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Background: Despite a radical operation, about half of gastric cancer (GC) patients with advanced GC experience peritoneal metastasis (PM), and the patients with PM have a poor prognosis. However, because staging laparoscopy was a highly invasive procedure for patients, identification of PM using a liquid biopsy can be useful for patients with GC., Methods: This study analyzed two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA). The study prioritized biomarkers in pretreatment plasma specimens from clinical training and validation cohorts of patients with GC. The authors developed an integrated exosomal miRNA panel and established a risk-stratification model, which was combined with the miRNA panel and currently used tumor markers (CEA, CA19-9, CA125, and CA72-4 levels)., Results: The comprehensive discovery effort identified a four-miRNA panel that robustly predicted the metastasis with excellent accuracy in the TCGA dataset (area under the curve [AUC] 0.86). A circulating exosomal miRNA panel was established successfully with remarkable diagnostic accuracy in the clinical training (AUC 0.85) and validation (AUC 0.86) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to that of conventional clinical factors (P < 0.01), and the risk-stratification model was dramatically superior to the panel and currently used clinical factors for predicting PM (AUC 0.94; univariate: odds ratio [OR] 77.00 [P < 0.01]; multivariate OR 57.71 [P = 0.01])., Conclusions: The novel risk-stratification model for predicting PM has potential for clinical translation as a liquid biopsy assay for patients with GC. The study findings highlight the potential clinical impact of the model for improved selection and management of patients with GC., (© 2024. Society of Surgical Oncology.)

Background: Laparoscopic gastrectomy (LG) requires a long learning curve because of the complicated surgical procedures. Infrapyloric (No. 6) lymph node dissection (LND) is one of the difficult procedures in LG, especially for trainees. This study investigated the impact of the prediction of the difficulty of No. 6 LND., Methods: We retrospectively reviewed the preoperative computed tomography (CT) images and individual operative video records of 57 patients who underwent LG with No. 6 LND to define and predict the No. 6 LND difficulty. To evaluate whether prediction of the difficulty of No. 6 LND could improve surgical outcomes, 48 patients who underwent laparoscopic distal gastrectomy were assessed (30 patients without prediction by a qualified surgeon and 18 patients with prediction by a trainee)., Results: The anatomical characteristic that LND required > 2 cm of dissection along the right gastroepiploic vein was defined as difficulty of No. 6 LND. Of the 57 LG patients, difficulty was identified intraoperatively in 21 patients (36.8%). Among the several evaluated anatomical parameters, the length between the right gastroepiploic vein and the right gastroepiploic artery in the maximum intensity projection in contrast-enhanced CT images was significantly correlated with the intraoperative difficulty of No. 6 LND (p < 0.0001). Surgical outcomes, namely intraoperative minor bleeding, postoperative pancreatic fistula, and drain amylase concentration were not significantly different between LG performed by a trainee with prediction compared with that by a specialist without prediction., Conclusions: Preoperative evaluation of the difficulty of No. 6 LND is useful for trainees, to improve surgical outcomes., (© 2024. The Author(s).)

Background: Laparoscopic and endoscopic cooperative surgery (LECS) is an effective treatment for gastric gastrointestinal stromal tumors (GISTs). The utility of LECS for gastric GISTs of > 5 cm remains controversial. This study was performed to investigate the feasibility of LECS for gastric GISTs with a tumor diameter of >5 cm., Methods: We analyzed 43 patients with gastric GISTs who underwent LECS or laparoscopic partial gastrectomy (Lap-Partial Gx). We compared the surgical outcomes of LECS versus Lap-Partial Gx and of LECS for a tumor diameter of > 5 versus ≤ 5 cm., Results: In the comparison of LECS versus Lap-Partial Gx, there were no significant intergroup differences in the operative time or blood loss volume. The morbidity rate was similar between the groups. No postoperative mortality occurred in either group. In the comparison of LECS for a tumor diameter of > 5 versus ≤ 5 cm, there were no significant intergroup differences in operative time, or blood loss volume. The morbidity rate was similar between the > 5-cm and ≤ 5-cm groups (0.0% vs. 4.5%, respectively ; p = 0.56). Additionally, no recurrence or death occurred during follow-up in either group., Conclusion: LECS is a feasible option for gastric GISTs with a tumor diameter of > 5 cm. J. Med. Invest. 71 : 148-153, February, 2024.

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This study aimed to investigate the feasibility and safety of our enhanced recovery after surgery protocol including early oral intake and omitting nasogastric tube (NGT) placement after total gastrectomy., Methods: We analyzed 182 consecutive patients who underwent total gastrectomy. The clinical pathway was changed in 2015, and patients were divided into 2 groups (conventional group and modified group). Postoperative complications, bowel movement, and postoperative hospital stays were compared in the two groups in all cases and propensity score matching (PSM)., Results: Flatus and defecation were significantly earlier in the modified group compared with those in the conventional group (flatus: 2 (1-5) days vs 3 (2-12) days, p = 0.03; defecation: 4 (1-14) days vs 6 (2-12) days p = 0.04). The postoperative hospital stay was 18 (6-90) days in the conventional group and 14 (7-74) days in the modified group (p = 0.009). Days until discharge criteria were met were earlier in the modified group compared with that in the conventional group (10 (7-69) days vs 14 (6-84) days p = 0.01). Overall and severe complications occurred in nine patients (12.6%) and three patients (4.2%) in the conventional group and twelve patients (10.8%) and four patients (3.6%) in the modified group, respectively (p = 0.70 and p = 0.83) in all cases. In PSM, there is no significant difference between the two groups concerning the postoperative complications (overall complication 6 (12.5%) vs 8 (16.7%) p = 0.56, severe complications 1 (2%) vs 2 (4.2%) p = 0.83)., Conclusions: Modified ERAS for total gastrectomy may be feasible and safe., (© 2023. The Author(s).)

Background: Robotic surgery (RS) has been rapidly adopted for gastric cancer and adenocarcinoma of the esophagogastric junction (AEG). However, the utility of RS for Siewert type II/III AEG remains unclear., Methods: Forty-one patients who underwent either transhiatal RS (n = 15) or laparoscopic surgery (LS) (n = 26) for Siewert type II/III AEG were enrolled in this study. The surgical outcomes of the two groups were compared., Results: In the entire cohort, there were no significant intergroup differences in the operative time, blood loss volume, or number of retrieved lymph nodes. The length of the postoperative hospital stay was shorter in the RS group than in the LS group (14.20 ± 7.10 days vs. 18.73 ± 17.82 days, respectively; p = 0.0388). The morbidity rate (Clavien-Dindo grade ≥ 2) was similar between the groups. In the Siewert II cohort, there were no significant intergroup differences in short-term outcomes. In the entire cohort, there was no significant difference between the RS and LS groups in the 3-year overall survival rate (91.67% vs. 91.48%, N.S.) or 3-year disease-free survival rate (91.67% vs. 91.78%, N.S.), respectively. Likewise, in the Siewert type II cohort, there was no significant difference between the RS and LS groups in the 3-year overall survival rate (80.00% vs. 93.33%, N.S.) or 3-year disease-free survival rate (80.00% vs. 94.12%, N.S.), respectively., Conclusions: Transhiatal RS for Siewert II/III AEG was safe and contributed to similar short-term and long-term outcomes compared with LS., (© 2023. The Author(s).)

