H pylori-infected mice and gastric tissues (normal and tumor) from H pylori-positive patients were also analyzed., Results: In human gastric cells, aberrant AID activity induced copy number changes at various chromosomal loci. In AID-expressing cells and gastric mucosa of AID transgenic mice, point mutations and reductions in copy number were observed frequently in the tumor suppressor genes CDKN2A and CDKN2B. Oral infection of wild-type mice with H pylori reduced the copy number of the Cdkn2b-Cdkn2a locus, whereas no such changes were observed in the gastric mucosa of H pylori-infected AID-deficient mice. In human samples, the relative copy numbers of CDKN2A and CDKN2B were reduced in a subset of gastric cancer tissues compared with the surrounding noncancerous region., Conclusions: H pylori infection leads to aberrant expression of AID and might be a mechanism of the accumulation of submicroscopic deletions and somatic mutations in gastric epithelial cells. AID-mediated genotoxic effects appear to occur frequently at the CDKN2b-CDKN2a locus and contribute to malignant transformation of the gastric mucosa., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The sentinel node (SN) concept has been found to be feasible in gastric cancer. However, the lymphatic network of gastric cancer may be more complex, and it may be difficult to visualize all the SN distributed in unexpected areas by conventional modalities. In this study, we evaluate the feasibility and efficacy of CT lymphography for the detection of SN in gastric cancer. A total 24 patients with early gastric cancer were enrolled in the study. Three modalities (CT lymphography, dye and radioisotope [RI] methods) were used for the detection of SN. The images of CT lymphography were obtained at 10 min after injection of contrast agents. The SN were successfully identified by CT lymphography in 83.3% of patients; detection rates by the dye and RI methods were 95% and 100%, respectively. Most patients, in whom SN were successfully detected by CT lymphography, had positive results at 5 min after injection of the contrast material. The SN stations detected by CT lymphography were consistent with or included those detected by dye and/or RI methods. In conclusion, CT lymphography for the detection of SN in gastric cancer is feasible and has several advantages. However, based on this initial experience, CT lymphography had a relatively low detection rate compared with conventional methods, and further efforts will be necessary to improve the detection rate and widen the clinical application of CT lymphography for the detection of SN in gastric cancer., (© 2010 Japanese Cancer Association.)

Increasing evidence is being reported regarding the hypothesis that several proinflammatory and anti-inflammatory cytokines may promote tumor progression and affect the host antitumor response. However, the manner in which a local cytokine network operates in tumor development remains unclear. We reviewed the literature to examine the consequences of novel insights into inflammatory cytokines associated with gastric cancer progression. The Medline and EMBASE databases were searched for publications regarding the role of inflammatory cytokines in the development of gastric cancer. A number of studies have suggested that several proinflammatory and anti-inflammatory cytokines promote tumor progression through the direct activation of nuclear factor-κB (NF-κB) and the upregulation of angiogenesis and adhesion molecules. Furthermore, these processes suppress host antitumor immunity, leading to tumor progression and metastasis. In patients with advanced gastric cancer, most cytokines that enhance or suppress host antitumor immunity appear to have elevated serum and local expression levels. The net cytokine environment fluctuates at various stages of tumor development. In conclusion, a more detailed understanding of the differential roles of malignant cell-derived and hostderived cytokines at different stages of the malignant process could, consequently, open new avenues for the manipulation of cytokine expression and function in cancer immunotherapy for gastric cancer.

Gastric adenosquamous carcinoma is known as an infrequent histological cancer with a poor prognosis. A 69-year-old man was revealed to have gastric squamous carcinoma on the gastric body remote from esophagus (cT4 cN3, cStage IV). A curative operation was impossible so he was treated with systemic chemotherapy using S-1+docetaxel. After 1 course, we changed to second-line chemotherapy combining CPT-11+CDDP because of heterochronic multiple hepatic metastases. PET-CT and CT findings after 5 courses of second-line therapy showed reduced primary tumor and metastatic lesions. The curative operation was performed based on the effective response with downstaging. The final histological diagnosis showed gastric adenosquamous carcinoma. The adjuvant chemotherapy of CPT-11 was continued without relapse for almost 2 years.

