G protein ß3 subunit polymorphism and long-term prognosis of functional dyspepsia.

BACKGROUND/AIMS: A link between G protein ß3 (GNB3) polymorphism and functional dyspepsia (FD) has been suggested. The aim of this study was to determine the role of GNB3 polymorphism in the long-term prognosis of FD in Koreans. METHODS: FD patients and normal healthy controls were recruited from patients who visited our center between December 2006 and June 2007. All of the subjects completed Rome III questionnaires before undergoing upper gastrointestinal endoscopy and colonoscopy. Genomic DNA was extracted for GNB3 genotyping. After 5 years, the subjects were reevaluated using the same questionnaires. RESULTS: GNB3 825T carrier status was significantly related to FD in Koreans (p=0.04). After 5 years, 61.0% of the initial FD patients and 12.2% of the initial normal subjects were diagnosed with FD (odds ratio [OR], 11.7; 95% confidence interval [CI], 4.3 to 31.1; p<0.001). Regardless of the GNB3 genotype (p=0.798), female sex was strongly correlated with FD after 5 years (OR, 3.3; 95% CI, 1.2 to 9.1; p=0.017). CONCLUSIONS: The T allele of GNB3 is linked to FD in Koreans but does not predict long-term prognosis. Female sex is related to a higher prevalence of FD after 5 years.

Combining the serum pepsinogen level and Helicobacter pylori antibody test for predicting the histology of gastric neoplasm.

OBJECTIVE: To determine whether the combination test of serum pepsinogen (PG) levels and Helicobacter pylori (H. pylori) antibody was effective for predicting the incidence and histology of gastric neoplasms. METHODS: This study included asymptomatic Korean adults who underwent esophagogastroduodenoscopy with blood tests for PG levels and H. pylori immunoglobulin G antibody test on the same day. Participants with extragastric malignancy, history of H. pylori eradication or gastric neoplasms, or recent antacid medication were excluded. Gastric atrophy was defined as a serum PG I/II ratio ≤3.0 and PG I ≤70 ng/mL. The participants were classified into four groups according to the presence (+) or absence (-) of gastric atrophy and H. pylori infection. RESULTS: Of the 3328 included participants, 17 were incidentally diagnosed as having either gastric adenoma or carcinoma. The incidence of gastric neoplasm was highest in the gastric atrophy (+)/H. pylori (-) group (4.17%; OR 25.8, P = 0.009), but the neoplasm exhibited the least advanced histology. The gastric atrophy (-)/H. pylori (-) group exhibited the lowest incidence of gastric neoplasm (0.17%) but the most advanced histology. CONCLUSION: A combination of serum PG levels and H. pylori antibody test is useful for detecting gastric neoplasms based on the slow gastric carcinogenesis pathway progressing from gastric adenoma to Lauren's intestinal-type gastric cancer, but not for those with advanced histology such as Lauren's diffuse-type gastric cancer.

Low prevalence of microsatellite instability in interval gastric cancers.

BACKGROUND AND AIM: Esophagogastroduodenoscopy (EGD) is recommended at 2-year intervals in countries with a high prevalence of gastric cancer. The aim of this study was to determine whether interval gastric cancers that develop within 2 years of a previous complete screening are associated with microsatellite instability (MSI). METHODS: Newly diagnosed gastric cancer patients who had undergone gastrectomy were included. Of these 459 patients, 177 were classified as interval gastric cancer since they were diagnosed within 2 years of a previous EGD. Noninterval gastric cancer patients were subclassified into 65 patients who underwent previous EGD between the past 2 and 10 years and 217 patients without EGD during the last 10 years. Analysis for MSI was conducted using two mononucleotide and three dinucleotide markers. RESULTS: MSI was found more frequently in noninterval gastric cancers than in interval gastric cancers (p = 0.009). Interval gastric cancers were associated with a higher prevalence of early gastric cancer (p = 0.006), smaller size (p < 0.001), and lower TNM stages (p = 0.006). On logistic regression analysis, noninterval gastric cancers were related to MSI (p = 0.010) and larger size (≥4 cm) (p = 0.009). Subjects with interval gastric cancer showed better survival than those with noninterval gastric cancer (p = 0.006). CONCLUSIONS: During a 2-year screening interval, noninterval gastric cancers tend to be larger, more advanced, and associated with MSI. Biannual EGD screening is effective for detecting small gastric cancers at an early stage, but is not useful in detecting gastric cancers with MSI.