Background/aims: Although undifferentiated gastric cancer (UGC) diagnosed after Helicobacter pylori eradication (HPE) carries a poor prognosis, characteristics of post-HPE UGC have not been evaluated in detail because of its low incidence. Therefore, we compared the clinicopathologic characteristics of UGC and differentiated gastric cancers (DGC) diagnosed after successful HPE., Methods: GC lesions from patients who had successfully completed HPE and who had undergone upper gastrointestinal endoscopy between January 2004 and March 2016 were analyzed. Tumors were divided into DGC and UGC groups. Clinicopathologic factors of background and tumor characteristics were compared using univariate and multiple logistic analyses., Results: A total of 129 tumors from 115 patients were evaluated; 113 tumors were in the DGC group and 16 in the UGC group. Depressed-type tumors (P = 0.024) and sub-submucosal invasion (P<0.001) were significantly higher in the UGC group. The UGC group had larger tumor diameters (25.9±7.3 mm) than the DGC group (13.2±10.2 mm) (P<0.001). Multivariate analysis showed that female sex (odds ratio [OR] 3.24, 95%CI:1.02-10.37; P = 0.047) and absent follow-up (OR 4.99, 95%CI:1.60-15.57; P = 0.006) were significant independent risk factors for UGC. The DGC group showed a gradually decreasing temporal trend by trend test (P = 0.015), while the UGC group showed a relatively constant incidence over time, although the number of cases was small., Conclusion: UGC was diagnosed even after long time spans following HPE, although the number of cases was small. Female sex, and especially absent follow-up, were risks for post-HPE UGC, suggesting that diligent long-term follow-up after HPE is essential., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kodama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Roux stasis syndrome (RSS) after Roux-en-Y (RY) reconstruction significantly prolongs the hospital stay and decreases the quality of life. The purpose of the present study was to evaluate the incidence of RSS in patients who underwent distal gastrectomy for gastric cancer and to identify the factors related to the development of RSS after mechanical RY reconstruction in minimally invasive surgery (MIS)., Methods: This study included 134 patients who underwent distal gastrectomy in MIS with mechanical RY anastomosis. RSS was defined as the presence of symptoms such as nausea, vomiting, or abdominal fullness, and the confirmation of delayed gastric emptying on imaging or gastrointestinal fiber testing. Clinical data were checked, including body mass index, operative procedure, age, sex, operative time, blood loss volume, extent of lymph node dissection, final stage, stapler insertion angle, method of entry hole closure. The relationship between the incidence of RSS and these factors was analyzed., Results: RSS occurred in 24 of 134 patients (17.9%). RSS occurred significantly more frequently in patients with D2 lymphadenectomy than in patients with D1 + lymphadenectomy (p = 0.04). All patients underwent side-to-side anastomosis via the antecolic route. The incidence of RSS was significantly greater in patients with a stapler insertion angle toward the greater curvature (n = 20, 22.5%) versus the esophagus (n = 4, 8.9%) (p = 0.04). The multivariate logistic regression model revealed that the stapler insertion angle to the greater curvature is identified as independent risk factor for RSS (OR 3.23, 95%Cl 1.01-10.3, p = 0.04)., Conclusion: Stapler insertion angle toward the esophagus may reduce the incidence of early postoperative RSS rather than toward the greater curvature., (© 2023. The Author(s).)

Pyloric outflow obstructions can be caused by several types of lesions. When a thickened gastric wall and pyloric mass are detected, malignant neoplasia must be differentiated from chronic hypertrophic pyloric gastropathy. CT can characterize gastric tumors. However, based on the authors' review of the literature, there is limited information about the CT findings of pyloric lesions. The purpose of this retrospective case series study was to assess the CT findings of canine pyloric lesions. The following CT parameters were recorded: anatomical area, involved area, lesion shape, growth patterns of wall thickening lesions, enhancement pattern of the lesion in the early and delayed phases, lymphomegaly, and pulmonary metastasis. Seventeen dogs were included in this study and had the following final diagnoses: hyperplasia (five dogs), adenoma (five dogs), adenocarcinoma (three dogs), gastrointestinal stromal tumor (GIST; two dogs), polyposis (one dog), and pyogenic granuloma (one dog). Hyperplasia, adenoma, and polyposis formed mass lesions that involved the mucosal layer. Lymphomegaly was detected in two Jack Russell terriers with hyperplasia; however, the causes were unknown because we did not perform biopsies. All adenocarcinomas formed wall-thickened lesion that involved the outer layer, with lymphomegaly. All GISTs formed mass lesion that involved the outer layer. The pyogenic granulomas formed symmetric wall-thickened lesion that involved the mucosal and outer layers. CT facilitated the characterization of canine pyloric lesions using contrast enhancement, based on the involved area and lesion shape. However, polyposis may require caution in diagnosis based on CT findings alone., (© 2022 American College of Veterinary Radiology.)

Reports on pleomorphic type of undifferentiated sarcoma (PUS) originating from the gastrointestinal tract, especially the stomach, are extremely rare. We herein report a case of pleomorphic type undifferentiated gastric sarcoma. The patient was a 67-year-old woman. The chief complaint was upper abdominal pain. Upper gastrointestinal endoscopy, ultrasonography, and contrast-enhanced computed tomography showed two submucosal tumors at the greater curvature of the fundus and the lesser curvature of the gastric angle. Endoscopic ultrasound-guided fine-needle aspiration revealed a c-kit-negative spindle cell tumor at the greater curvature of the fundus. Total gastrectomy, splenectomy, and partial resection of the diaphragm and liver were performed. One lesion had invaded the lateral segment of the liver, left diaphragm and spleen. The postoperative course was uneventful. Histopathological and immunohistochemical examinations of the resected specimen revealed PUS. Peritoneal dissemination was detected at 8 months after surgery. However, no effective therapeutic agents were adopted for chemotherapy. The patient had poor performance status due to disease progression and underwent best supportive care. The patient died 10 months after surgery. This case highlights the imaging, histological diagnosis, and treatment strategy for PUS originating from the stomach. Surgeons should be aware of PUS as a differential diagnosis in cases with submucosal tumor of the stomach., (© 2022. Japanese Society of Gastroenterology.)