Hybrid liposomes (HLs) composed of 90 mol% dimyristoylphosphatidylcholine (DMPC) and 10 mol% polyoxyethylene(23)dodecyl ether (C(12)(EO)(23)), having a hydrodynamic diameter under 100 nm, were preserved for a period of one month. The inhibitory effects of HLs on the growth of gastric carcinoma (CoRa 622 G6) cells in vitro were investigated. Decrease in mitochondrial membrane potential and activation of caspase-8, caspase-9 and caspase-3 were observed, indicating that apoptotic signals induced by HLs should pass through mitochondria and these caspases. Remarkable inhibitory effects on the metastasis of gastric carcinoma along with apoptosis and prolonged survival were obtained for mouse models of gastric carcinoma with peritoneal dissemination after the treatment with HLs in vivo.

H. pylori infection causes gastric cancer development through gastritis. However, the precise mechanism for H. pylori-induced carcinogenesis remains unclear. On the other hand, accumulation of gene mutations is a hallmark of cancers, but mechanism of endogenous induction of mutation also remains unknown. Here, we found that H. pylori infection triggers aberrant expression of activation-induced cytidine deaminase (AID), a molecule that can induce DNA somatic hypermutation of immunoglobulin gene in B cells under physiological condition, in the gastric mucosa via NFkappaB-dependent mechanism. Induction of AID then enhances various gene mutations including p53. This mechanism appears to play important roles in gastric carcinogenesis by H. pylori infection.

Background: Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail., Methods: We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnTbetaRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided., Results: Expression of dnTbetaRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTbetaRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTbetaRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTbetaRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues., Conclusions: Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

We focused on the impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer. Postoperative surgical and medical complications have been implicated as a negative predictor of long-term outcome in various malignancies. However, there have been no published reports assessing the impact of complications arising from postoperative infection on survival in gastric cancer. We studied a population of 1,332 patients who underwent curative resection for gastric cancer. These patients were divided into two groups based on the occurrence (141 patients, 10.6%) or absence (1,191 patients, 89.4%) of postoperative complications due to infection. We investigated the demographic and clinicopathological features of each patient with and without postoperative complications from infection, and thereby the impact of postoperative infection on long-term survival. Patients with postoperative infection had significantly higher frequency of males, upper side tumor location, and total gastrectomy as a surgical procedure, more advanced stage of gastric cancer, and greater age compared with those without postoperative infection. Patients with complications due to postoperative infection had significantly more unfavorable outcome compared with those patients without postoperative infection. Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement, and postoperative infection correlated with overall survival. We conclude that postoperative complications from infection are a predictor of adverse clinical outcome in patients with gastric cancer. However, further immunological study and prospective trials are necessary to confirm the biological significance of these findings.

Helicobacter pylori (H. pylori) infection plays an important role in gastric carcinogenesis. We conducted a systematic review concerning gastric cancer development after H. pylori eradication therapy. In total 15 papers matched our criteria, the results were reviewed. The H. pylori eradication therapy statistically diminished the prevalence of clinical gastric cancer by approximately one-third. The studies from Japan supported this conclusion; however, studies from overseas reported conflicting results. The differences in these conclusions lie in the diagnostic ability of endoscopic examination, since the clinical stage was quite different between these studies. Gastric cancer that developed after eradication revealed a mainly intestinal type histology and depressed-type appearance. The following are possible reasons for reduced gastric cancer: (1) eradication therapy inhibits the new occurrence of gastric cancer, (2) eradication regresses or inhibits the growth of gastric cancer, and (3) eradication interferes with the discovery of gastric cancer. Considering the biological nature of cancer cell proliferation, a sufficiently long-term follow-up may clarify the effect of eradication therapy on inhibition of the development (not discovery) of gastric cancer and reduction of gastric cancer-related mortality.