Early Gastric Cancer-Like Advanced Gastric Cancer versus Advanced Gastric Cancer-Like Early Gastric Cancer.

BACKGROUND/AIMS: Improvements in the endoscopic evaluation and management of gastric cancer have made it possible to determine the depth of invasion during endoscopic examination. The aim of this study was to elucidate the differences between early gastric cancer (EGC) that resembles advanced gastric cancer (AGC) and AGC that resembles EGC. METHODS: We retrieved cases of EGC-like AGC and AGC-like EGC from consecutive gastric cancers that had been completely resected. The endoscopic diagnoses and clinicopathological findings were analyzed. RESULTS: AGC-like EGCs were located mainly in the distal part of the stomach, whereas EGC-like AGCs were located mainly in the proximal part of the stomach (p<0.001). Sixty percent of AGC-like EGCs were moderately differentiated adenocarcinomas, while 64% of EGC-like AGCs were poorly differentiated adenocarcinomas (p=0.015). According to Lauren's classification, 68% of AGC-like EGCs were intestinal type, whereas 71% of EGC-like AGCs were diffuse type (p=0.020). CONCLUSIONS: AGC-like EGCs predominate in the distal part of the stomach, while EGC-like AGCs predominate in the proximal part. When evaluating the depth of a gastric cancer, care should be taken not to underestimate measurements in proximal gastric cancers since they tend to be poorly-differentiated adenocarcinomas, in Lauren's diffuse type, and invade deeper than their endoscopic appearance might suggest.

Endoscopic diagnosis of open-type atrophic gastritis is related to the histological diagnosis of intestinal metaplasia and Cdx2 expression.

BACKGROUND AND OBJECTIVES: Long-term Helicobacter pylori infection results in atrophic gastritis and intestinal metaplasia (IM) with Cdx2 expression. We have tried to determine if there was a link between endoscopic and histological diagnosis of IM based on the status of aberrant Cdx2 expression. METHODS: One hundred and one subjects agreed to upper gastrointestinal endoscopic examination, with biopsy sampling for histology, Giemsa, and Cdx2 immunohistochemical staining before and after the treatment. On endoscopic examination, atrophic gastritis was defined as discoloration with blood vessel transparency, and was classified as either closed or open. Metaplastic gastritis was defined by the presence of whitish patches, whitish plaques, and/or homogeneous whitish discoloration. Histologic analysis was performed to determine H. pylori density, intensity of acute polymorphonuclear cell infiltrates and chronic mononuclear infiltrates, gastric atrophy, and IM as demonstrated using immunohistochemistry for cdx2. RESULTS: Cdx2 protein expression (P=0.018) and the prevalence of histologically detected IM (P=0.011) were higher in cases of endoscopically diagnosed open-type atrophic gastritis and metaplastic gastritis than in closed-type atrophic gastritis and nonatrophic/nonmetaplastic cases. The degree of activity (P=0.006) and inflammation (P=0.007) improved significantly after four weeks of successful H. pylori eradication treatment, whereas the degree of atrophy, metaplasia, and Cdx2 expression did not. CONCLUSIONS: Unlike endoscopic diagnosis of closed-type atrophic gastritis, that of open-type atrophic gastritis is highly correlated with the histological diagnosis of IM and Cdx2 expression. Endoscopically diagnosed open-type atrophic gastritis and endoscopically diagnosed metaplastic gastritis have similar histological features, which suggests that a high percentage of IM cases are diagnosed as open-type atrophic gastritis by endoscopic examination.

The origin of non-H. pylori-related positive Giemsa staining in human gastric biopsy specimens: A prospective study.

BACKGROUND: Upper gastrointestinal endoscopically biopsied specimens are usually sent for the diagnosis of Helicobacter pylori infection. The study aimed to determine the relationship between the origin of positive Giemsa staining and the grade of gastritis based on the updated Sydney system. METHODS: Gastric biopsy specimens taken at the lesser curvature and greater curvature sides of the corpus and greater curvature side of the antrum were stained with H&E, Giemsa, anti-East Asian-specific antibody and anti-H. pylori antibody stains. Pyrosequencing analysis was performed in cases that showed discrepancy between the Giemsa and anti-H. pylori antibody staining. RESULTS: Seventy-two out of 150 cases (48%) stained positive for anti-H. pylori antibody, of which 68 (94.4%) stained positive for anti-East Asian-specific antibody stain. Twelve of the 20 cases with discrepant results for Giemsa and anti-H. pylori antibody stains exhibited Campylobacter hyointestinalis infection. The grades of neutrophil activity (p<0.001) and chronic inflammation (p<0.001) were lower for Campylobacter infection than for East Asian CagA H. pylori-related infection. CONCLUSION: C. hyointestinalis is the most common cause of non-H. pylori-related Giemsa positive infection, and is associated with lower grades of neutrophil activity and chronic inflammation than East Asian CagA H. pylori-related infection.