Background: Frailty plays a crucial role in cancer patients who have received surgery in this recent aging society. We aimed to investigate frailty as a prognostic factor in elderly gastric cancer (GC) patients who underwent curative gastrectomy., Methods: We analyzed 86 elderly (over 75 years old) GC patients who underwent curative gastrectomy. Patients were assigned to two groups;frailty group (n=29) and no-frailty group (n=57). Clinicopathological values were compared between the two groups., Results: The OS rate of the frailty group was significantly poorer than that of the no-frailty group (5-yr OS rate;frailty group 52.49% vs. no-frailty group 74.87%, p<0.05). Multivariate analysis of the OS showed that frailty tended to be significant prognostic factor (p=0.09). The DFS rate of the frailty group was significantly poorer than that of the no-frailty group (5-yr DFS rate;frailty group 42.30% vs. no-frailty group 71.55%, p<0.05). Multivariate analysis of the DFS showed that frailty tended to be significant prognostic factor (p=0.14)., Conclusion: We identified the clinical impact of frailty prognostic factor for elderly GC patients who underwent gastrectomy. J. Med. Invest. 70 : 423-429, August, 2023.

Background: Although eradication therapy for chronic Helicobacter pylori (H. pylori) reduces the risk of gastric cancer (GC), its effectiveness is not complete. Therefore, it is also critically important to identifying those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status, efficacy of eradication therapy, and GC risk in H. pylori-eradicated mucosa, and to reveal the potential downstream molecules of eEF1A dimethylation., Methods: Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9 mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2., Results: The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with the negative mucosa (surface, p = 0.0031; basal, p = 0.0036, respectively). The eEF1A dimethyl-levels in the surface area were significantly reduced by eradication therapy (p = 0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio = 3.6611, 95% confidence interval = 1.0350-12.949, p = 0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors, Oct4 and Nanog, by immunohistochemistry and in vitro genome editing experiments., Conclusions: The results indicated that H. pylori infection induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori eradicated-gastric mucosa., (© 2022. The Author(s).)

Background: The frailty was associated with the worse surgical outcomes and poor prognosis in several cancers. Therefore, we aimed to identify the usefulness of nutrition and exercise intervention (NEI) in frailty patients with GC., Methods: We analyzed 58 frailty patients with GC who underwent radical surgery. Among these, 15 patients were performed NEI by nutritional and rehabilitation support team. We compared the surgical outcomes between NEI and non-NEI groups with frailty patients and evaluated the nutrition and rehabilitation markers in pre- and post-NEI groups., Results: The postoperative complication of NEI groups was 6.7% and less than that of non-NEI groups (p = 0.08). The mean postoperative hospital stay of NEI groups was 13.0 ± 1.0 days for NEI groups and significantly shorter than that of non-NEI groups (p = 0.03). The NLR was 4.3 ± 0.6 for pre-NEI and significantly improved by NEI between pre- and post-NEI (p = 0.03)., Conclusion: We identified the clinical importance of NEI for improving the surgical outcomes in frailty patients with GC. Our findings highlight the potential clinical impact of optimizing treatment strategies to select and manage the frailty patients., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Robotic gastrectomy (RG) has been rapidly adopted for gastric cancer (GC) treatment. However, the benefits of RG over laparoscopic gastrectomy (LG) for GC remain unclear., Methods: A total of 451 patients who underwent either RG (n = 83) or LG (n = 368) for GC were enrolled in this study. A 1:1 matched, propensity score-matched analysis was performed using the following factors: age, sex, body mass index, pT, pN, pStage, tumor location, vessel invasion, tumor markers, surgical procedure, reconstruction method, extent of lymphadenectomy, and Endoscopic Surgical Skill Qualification System qualified surgeon as an operator. The surgical outcomes of the two groups were compared., Results: A well-balanced cohort of 158 patients was analyzed (n = 79 in the RG group, n = 79 in the LG group). Regarding the short-term outcomes, the respective blood loss volume, drain amylase content, and number of retrieved lymph nodes in the RG and LG groups were 38.62 ± 73.06 ml and 67.53 ± 108.20 ml (p < 0.05), 450 ± 371 IU/l and 1590 ± 6392 IU/l (p < 0.01), and 35.02 ± 15.51 and 25.28 ± 11.70 (p < 0.01). The morbidity rate was similar between the RG and LG groups (not significant [NS]). Regarding the long-term survival outcomes, there were no intergroup differences in 3-year overall survival (91.72% in the RG group vs. 83.39% in the LG group: NS) and 3-year, disease-free survival (93.31% in the vs. 90.44%: NS)., Conclusions: RG was safe and contributed to better short-term outcomes and similar long-term survival outcomes compared with LG., (© 2021. Society of Surgical Oncology.)

Purpose : This study aimed to investigate the short-term outcomes of laparoscopic gastrectomy / robotic gastrectomy after chemotherapy in patients with advanced gastric cancer and compare these outcomes with those of open gastrectomy. Methods : Fifty patients who underwent radical gastrectomy for advanced gastric cancer after chemotherapy between 2007 and 2021 were retrospectively analyzed. The patients were divided into two groups : the laparoscopic gastrectomy / robotic gastrectomy (n = 11) and open gastrectomy (n = 39) groups. The short-term outcomes of these procedures were subsequently examined. Results : The laparoscopic gastrectomy / robotic gastrectomy group had significantly shorter hospital stays and lower intraoperative blood loss than the open gastrectomy group. The overall complication rates were 12.8% (5 of 39 patients) and 0% (0 of 11 patients) in the open gastrectomy and laparoscopic gastrectomy / robotic gastrectomy groups, respectively (P  =  0.1). Conclusions : Laparoscopic gastrectomy / robotic gastrectomy may be a surgical option after chemotherapy for patients with advanced gastric cancer. J. Med. Invest. 69 : 261-265, August, 2022.

Purpose: The aim of this study was to investigate advantages of the left-handed ultrasonic shears technique in robotic gastrectomy for gastric cancer., Methods: We retrospectively analyzed 67 consecutive gastric cancer patients who underwent robotic gastrectomy. Fifty-six patients underwent gastrectomy with the left-handed ultrasonic shears technique (the left hand group), and 11 patients underwent surgery with the conventional approach (the conventional group). Intraoperative and postoperative outcomes were compared between the 2 groups., Results: Operative blood loss, morbidity, and mortality were similar between the 2 groups. We observed a trend toward a shorter operation time and higher number of retrieved lymph nodes in the left hand group compared with the conventional group. Console time (docking-gastrectomy) in the left hand group was significantly shorter than in the conventional group (192.20 vs. 218.36 min, P<0.05). In robotic distal gastrectomy, both operation time and console time in the left hand group were significantly shorter than in the conventional group (276.10 vs. 354.80 min, 176.43 vs. 209.20 min, P<0.05 for both). The postoperative intra-abdominal infectious complication (Clavien Dindo≥1) rate in the left hand group was significantly lower than that in the conventional group (0% vs. 20%, P<0.05)., Conclusions: Use of the left-handed ultrasonic shears technique is safe and provides a technically superior operative environment with satisfactory postoperative results., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Determining the depth of invasion is important when considering therapeutic strategies for early gastric cancer (EGC). We determined the effects of learning the non-extension sign, that is, an index of T1b2 in EGC, on identifying its depth of invasion., Methods: Endoscopic images of 40 EGC cases (20 showing positive non-extension sign on endoscopy as T1b2 and 20 showing negative non-extension sign on endoscopy as T1a-T1b1) were randomly displayed on PowerPoint. Participants read endoscopy findings (pretest) and attended a 60-min lecture on how to read the non-extension sign. Then, they read the same images using the non-extension sign as the marker (posttest). The primary endpoint was a change in accuracy rate for determining the depth of invasion before and after attending the lecture, for nonexperts (< 80%)., Results: Among 35 endoscopists, 12 were nonexperts; their test results were used for analyses. Accuracy rates for pretest and posttest among nonexperts were 75.2 and 82.5%, respectively, showing a significant increase in the accuracy rate after learning to read the non-extension sign (p = 0.003)., Conclusion: Nonexperts' diagnostic ability to determine the depth of invasion of EGC improved by learning to read the non-extension sign. Thus, the non-extension sign is considered a simple and useful diagnostic marker., (© 2019 S. Karger AG, Basel.)