Background: In sentinel node (SN) detection for cases of early gastric cancer, the submucosal dye injection method appears to be more reasonable than the subserosal injection. To compare the two injection methods, we have focused on the rate of concordance between hot nodes (HNs) obtained from the radioisotope (RI) method and green nodes (GNs) obtained from the dye-guided method in addition to the number and distribution of GNs detected, and the sensitivity of metastatic detection., Methods: The subjects of this study were 63 consecutive patients with gastric cancer (sT1-T2, sN0, tumor diameter <== 4 cm) in whom we attempted SN detection using a combination of RI and dye methods. 99mTc-tin colloid was injected a day before the surgery, and indocyanine green was injected either submucosally (n = 43) with endoscopes or subserosally (n = 20) by direct vision., Results: An average of hot and green nodes (H&G: 4 +/- 3 vs. 4 +/- 3), hot and non-green nodes (H&NG: 2 +/- 3 vs. 1 +/- 2), cold and green nodes (C&G: 2 +/- 2 vs. 3 +/- 4), and the rate of concordance (H&G/H&G + H&NG + C&G: 45 + 27% vs. 48 +/- 30%) were not significantly different between the submucosal and subserosal injection methods. The spread of GNs to tier 2 stations (24% vs. 30%) and metastatic detection sensitivity (86% vs. 100%) were also not different between the submucosal and subserosal injection methods., Conclusion: The tracer injection sites do not have to be limited to the submucosa.

We established cell-line (CoRa 622 G6) of gastric carcinoma using cotton rats with spontaneous malignant gastric carcinoma with hypergastrinaemia. Inhibitory effects of hybrid liposomes (HL) composed of dimyristoylphosphatidylcoline (DMPC) and polyoxyethylene (n) dodecyl ether (C(12)(EO)(n): n=21, 23, 25) on the growth of CoRa 622 G6 cells were clarified on the basis of WST-1 assay. Fusion and accumulation of HL including fluorescence probe into CoRa 622 G6 cell membrane were clarified using confocal laser microscopy and total internal reflection fluorescence microscopy. Induction of apoptosis of CoRa 622 G6 cells after the treatment with HL was observed in fluorescence micrographs on the basis of Annexin-V binding assay and TUNEL method using confocal laser microscopy. The results in this study could contribute to the chemotherapy for patients with gastric carcinoma.

Background and Aim: Metallothionein (MT) has a proven relationship with various kinds of cancer and reduces tissue damage. Helicobacter pylori (H. pylori) infection is associated with the alteration of gastric epithelial cell cycle events, a condition implicated in the initiation and development of gastric cancer. This study investigates the role of MT in H. pylori-induced gastritis with or without early gastric cancer (ECG) and evaluates the effect on MT expression after eradication therapy., Methods: Gastric biopsy samples were immunohistochemically examined for MT expression in 36 H. pylori-negative patients without ECG and 98 positive patients with or without ECG. Real time polymerase chain reaction was performed in 14 antral biopsy samples with or without H. pylori. The severity of gastritis was also evaluated according to the updated Sydney System. In 31 successfully eradicated patients, the above assessment was repeated for two consecutive years., Results: MT expression was higher in H. pylori-negative patients than in positive patients (P < 0.01). Moreover, in the corpus it was higher in H. pylori-positive patients without ECG compared to those with ECG (P < 0.05). The MT labeling index had a negative correlation with the severity of gastritis (P < 0.01). A positive correlation was shown between the MT labeling index and apoptosis: proliferation ratio (r = 0.41, P < 0.01). The MT labeling index in H. pylori-positive patients was gradually recovered after eradication (P < 0.05)., Conclusion: The decrease of MT expression cannot prevent tissue damage in H. pylori-positive gastric mucosa and leads to more severe gastritis. This phenomenon may be attributed to gastric carcinogenesis. H. pylori eradication increases MT expression and may reduce the risk of ECG.

Inhibitory effects of hybrid liposomes (HL) composed of L-alpha-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(20) sorbitan monooleate (Tween 80) including polyunsaturated fatty acids on the growth of human tumor cells were examined in vitro. Remarkably high inhibitory effects of HL including docosahexaenoic acid (HL-DHA) on the growth of lung carcinoma (RERF-LC-OK), colon tumor (WiDr), and stomach tumor (MKN45) cells were obtained. The induction of apoptosis by HL-DHA was revealed on the basis of fluorescence microscopic and flow cytometric analyses.

Background and Aim: Gastrin is one of the most important gut hormones. However, the role of the gastrin-gastrin receptor (GR) system in the growth of gastric tumors is still unclear., Methods: We examined serum gastrin levels in 957 patients with early gastric carcinoma. Next, we raised antibody against the GR and examined GR expression in 5 gastric carcinoma cell lines and 48 human gastric tumor tissues. In 28 cases, Helicobacter pylori eradication therapy was performed and morphological tumor changes were examined., Results: Serum gastrin levels were significantly higher in patients with elevated tumors than in patients with depressed tumors (p = 0.02). All gastric carcinoma cell lines expressed GR. Thirty-one of 48 (65%) gastric tumors expressed GR, and its expression was prominent in elevated-type tumor with an intestinal histologic feature. Of 28 patients who underwent eradication therapy, 9 showed gastric tumors that became flat or depressed. In these 9 cases, GR expression was detected in all tumors, and the decrease in gastrin levels was more prominent than in those without morphological change (p = 0.01)., Conclusion: The gastrin-GR system plays an important role in the elevated morphology of gastric tumors., (Copyright 2008 S. Karger AG, Basel.)

Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.

Introduction: In recent years, a high success rate of combination chemotherapy with TS-1/CDDP has been reported against advanced gastric carcinoma. We, this time, experienced a case of advanced hemorrhagic gastric cancer with multiple hepatic metastases for which total gastrectomy was performed, followed by postoperative combination chemotherapy with TS-1/CDDP which culminated in achieving CR for the liver metastases., Case Report: The patient was a 59-year-old woman who was hospitalized for a type IV gastric carcinoma in the upper part of the gastric body. Further examination revealed liver (S 2, S 5, S 7) and lymph node metastases. Due to hemorrhage from the tumorous lesion, the treatment strategy selected was total gastrectomy followed by postoperative chemotherapy. Operative and clinicopathological findings revealed a mass lesion of MLU, type IV, 16.0x14.0 cm, sT 3 (SE), sH 1 (bilobular multiple metastases) and CY 0, and por 1, pT 2 (SS), pN 1 (+) [23/38], int, INF beta, ly 3 and v 1, respectively. Combination chemotherapy with TS-1/CDDP was instituted after surgery. As for the dosing method of combination chemotherapy,the patient was treated with a course of TS-1 80 mg daily divided into two doses over 21 days continuously, followed by a 14-day cessation of the drug,together with a dose of CDDP 70 mg on day 8. The patient received a total of four courses. At the completion of the third chemotherapy course, her multiple hepatic metastases disappeared. Further, the preoperative CA 19-9 level of 370 U/mL returned to normal after chemotherapy. Adverse events observed were leukopenia and thrombocytopenia, both of which were judged to be grade 2. At two years and nine months, the patient is being followed on an outpatient basis without any sign of postoperative recurrent disease., Conclusion: We experienced a patient who was successfully treated with combination chemotherapy and demonstrated disappearance of her multiple hepatic metastases, showing a clinical response of CR lasting for more than two years against the metastases. It was inferred that this regimen of TS-1/CDDP is an effective treatment modality not only as preoperative but also postoperative chemotherapy after surgery for advanced gastric carcinoma.

Case: A 75-year-old man was admitted to our hospital with hematoemesis. Gastrofiber-scopy revealed that type 3 gastric cancer was widespread in the lesser curvature. Multiple liver metastases 5 cm in diameter were shown on CT. We thought that the case was unresectable, and TS-1/CDDP chemotherapy was performed. TS-1 (80 mg/body/day) was orally administered and CDDP at 20 mg/body/day by intravenous drip infusion a week for 3 weeks followed by a drug-free 2 week period as the first course. After the third course, the primary lesion and the liver metastasis showed a partial response in terms of size. No serious drug adverse reaction was observed. Since there was no longer any reduction of the tumor, gastrectomy and coagulation therapy for liver metastasis were performed, and he has been alive for 15 months without recurrence. Combined use of TS-1 and CDDP is effective as neoadjuvant chemotherapy for advanced gastric cancer.