A 70-year-old man was admitted for lymph node metastasis detected by FDG-PET/CT showing a mass 10mm in diameter. He had a history of a distal gastrectomy for advanced gastric cancer and was administered postoperative adjuvant chemotherapy consisting of 2 courses of TS-1 with CDDP and TS-1 only for 1 year. Lymph node recurrence was diagnosed and resected 4 years after the initial surgery. Histological examination revealed lymph node metastasis of the gastric cancer. He was administered adjuvant chemotherapy using TS-1 and has been followed-up without recurrences for 17 months after the second operation. We reported a case in which FDG-PET/CT was potentially beneficial for the diagnosis of the postoperative small lymph node metastasis.

Background: Indications and efficacy of surgical treatment for liver metastases from gastric cancer (LMGCs) remain controversial. This retrospective study was designed to clarify the benefits of surgical treatment and identify prognostic factors., Methods: Between December 1997 and December 2015, 34 consecutive patients underwent hepatic resection and surgical microwave ablation for synchronous or metachronous LMGCs at our institution. We analyzed their cumulative overall survival (OS) and recurrence-free survival (RFS) rates and clinical parameters to identify predictors of prognosis., Results: Of the 34 patients, 14 underwent hepatic resection, 13 underwent surgical microwave ablation, and 7 underwent hepatic resection combined with surgical microwave ablation. Their OS rates were 1-year: 84.4%, 3-year: 38.6%, and 5-year: 34.7%; and their RFS rates were 1-year: 38.5%, 3-year: 28.0%, and 5-year: 28.0%. OS did not significantly vary among the surgical procedures. In multivariable analysis, positive of both CEA and CA19-9 were independent predictors of poor survival (hazard ratio [HR] 4.51; P = 0.049) and early recurrence (HR 5.70; P = 0.047)., Conclusions: Both hepatic resection and surgical microwave ablation for LMGCs are effective and can improve survival in selected patients., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Background/aim: Indoleamine 2,3-dioxygenase (IDO) down-regulates T cell activation, attenuates regulatory T cell (Treg) activation and is related to immune tolerance. The aim of the study was to clarify the significance of IDO expression and analyze the relationships between the expression of IDO, TGF-β, and Foxp3 in gastric cancer (GC)., Patients and Methods: A total of 60 patients who underwent curative gastrectomy for stage III gastric cancer were included in the study. The expression of IDO, TGF-β, and Foxp3 was examined by immunohistochemistry and the relationship of each expression level to several prognostic factors was examined using univariate and multivariate analyses., Results: IDO expression was not positively correlated with any of the factors examined. IDO expression was positively correlated with TGF-β expression (p<0.05), and TGF-β expression was positively correlated with FoxP3 expression (p<0.05). Overall survival (OS) rates were significantly poorer in the IDO-positive group compared to the IDO-negative group (3-year OS, 78.5% vs. 90%, respectively; p<0.05). Multivariate analysis confirmed IDO expression as independent prognostic factors in OS. Disease-free survival (DFS) was significantly poorer in the IDO-positive group compared to the IDO-negative group (3-year DFS, 59.3% vs. 69.3%, respectively; p<0.05)., Conclusion: IDO is associated with poor prognosis and immuno-tolerance through attenuation of Treg activation in Stage III GC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Surgical indication for hepatic resection is controversial in gastric cancer liver metastasis (GLM). The aim of this study is to clarify the effect of hepatic resection for GLM., Methodology: Ten patients who underwent hepatic resection for GLM between 2001 and 2013 were enrolled in this study. Six patients underwent synchronous hepatic resection and gastrectomy, and the remaining four patients underwent metachronous hepatic resection. Six patients had solitary liver metastasis, and 4 patients had multiple liver metastasis. The median follow-up period was 12.4 months (the range being 0.5 months to 50 months)., Result: The actual 1- year and 3-year overall survival rates for the patients who underwent hepatic resection are 88.9% and 17.8%, respectively. The median survival time was 21.5 months. And the 1-year recurrence free survival time was 20.0%. The median recurrence free survival rate was 4.7 months. Regarding post-operative recurrence, synchronous hepatic resection tended to be a recurrence factor (p=0.08)., Conclusion: Hepatic resection for GLM has an acceptable outcome. Metachronous hepatic resection tends to have a better outcome than synchronous hepatic resection for the treatment of GLM. J. Med. Invest. 65:27-31, February, 2018.

Background: Previous studies for surgical audit have focused on short-term outcomes, such as perioperative mortality. There has been no gold standard how to evaluate quality of care for long-term outcomes in surgical oncology. This preliminary study aims to propose a method for surgical audit targeting long-term outcome following gastrectomy for gastric cancer., Methods: We prospectively investigated a set of variables relating to physiologic conditions, tumor characteristics and operations in patients who underwent gastrectomy for gastric cancer between June 2005 and July 2008 in 18 referral hospitals in Japan. Overall survival (OS) is the endpoint. Cox hazard regression analysis was used to generate a model to predict OS. The calibration and discrimination power of the model were assessed using the Hosmer-Lemeshow (H-L) test and area under the receiver-operating characteristic curve (AUC), respectively. The ratio of observed-to-estimated 5-year OS rates (OE ratio) was defined as a measure of quality., Results: Among 762 patients analyzed, 697 (91%) completed the 5-year follow-up. The constructed model for OS exhibited a good discrimination power (AUC, 95% confidence interval 0.89, 0.86-0.91), which was significantly better than that for the UICC stage (0.81, 0.77-0.84). This model also demonstrated a good calibration power (H-L: χ(2) = 27.2, df = 8, P = 0.77). The OE ratios among the participating hospitals revealed no significant variation between 0.74 and 1.1., Conclusions: The current study suggests the possibility of surgical audit for postoperative OS in gastric cancer. Further studies including high-volume centers will be necessary to validate this idea.

A 66-year-old woman was diagnosed with unresectable advanced gastric cancer with Schnitzler metastasis in January 2012. She was treated with combination chemotherapy comprising S-1 and docetaxel (DTX). However, in January 2013, after 13 courses of treatment, a computed tomography (CT) indicated peritoneal dissemination growth. The chemotherapy regimen was changed to a combination of S-1 and irinotecan (CPT-11), but after a single course of treatment the patient complained of stomachaches and vomiting. The patient developed ileus from the stenosis of the rectum, and a transanal ileus tube was used to decompress the bowel tract. Due to the patient's poor general condition, a metallic stent was inserted, and she could resume eating. Thereafter, we changed the chemotherapy regimen to weekly paclitaxel (PTX). However, 1 year and 4 months after starting treatment she died of regrowth of the peritoneal disseminating lesions. We recommend a combination of chemotherapy and metallic stent placement to improve quality of life and long-term survival.

A 66-year-old man underwent distal gastrectomy with Roux-en-Y anastomosis and D2 dissection for the treatment of advanced gastric cancer (pT4a, N0, M0, stage IIB) in June 2009. He was treated with adjuvant postoperative chemotherapy consisting of S-1. However, in September 2010, computed tomography (CT) showed #16a2 lymph node recurrence, which was treated with combination chemotherapy of S-1 and cisplatin. After 7 courses of this combination chemotherapy, CT revealed a significant reduction in the size of the metastatic lesion as well as a new peritoneal dissemination recurrence around the right kidney. We therefore changed the regimen to combination chemotherapy of S-1 and docetaxel. After 3 courses of this treatment, the dissemination lesion was no longer evident by CT. After 6 more courses of treatment, the lymph node and peritoneal dissemination recurrence showed no regrowth. In response to the patient's wish, we changed the chemotherapy to S-1 alone beginning in June 2012. He survived without recurrence for approximately 2 years after gastrectomy. We suggest that the taxane drug was effective as second-line chemotherapy for the treatment of patients with peritoneal dissemination recurrence.

Herein, we report the case of 57-year-old woman who visited our hospital for abdominal distention, difficulty in walking, and edema of the legs in January 2012. She underwent gastroendoscopy, resulting in a diagnosis of advanced gastric cancer of the pyloric antrum. A diagnosis of unresectable advanced gastric cancer was made because computed tomography (CT) showed the presence of ascites (suspected to indicate peritoneal dissemination), para-aortic lymph node metastases, and brain metastases. Stenting was performed for pyloric stenosis and cell-free and concentrated ascites reinfusion therapy (CART) was administered to facilitate oral intake. We administered two courses of chemotherapy with weekly paclitaxel. However, CT showed the presence of ascites and growth of the main tumor in the first month after the initiation of chemotherapy. We performed CART, and treatment was changed to S-1/paclitaxe(l 5 courses). Ascites decreased markedly and activities of daily living improved. However, 11 months after the initiation of therapy, the patient died.

Objective: To develop a set of process-of-care quality indicators (QIs) that would cover a wide range of gastric cancer care modalities and to examine the current state of the quality of care provided by designated cancer care hospitals in Japan., Design: A retrospective medical record review., Setting: Eighteen designated cancer care hospitals throughout Japan., Participants: A total of 1685 patients diagnosed with gastric cancer in 2007., Main Outcome Measures: Provision of care to eligible patients as described in the 29 QIs, which were developed using an adaptation of the RAND/UCLA (University of California, Los Angeles) appropriateness method by a panel of nationally recognized experts in Japan., Results: Overall, the patients received 68.3% of the care processes recommended by the QIs. While 'deep venous thrombosis prophylaxis before major surgery' was performed for 99% of the cases, 'documentation before endoscopic resection' was completed for only 12% of the cases. The chemotherapy care was less likely to meet the QI standards (61%) than pre-therapeutic care (76%), surgical treatment (66%) and endoscopic resection (71%; overall difference: P < 0.001). A comparison based on the types of care showed that documentation and patient explanation were performed less frequently (60 and 53%, respectively) than were diagnostic and therapeutic processes as recommended in the QIs (85%; overall P < 0.001)., Conclusions: Although many required care processes were provided, some areas with room for improvement were revealed, especially with respect to chemotherapy, documentation and patient explanation. Continuous efforts to improve the quality and develop a system to monitor this progress would be beneficial in Japan.

Background and Aim: Serum screening systems are beneficial for gastric cancer mass surveys; however, the marker for diffuse type gastric cancer (DGC) is not defined. We attempted to define the high-risk group for DGC by using serum markers of anti-Helicobacter pylori antibody and pepsinogens (PG)., Methods: Forty-two patients in the early stage of DGC and 511 controls were enrolled. Fasting serum samples were collected, and anti-H. pylori antibody and PG were evaluated. The risk for DGC was calculated., Results: The prevalence of DGC was higher in H. pylori-positive patients (odds ratio [OR] = 4.3 in men, 9.6 in women). DGC prevalence was significantly higher in the PG1+ group in women (OR = 10.7); however, it was lower in the PG3+ group in both men and women. Patients with PG II ≥ 30 revealed a significantly higher risk for DGC. By combining factors, higher OR (OR = 12.5 in men, 42.7 in women) were obtained when we defined the risk group as H. pylori-positive, PG-negative, and having PG II ≥ 30., Conclusion: The risk group for DGC can be defined by evaluating ordinary serum gastritis markers., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: We recently modified our prediction scoring system "Estimation of Physiologic Ability and Surgical Stress" and have designated the current version mE-PASS. This scoring system has been designed to obtain predicted postoperative mortality rates before surgery and this study was performed to assess its usefulness in elective surgery for gastric carcinoma., Methods: We investigated seven variables for mE-PASS and evaluated the postoperative course in 3,449 patients who underwent elective surgery for gastric carcinoma in Japan between August 20, 1987 and April 9, 2007, in order to quantify the predicted in-hospital mortality rates (R). The calibration and discrimination power of R were assessed using the Hosmer-Lemeshow test and the area under the receiver operating characteristic curve (AUC), respectively. The ratios of observed-to-estimated mortality rates (OE ratios) were quantified as a measure of quality., Results: The overall postoperative morbidity and mortality rates were 19.0 and 2.0%, respectively. R demonstrated good power in calibration (χ(2) value, 12.5; df 8; P = 0.89) as well as discrimination (AUC, 95% confidence intervals: 0.80, 0.75-0.85). The OE ratios between hospitals ranged from 0.44 to 1.8. Overall, the OE ratios seemed to improve with time (OE ratio, 95% confidence intervals: 1.3, 0.73-2.4 for the early period between 1987 and 2000; 1.0, 0.59-1.7 for the middle period between 2001 and 2004; and 0.65, 0.36-1.2 for the late period between 2005 and 2007)., Conclusion: Based on these findings, mE-PASS might be useful for medical decision-making and for assessing the quality of care in elective surgery for gastric carcinoma.