RUNX3 is a novel tumor suppressor gene that is frequently silenced by promoter hypermethylation in gastric cancer. The methylation status of multiple regions within the RUNX3 promoter CpG island (3,478 bp) was examined in gastric cancer cell lines, primary gastric cancers and non-neoplastic gastric mucosa to clarify how methylation spreads within the CpG island. The critical regions for RUNX3 silencing were evaluated by analysis of cell lines. The most 5' region of the CpG island was methylated in 90% (9/10) of gastric cancer cell lines, 96% (43/45) of primary gastric cancers and in 96% (43/45) of non-neoplastic gastric mucosa. The frequencies of methylation were less near the transcription start site and were 40% (4/10) in cell lines, 53% (24/45) in primary gastric cancers and 11% (5/45) in non-neoplastic gastric mucosa, where methylation was proven to be critical for gene silencing. Thus, hypermethylation initially occurs at the most 5' region of the RUNX3 CpG island and spreads to the transcription start site before ultimately shutting down RUNX3 mRNA expression. The detection of hypermethylation at multiple regions within the RUNX3 CpG island may be useful in the diagnosis and risk assessment of gastric cancer., ((Cancer Sci 2005).)

Aim: To identify chromosomal translocations specific to gastric cancer (GC), spectral karyotyping (SKY) analysis was performed on established cell lines and cancerous ascitic fluids., Methods: SKY analysis of 10 established cell lines and seven cancerous ascitic fluid samples identified recurrent chromosomal breakpoints and translocations in GC, several of which involved chromosomal loci of oncogenes or tumor suppressor genes., Results: A total of 630 chromosomal breaks were identified. Chromosome no.8 was the most frequently involved in rearrangements (65 breaks), followed by chromosomes no.11 (53), no. 1 (49), no. 7 (46), no. 13 (37), no. 3 (36), no. 17 (33), and no. 20 (29). Frequent breakpoints were detected in 8q24.1 (30 breaks), 11q13 (29), 13q14 (16), 20q11.2 (14), 7q32 (13), 17q11.2 (13), 18q21 (12), 17q23 (9), 18q11.2 (9). SKY analysis identified a total of 242 chromosomal rearrangements including 190 reciprocal and non-reciprocal translocations. The recurrent combinations of chromosomal bands involved in translocations were 8q24.1 and 13q14 (3 cases), 8q24.1 and 11q13 (3), 11q13 and 17q11.2 (2), and 18q11.2 and 20q11.2 (2). Our study validated the ability of SKY to characterize in detail the chromosomal rearrangements in solid tumors and derived cell lines. Moreover, fluorescence in situ hybridization helped to identify the insertions, translocations, and homogeneously staining regions of MYC and CCND1 gene loci., Conclusion: The non-random co-localization of certain cytogenetic bands suggests the importance of chromosomal translocations in gastric carcinogenesis, by serving as landmarks for the cloning of GC causing genes.

A 75-year-old male with malignant lymphoma (ML) accompanied with gastric lesion was treated with combination chemotherapy. The patient produced tarry stool on the 4th d, and emergency gastroscopy showed arterial bleeding from the lesion. Hemostasis was achieved by injecting pure ethanol and using hemostatic clips. There is only one previous report on endoscopic hemostasis being effective for bleeding due to lymphoma. Since gastric bleeding causes significant mortality, endoscopic hemostasis should be considered as first-line treatment for ML patients who were treated with chemotherapy.

Pseudomembranous colitis (PMC) usually manifests as fever and diarrhea in hospitalized patients treated with systemic antibiotics. We described a case of PMC with intestinal obstruction but without diarrhea. A 60-year-old man was hospitalized for chemotherapy for the treatment of Burkitt lymphoma of the stomach. The patient became febrile and complained of crampy abdominal pain during the post-chemotherapy nadir. Plain abdominal radiography showed some intestinal gas and niveau. Because stool cytotoxin assay for clostridium difficile was positive and colon fiberscopic examination showed a pseudomembrane at the left side of the colon, and a diagnosis of PMC was made. Treatment with intracolonic vancomycin administration by colonoscopy and nasoileus tube was successful. Physicians should take into account the possibility of bowel obstruction due to PMC occurring in patients undergoing chemotherapy and perform emergency colonoscopy examination of suspected cases.