Background: Both endoscopic and surgical approaches are employed in the treatment of early gastric cancer (EGC). The aim of this study was to establish appropriate treatment strategies for early gastric cancer., Methods: We retrospectively examined clinicopathological data of EGC patients who had undergone surgery., Results: A total of 327 patients (204 males and 123 females, mean age 63.2 years) were eligible for inclusion in the study. The median follow-up period was 31 months. Of 161 mucosal (pT1a) tumors, 87 were mainly undifferentiated and 110 had an undifferentiated component. Four patients with pT1a tumors had lymph node metastases; all these tumors were signet-ring cell carcinomas and were macroscopic type 0-IIc with ulceration, and only one of them had lymphatic invasion. Among patients with submucosal tumors, four of 43 patients with pT1b1 tumors and 37 of 123 patients with pT1b2 tumors had nodal metastases. Lymph node metastases were significantly higher in mixed undifferentiated type group than differentiated type group for both groups, pT1a-pT1b1 (p = 0.0251) and pT1b2 (p = 0.0430) subgroups. Only four of 45 patients with nodal metastases were diagnosed preoperatively by computed tomography (sensitivity 8.9%, specificity 96.2%). Nine patients with pT1b tumors had recurrence after surgery, and died. The sites of initial recurrence were liver, bone, peritoneum, distant nodes, and the surgical anastomosis., Conclusions: The incidence of nodal metastases was approximately 5% in undifferentiated type mucosal (pT1a) tumors, and higher in submucosal (pT1b) tumors. The sensitivity of preoperative diagnosis of nodal metastases in EGC using computed tomography was relatively low in this study. Therefore at present surgery with adequate lymphadenectomy should be performed as curative treatment for undifferentiated type EGC.

Background: Narrow-band imaging magnifying endoscopy is widely used in Japan, but still there is no set of consistent guidelines for gastric lesions., Aims: To introduce a new narrow-band imaging magnifying endoscopic classification and report the accuracy of diagnosis in comparison to underlying histopathology of gastric lesions., Methods: Two hundred and fifty-seven consecutive patients with early gastric cancer lesions were enrolled into this study. Narrow-band imaging magnifying images were classified into four categories based on abnormal microvascular patterns and irregularities in the superficial glandular structure: fine-network pattern, corkscrew pattern, intra-lobular loop pattern-1 and intra-lobular loop pattern-2. The narrow-band imaging magnifying endoscopic classification was compared with the histopathological findings., Results: Amongst the differentiated-type adenocarcinoma lesions, fine-network pattern, intra-lobular loop pattern-1, intra-lobular loop pattern-2 and corkscrew pattern were observed in 15.7%, 59.6%, 24.2% and 0.5%, respectively. Differentiated-type adenocarcinomas mainly exhibited fine-network pattern or intra-lobular loop pattern. In undifferentiated-type adenocarcinoma lesions, intra-lobular loop pattern-2 and corkscrew pattern were observed in 41.2% and 58.8%, respectively. Therefore, undifferentiated-type adenocarcinomas were all classified as intra-lobular loop pattern-2 and corkscrew pattern. The histopathological types were not equivalent with the narrow-band imaging magnifying classification categories (P<0.001)., Conclusions: The new narrow-band imaging magnifying classification that incorporates the intra-lobular loop pattern may be able to predict the histological subtype of most gastric carcinomas., (Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.

Background/aims: Tyrosine phosphorylation of the EPIYA motif in Helicobacter pylori CagA (CagA-P) plays an important role in toxic reaction. Diffuse-type gastric cancer (DGC) has a poor prognosis. We tried to clarify the expression level of CagA-P in DGC patients., Methods: We enrolled 42 early-stage DGC patients (DGC group; 20 males, 22 females, mean age 58.2 years) and 42 age- and gender-matched atrophic gastritis (AG) patients (AG group) as controls. We evaluated histological and serological gastritis and examined two markers; the serum titer of anti-CagA-P antibody and CagA-P expression in gastric mucosa., Results: In the DGC group, we found significantly higher corpus histological gastritis scores for activity, atrophy, and intestinal metaplasia. The titer of anti-CagA-P antibody and CagA-P expression in the corpus were significantly higher in the DGC group, especially in females (p < 0.05). Sixteen patients (38.1%) in the DGC group showed both positive markers, and the odds ratio for DGC occurrence was 4.00 (95% CI = 1.07-14.91), while that for females was 9.00 (95% CI = 1.29-62.97)., Conclusions: CagA-P plays a role in active corpus gastritis, which may link to DGC carcinogenesis. Clinical quantification of CagA-P-related markers may be useful for the evaluation of DGC risk, especially in females., (2010 S. Karger AG, Basel.)

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.

To elucidate the mechanism of resistance to 5-fluorouracil (5-FU) in human gastric cancer cells, we established a cell line MKN45/F2R, which acquired 5-FU resistance as a result of continuous exposure to increasing dosages of 5-FU over a year. The cell line showed 157-fold elevated 5-FU resistance compared to the MKN45 human gastric cancer parental cell line. Furthermore, the cells acquired crossresistance to paclitaxel and docetaxel. To identify the mechanism of 5-FU resistance, the expressions of 5-FU metabolic enzymes were examined. Although protein expression and activity of thymidylate synthase and dihydropyrimidine dehydrogenase did not change, orotate phosphoribosyl-transferase (OPRT) protein expression and activity significantly decreased in the 5-FU resistant MKN45/F2R cells. Interestingly, expression of proteins related to taxane resistance including P-glycoprotein, class III beta-tubulin and Bcl-2 increased in MKN45/F2R cells. OPRT-knockout MKN45 parent cells using small interfering RNA demonstrated 15.8-fold increased resistance to 5-FU compared to the control cells. However, resistance to paclitaxel and docetaxel was not observed. These results strongly indicate that decreased activity of OPRT plays an important role in the acquired resistance of gastric cancer cells towards 5-FU; however, it does not play a direct role in paclitaxel and docetaxel resistance. Further studies are now underway to identify genes related to crossresistance to these chemotherapeutic agents.

Background/aims: Diffuse-type gastric carcinoma is associated with a poor prognosis. However, the clinical behavior of diffuse-type gastric cancer is not fully understood. The aim of this study is to distinguish the behaviors of early diffuse-type gastric carcinomas by sub classifying tumors according to their histologic features., Methodology: A total of 114 cases of diffuse-type early gastric cancer were studied retrospectively. We analyzed and compared the resected cancer specimens according to the histologic components: as poorly differentiated adenocarcinoma component-present (poor+) versus poorly differentiated adenocarcinoma component-absent (poor-). Helicobacter pylori status was evaluated by Giemsa staining and IgG serology. We assessed the degree of cancer invasion and compared background status of gastritis in accordance with the updated Sydney System criteria and serologic markers., Results: In comparison to the poor+ cancers, the poor- cancers had a significantly larger portion of cells confined to the mucosa (p=0.002). Only 8 of the 114 cases were regarded as H. pylori-negative. Although we could not detect any serologic markers specific for gastritis with poor+ cancer, but the serum levels of gastrin was slightly higher in patients with poor+ cancers than in those with poor- cancers., Conclusions: The biologic behavior of poor+ gastric carcinoma is worse than that of poor- carcinoma. There is a close relation between H. pylori infection and carcinogenesis of poorly differentiated adenocarcinoma.