Aim: To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosa-associated lymphoid tissue (MALT) lymphoma and to determine the clinical value of aneuploidy., Methods: We studied 13 patients with localized gastric MALT lymphoma of stage E1. Before eradication therapy, the depth of tumor invasion was assessed by endoscopic ultrasonography in 8 patients and by endoscopic examination and gastrointestinal series in the remaining patients. To detect chromosomal abnormalities, paraffin-embedded tissue sections of diagnostic biopsy specimens underwent tissue-fluorescence in situ hybridization (FISH), using chromosome-specific alpha-satellite DNA probes for chromosomes 3,7,12, and 18 and YAC clones for t(11;18)(q21;q21)., Results: Seven of the 13 patients had complete regression (CR) in response to H pylori eradication therapy. No patient with CR had submucosal tumor invasion. Trisomy 18 was seen in 1 patient with CR, and both trisomies 12 and 18 were present in another patient with CR. All patients with no response or progressive disease had deep submucosal tumor invasion and showed t(11;18)(q21;q21) or trisomy 3. Trisomy 7 was not detected in this series of patients., Conclusion: The depth of tumor invasion is an accurate predictor of the response of stage E1 MALT lymphoma to H pylori eradication therapy and is closely associated with the presence of chromosomal abnormalities. Trisomy 3 may predict the aggressive development of MALT lymphoma.

Purpose: Dendritic cells (DCs) play an important role in the host's immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreased in a cancer-bearing host. In the present study, we investigated the mechanism of down-regulation of DCs in a cancer-bearing host., Methods: We evaluated the relationship between DC infiltration and production of vascular endothelial growth factor (VEGF) in carcinoma tissue by immunohistochemistry. Furthermore, functional and phenotypical alterations of DCs were evaluated when monocyte-derived, mature DCs were treated with VEGF in vitro. Monocyte-derived DCs were generated in a culture of monocyte with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and the maturation of DCs was induced by either lipopolysaccharide (LPS) or a proinflammatory cytokine cocktail: tumor-necrosis factor alpha, prostaglandin E2, IL-6, and IL-1beta., Results: A significant inverse correlation was found between the density of DCs and the quantity of VEGF production in gastric carcinoma tissue (r=-0.39, p<0.05). In LPS-induced maturation, the ability of mature DCs to stimulate allogenic T cells and produce IL-12 (p70 heterodimer) was suppressed by the addition of VEGF in a dose-dependent manner. A lesser expression of costimulatory molecules (CD80 and CD86) was seen in DCs treated with exogenous VEGF than in DCs not treated with VEGF. The population of dead DCs (early and late apoptosis) treated with VEGF increased more than that without VEGF treatment, using the annexin V and propidium iodide evaluation in DCs matured by LPS. In contrast, in DCs matured by the proinflammatory cytokine cocktail, the down-regulation of costimulatory molecules and induction of DC apoptosis was not seen., Conclusions: These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs.

Promoter hypermethylation of various tumor-related genes is extremely frequent in Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To investigate the significance of the promoter methylation in EBVaGC, we focused on one of the important proteins in the carcinogenesis of the stomach, E-cadherin. Methylation-specific PCR analysis (MSP) was applied to surgically resected gastric carcinomas, together with immunohistochemistry, PCR-based analysis of mutations and allelic loss, and site-specific MSP of E-cadherin gene. By MSP, nearly all of the carcinomas showed aberrant methylation of E-cadherin promoter in EBVaGC (21/22), and the frequency of this aberration was significantly higher than that in EBV-negative gastric carcinoma (GC; 45/81; p = 0.0003). According to immunohistochemistry of E-cadherin, the frequency of abnormal staining pattern in EBVaGC (87%) was comparable to that in the diffuse type (80%), but higher than that in the intestinal type of EBV-negative GC (47%). Promoter methylation was well correlated with abnormal staining pattern in EBVaGC, but not in EBV-negative GC. Neither mutation nor allelic loss of E-cadherin was observed in EBVaGC. Methylation status of E-cadherin within each carcinoma was heterogeneous as far as examined. Thus, in addition to the known association involving p16, we determined that promoter methylation-mediated silencing of E-cadherin gene was also closely associated with the development of EBVaGC, although it becomes heterogeneous within a given tumor along its progression., (Copyright 2003 Wiley-Liss, Inc.)