We evaluated the topography of histological gastritis, which may be risk factors for gastric cancer (GCa). A total of 530 Helicobacter pylori-positive patients underwent diagnostic upper-gastrointestinal endoscopy. Biopsy specimens were obtained from the gastric antrum and body to assess the grade of gastritis. Subjects were divided into four groups by the topography of active gastritis (antrum predominant gastritis, AP; pan-gastritis with or without corpus atrophy, Pan-1 and Pan-2; and corpus predominant gastritis, CP). A higher prevalence of GCa followed the order of Pan 2-->CP-->Pan 1-->AP. The age of patients decreased in the same order. When we set Pan 2 and CP as a high-risk group, the sensitivity and specificity for GCa detection were 77.3 and 54.7%, which were superior to the serum criteria using pepsinogens. These suggest that topography of histologic gastritis is an important marker to identify the high-risk group.

NBI magnifying imaging with crystal violet (CV-NBI magnifying imaging) makes recognition of micro-vascular pattern and grandular structure in the gastric mucosa better. NBI image emphasizes micro-vascular structure in mucosal surface. Magnification endoscopy with crystal violet staining delineates surface grandular structure better than without it. Crystal violet stained epithelium is clearly observed as cobalt green with NBI imaging. In the classification of CV-NBI magnification findings, 71% of differentiated type lesion was classified into ILL (intralobular loop pattern), and the rest (29%) was diagnosed as FNP (fine network pattern) which was originally advocated by Nakayoshi, et al. ILL is the new category of magnifying endoscopy. ILL corresponded mainly to differentiated-type adenocarcinoma, but it also includes undifferentiated-type adenocarcinoma. Corkscrew pattern is corresponding well to undifferentiated-type adnocarcinoma (Nakayoshi, et al). CV-NBI magnifying classification is considered to be related to tissue characterization in gastric cancer.

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.)

Melanoma-associated antigen (MAGE) genes are cancer-testis antigen genes that serve as immunotherapy targets in several human cancers. Previous studies have revealed that the forced expression of MAGE genes induces a paclitaxel-resistant phenotype. In the present study, we examined whether the expression of MAGE-A1 could predict the response of advanced and recurrent gastric cancers (GCs) to taxan (doce-taxel or paclitaxel)-based chemotherapy. The expression of MAGE-A1 was analyzed by immunostaining in 41 primary GC samples. DNA demethylation was assessed by methylation-specific polymerase chain reaction and the effect of the forced expression of MAGE-A1 on drug resistance to taxan drugs was monitored by MTT assay. The expression of MAGE-A1 in primary GC was observed in 4 (9.8%) of 41 cases. All 4 patients with MAGE-A1-positive GC showed progressive disease, whereas MAGE-A1 expression was not detected in any of the 23 patients showing partial response (P=0.0302). There was no association between MAGE-A1 gene demethylation and response to chemotherapy (P=0.7245). The forced MAGE-A1 expression in the TMK-1 GC cell line increased the sensitivity to paclitaxel and docetaxel. These results suggest that although MAGE-A1 does not participate directly in the drug-resistant phenotype, the expression of MAGE-A1 could be a marker for the prediction of resistance to taxan-based chemotherapies in patients with GC.

We report a rare case of kidney metastasis of resected early gastric cancer in a 67-year-old man. We performed distal gastrectomy with D2 lymph node dissection for early gastric cancer, which was histologically diagnosed as moderately differentiated adenocarcinoma (T1N0M0, stage IA). Preoperatively, his serum carcinoembryonic antigen (CEA) level was 9.5 ng/ml, and this dropped to 7.0 ng/ml postoperatively. However, 1 year 10 months after the operation, we performed partial kidney resection and the lesion was confirmed to be a metastasis of the gastric cancer. Unfortunately, 5 months later, multiple liver metastasis was found, accompanied by a further increase in the serum CEA level to 2 650.8 ng/ml. This case illustrates the poor prognosis associated with a high preoperative serum CEA level, even if early gastric cancer is resected curatively.

Orotate phosphoribosyltransferase (OPRT) is an enzyme that causes the activation of 5-fluorouracil (5-FU). Dihydropyrimidine dehydrogenase (DPD) is known to catabolize 5-FU, which is widely used in chemotherapeutic treatments for patients with a variety of malignant tumors including gastric and colorectal cancer. The expression and activities of these two enzymes therefore play important roles in the response of cancer patients to chemotherapy. However, little is known about the expression of these enzymes in gastric cancer. In the present study, we further elucidate the expression patterns of ORPT and DPD and their clinicopathological significance by immunohistochemical analysis in 221 and RT-PCR in 36 gastric cancer samples. The expression of OPRT by immunohistochemical analysis was detected in 117 (52.9%) cases, whereas DPD was detected in 66 (29.9%) cases. Moreover, the level of expression of OPRT was found to correlate with the depth of tumor invasion and a poorer prognosis. Although the mRNA and protein expression of OPRT and DPD levels did not correlate, an inverse correlation in the expression of OPRT and DPD was observed by RT-PCR. The survival benefit of post-operative adjuvant chemotherapy could not be confirmed in our present analysis. However, among the patients who had received such treatment with 5-FU or its derivatives, the prognosis in cases with low DPD levels was better than that in cases with high DPD expression by immunohistochemical analysis. These results indicate that the expression of OPRT and DPD are important predictors of both survival and the response to adjuvant chemotherapy in gastric cancer patients.

Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 microg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1,000 microg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-alpha, using ELISA. NE increased the cleavage of TGF-alpha from the cell surface 30-fold compared with the cells without treatment. Interestingly, sivelestat significantly reduced NE-induced EGFR phosphorylation and ERK1/2 activation and completely blocked the release of TGF-alpha from the TMK-1 cell surface. In a xenograft study, the addition of ventrotomy as a surgical stress promoted tumor growth. Sivelestat significantly suppressed the tumor growth induced by surgical stress. These results indicate that sivelestat suppresses the growth of gastric cancer cells by inhibiting the release of TGF-alpha stimulated by NE, which often occurs after surgical stresses.

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors., (Copyright 2006 Wiley-Liss, Inc.)

In the present article, we have summarized the phase I/II clinical trials on combination therapy of S-1 and docetaxel. With result of the phase I study, patients were treated with intravenous infusion of 40 mg/m2 docetaxel on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. Forty eight patients received a total of 272 treatment cycles. No complete responses (CRs) and 27 partial responses (PRs) were observed for an overall response rate (CR+PR) of 56.2% (95% CI, 38-66%). Eighteen patients (37.5%) had stable disease (SD), and 3 patients (6.2%) had progressive disease (PD) as best response. The tumor control rate (CR+PR+SD) was 93.8% (95% CI, 83-98%). The median overall survival was 14.3 months (95% CI: 10.7-20.3 months) and the median time to tumor progression was 7.3 months (95% CI: 4.2-10.7 months). The most common grade 3-4 hematologic toxicities were neutropenia 58.3%, leukopenia 41.7%, febrile neutropenia 8.3%, and anemia 8.3%. The most common grade 3 nonhematologic toxicities were anorexia 14.6%, stomatitis 8.3%, nausea 6.3%, diarrhea 4.2%, constipation 4.2%, and vomiting 2.1%. No grade 4 nonhematologic toxicities were reported, and all treatment-related toxicities were resolved. The mechanisms underlying these synergistic effects of S-1 and docetaxel were examined by expression and activity analyses of 5-FU metabolic enzymes. The expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were decreased and that of orotate phosphorybosyl transferase (OPRT) was increased in mRNA, protein level and activity assay after the treatment with docetaxel and 5-FU in the TMK-1 gastric cancer cell. These findings strongly indicate that the combination chemotherapy of docetaxel and S-1 is effective against gastric carcinomas and therefore is a good candidate as a standard chemotherapeutic strategy in treating these tumors.

Objective: Orotate phosphoribosyl-transferase (OPRT) is the initial enzyme of the 5-fluorouracil (5-FU) metabolic pathway, converting 5-FU into 5-fluorouridinemonophosphate, which is the most important mechanism of 5-FU activation. We therefore investigated whether overexpression of the OPRT gene enhances sensitivity to 5-FU., Methods: An expression vector of the OPRT gene (pTARGET-OPRT) was transfected into two gastric cancer cell lines, TMK-1 and MKN-45, with low baseline expression levels of OPRT. The sensitivity to and anti-tumor activity of 5-FU were then investigated in vitro and in vivo in these two transfected clones (TMK-OPRT and MKN-OPRT)., Results: Although cell growth was unaltered compared to parent cells, overexpression of the OPRT gene was confirmed by Western blotting in both the TMK-OPRT and MKN-OPRT cells. OPRT enzyme activity increased 38-fold in TMK-OPRT cells and 8.0 fold in MKN-OPRT cells compared to their parent cells. Interestingly, although the sensitivity to Adriamycin, cis-platinum, mitomycin C and paclitaxel was unaltered in the transfected clones, the sensitivity to 5-FU was increased 14.2- and 6.0-fold in TMK-OPRT and MKN-OPRT cells, respectively, compared to their parent cells. Moreover, enhanced sensitivity was also confirmed in the in vivo study., Conclusion: The results indicate that overexpression of the OPRT gene plays an important role in the antiproliferative effect of 5-FU and might therefore be a predictive factor of response to 5-FU in gastric cancer patients., (Copyright 2006 S. Karger AG, Basel.)

The patient was a 58-year-old man who suffered from non-resectable gastric cancer, staged intraoperatively for peritoneal dissemination and paraaorta lymph node metastasis at another hospital in December 2002. He was initially treated with TS-1 as an outpatient. However, he was readmitted on March 4, 2003 for hematuria, general fatigue, jaundice and dyspnea. He was diagnosed with gastric cancer duodenum invasion, obstructive jaundice and lymphangitis carcinomatosa, and began weekly TXL as second-line chemotherapy on March 26. TXL (70 mg/ m2) was infused once a week for 3 weeks followed by a 1-week interval as one cycle. One week after the first infusion therapy, the jaundice and dyspnea were greatly improved. CT scan showed the lymphangitis carcinomatosa had disappeared and paraaorta lymph node metastasis was reduced to 60% after one cycle of the treatment. The toxic events were leukopenia (grade 1) and alopecia (grade 1).

A 64-year-old man developed progressive dementia and altered consciousness with myoclonus over 2 months. Neurological examination revealed mild dysphagia and negative myoclonus of both hands. Electroencephalography (EEG) showed continuous periodic synchronous discharge (PSD) of 1 Hz, although his EEG abnormality was not similar to that usually observed in Creutzfeldt-Jakob disease (CJD). Magnetic resonance imaging (MRI) of the brain revealed only few lacunes. Laboratory data were also normal. Since his consciousness level fluctuated and the PSD were spiky, we came to a diagnosis of nonconvulsive status epilepticus (NCSE). After administering the valproic acid, his symptoms and EEG finding improved. Nine months after the onset, despite his continued valproic acid, the patient had recurrent NCSE and PSD of 1 Hz. Diffusion-weighted MRI showed a T2-hyperintense lesion in the right parietal lobe, where SPECT scans showed hyperperfusion. After adding zonisamide, he improved slowly. The follow-up MRI and SPECT showed a disappearance of the previous lesion. Now CT scans of the abdomen showed enlarged periaortic lymph node and endoscopic ultrasonography disclosed a submucosal tumor of the stomach. Biopsy of the periaortic lymph node by laparotomy revealed undifferentiated adenocarcinoma with its origin being unclear. Chemotherapy didn't work well for the tumor and the patient underwent a downhill course, although his mental and neurological manifestation were mostly unremarkable. Two years and four months after the onset, he died in emaciation. Autopsy confirmed small cell carcinoma originating in the stomach and metastases in the liver and lungs. Neuropathological examination revealed only mild scattered gliosis. This case was unique in the prolonged CJD-like manifestations, which turned out to be due to NCSE. Despite anti-neuronal antibodies were not detected, we suspect yet another paraneoplastic brain syndrome in this patient.

Summary: We previously reported acid-extracted natural antigenic peptide (F4.2 [YSWMDISCWI]) of a gastric signet ring cell carcinoma HST-2 cells, recognized by HLA-A*31012-restricted autologous cytotoxic T lymphocytes, TcHST-2 line. In this study, the full-length cDNA (1101 bp), termed c98, predicting a protein composed of 170 amino acids was obtained. Because TcHST-2 cells could lyse the HLA-A31 antigen (+) allogeneic tumor cells that were introduced with c98 gene, this gene was suggested to possess antigenicity. Beginning at N-terminal 61 amino acid, the N-terminal six amino acid sequence that is completely identical to F4.2 was present in c98; however, a sequence of four amino acids in C-terminal was not found. Nevertheless, this peptide, c98(61-70), seemed to be immunogenic, because cells pulsed with c98(61-70) peptide were lysed in a dose-dependent manner by TcHST-2 cells. The c98 gene was expressed ubiquitously in tumor cells as well as in normal tissues. However, some tumor cells, including HST-2 cells, expressed this antigen in a high content, and such cells were lysed by TcHST-2 cells in the context of HLA-A31 antigen. However, TcHST-2 cells did not lyse cells that expressed lower amounts of c98 than HST-2 cells. These data suggested that c98-gene product and/or c98(61-70) peptides could be used as a candidate for tumor vaccines in cancer immunotherapy.