Background: It was previously reported that monocytes/macrophages play an important role in mediating T cell dysfunction in tumor-bearing hosts, in which monocytes/macrophages were found to induce the loss of T cell functions concomitantly with induction of defects in T cell signaling molecules. These observations encouraged us to investigate monocytes status in cancer-bearing hosts., Materials and Methods: We characterized peripheral blood monocytes in gastric cancer patients with advanced disease (n = 14), in those with early disease (n = 17), and in healthy individuals (n = 14), based on surface marker, oxygen-burst capacity, and intracellular cytokine status (IL-10 and IL-12)., Results: Intracellular IL-10 and IL-12 status on monocytes in advanced disease was significantly increased in comparison with those in early disease or healthy individuals, while there were no differences in the surface marker or oxygen-burst capacity of monocytes. To clarify which mediators induced the characteristic differences of monocytes in cancer-bearing hosts, healthy donor-derived monocytes were coincubated with the patient's plasma. The plasma from the patients with advanced disease could induce healthy monocytes to increased intracellular IL-10 and IL-12 status. The phenomenon was significantly inhibited with neutralizing mAbs specific for VEGF. Furthermore, the contents of VEGF in the patient's plasma correlated with their capacity to induce healthy monocytes to increased intracellular IL-10. In addition, the treatment of healthy monocytes with exogenous VEGF resulted in increased intracellular IL-10., Conclusions: Monocytes in gastric cancer patients with advanced disease showed different characteristics in comparison with those with early disease or healthy individuals, which might be potentially induced by circulating VEGF in the patients.

Objective: The invasion and metastasis of carcinoma cells require the proteolytic degradation of the extracellular matrix by various cell surface proteases. Among these, seprase is a type II transmembrane serine protease absent in normal tissues and it has been implicated in the invasion of the extracellular matrix by both tumor and stromal cells in human breast carcinoma and melanoma. In the present study, the expression of seprase mRNA, protein and its gelatin-degrading activity in human gastric carcinoma were examined to substantiate the potential role of seprase in gastric carcinoma invasion., Methods: We have examined the seprase expression in human gastric carcinoma (n = 34) by RT-PCR, Western immunoblotting analysis, immunohistochemistry, and gelatin zymography., Results: Immunoblotting analysis using mAb D8 directed against seprase showed that the carcinoma tissues in 26 out of 34 cases of gastric cancer expressed a dimeric form of seprase but their normal counterparts did not. Gelatin zymography confirmed that the isolated seprase exhibited the gelatin-degrading activity and was active. Seprase-expressing carcinoma tissues were more often found in the scirrhous type than in other types of gastric carcinoma. RT-PCR analysis showed that seprase mRNA was present in carcinoma tissues but not in normal tissues. Immunohistochemically, seprase was mainly located in gastric carcinoma cells, weakly in stromal cells and microvessel endothelial cells in the tumor nest, and none in normal cells., Conclusions: Our studies showed the unique expression and localization of seprase in the tumor and stromal cells within human gastric carcinoma but not in normal tissues, suggesting a role of seprase in the invasive and metastatic progression of gastric carcinoma., (Copyright (c) 2004 S. Karger AG, Basel)

Background: p300 is a transcriptional coactivator, and bi-allelic mutations of the p300 gene have been demonstrated in human cancers., Methods: In 80 gastric carcinoma tissues, loss of heterozygosity (LOH) was analyzed by polymerase chain reaction (PCR) analysis, using 14 primer pairs at the 22q11-13 locus containing NF2 and p300. The mutations of the p300 gene were examined by reverse transcriptase-PCR (RT-PCR) and single-stranded conformation polymorphism (SSCP) analysis., Results: LOH was frequently observed at the 22q13 locus containing the p300 gene in gastric carcinomas, with an equal frequency in the intestinal (21/34) and diffuse (30/46) types. However, LOH was significantly correlated with advanced stage and lymph node metastasis only in the intestinal type. Using RT-PCR-SSCP analysis, mutations of the p300 gene were identified in the intestinal (6/15) and in the diffuse (4/18) types, but all of the mutations were accompanied by LOH at the 22q13 locus only in the intestinal type., Conclusion: The p300 gene behaves as a tumor suppressor gene in the intestinal, but not in the diffuse type of gastric carcinoma. The significance of frequent gene alteration in the diffuse type should be further investigated by the clarification of other mechanisms of p300 inactivation and by clarification or of the functional role of p300 in cell adhesion/spreading.