Depressive mood and quality of life in functional gastrointestinal disorders: differences between functional dyspepsia, irritable bowel syndrome and overlap syndrome.

OBJECTIVE: To investigate the differences in depressive mood and quality of life in patients with between functional dyspepsia (FD), irritable bowel syndrome (IBS), and FD-IBS overlap as diagnosed based on Rome III criteria. METHODS: The subjects completed a questionnaire based on Rome III criteria, the Beck Depressive Inventory (BDI) including Cognitive Depression Index (CDI) for depressive mood evaluation and the 36-item Short Form general health survey (SF-36) for quality of life assessment. Upper gastrointestinal endoscopy and colonoscopy were performed to exclude organic disease. RESULTS: Of 279 subjects, 70 and 124 subjects were diagnosed as FD and IBS, respectively. FD-IBS overlap patients (n=42) and FD alone patients (n=28) showed higher BDI scores than normal subjects (n=127) (P<.001 and P=.02, respectively), whereas that of IBS alone patients (n=82) did not show difference (P=.17). All the SF-36 subscores of the FD-IBS overlap patients were significantly lower than normal subjects (P<.05). CONCLUSIONS: Depressive mood was significantly related to FD and FD-IBS overlap but not to IBS based on Rome III criteria. FD-IBS overlap patients have worse quality of life than FD-alone and IBS-alone patients.

[Cytomegalovirus infection-related spontaneous intestinal perforation and aorto-enteric fistula after abdominal aortic aneurysmal repair].

Gastrointestinal complications (GI) after thoracoabdominal aortic repair can be classified as biliary disease, heptic dysfunction, pancreatitis, GI bleeding, peptic ulcer disease, bowel ischemia, paralytic ileus, and aortoenteric fistula. Theses complications are associated with high post operative morbidity and mortality. Most of the aortoenteric fistulae after thoracoabdominal aortic surgery are found at the duodenum, near the surgical site. These rare complications are caused by an indirect communication with abdominal aorta that originated from an aneursymal formation ruptured into the duodenum. Such aorto-duodenal fistula formation is considered as a result of inflammatory change from secondary infection near the surgical instruments. Herein, we report two cases of massive upper GI bleeding from aorto-duodenal fistulae and spontaneous lower GI perforation related to cytomegalovirus infection after abdominal aortic aneurysmal repair operations.

Does a small biopsied gastric specimen limit the usage of two directional transnasal esophagogastroduodenoscopy?

BACKGROUND AND AIMS: It is difficult to approach certain gastric regions due to the limited bending ability of transnasal esophagogastroduodenoscopy (TN-EGD). We analyzed the TN-EGD biopsied specimens according to where they were obtained inside the stomach. METHODS: Two hundred and eighty-nine gastric biopsy specimens were obtained during diagnostic TN-EGD. The gastric biopsied specimens were quantified according to their diameter and depth in micrometers, and depth in layers (superficial mucosa, deep mucosa, muscularis mucosa and submucosa). The quality was measured by the degrees of anatomical orientation (good, intermediate and poor), presence of crush artifact (none to minimal, mild and moderate) and overall diagnostic adequacy (adequate, suboptimal and inadequate). RESULTS: Poor orientation, presence of crush and overall diagnostic inadequacy were present in 33 (11.4%), 26 (9.0%) and 37 (12.8%) of the 289 specimens, respectively. Deep mucosa was present in 211 specimens (73.0%), while muscularis mucosa was present in only 75 specimens (26.0%). Specimens taken from the posterior aspect of the cardia exhibited the shallowest depth (P = 0.011), poorest orientation (P < 0.001) and poorest diagnostic adequacy (P < 0.001). Fluoroscopic findings demonstrated that the posterior aspect of the cardia was difficult to approach closely and perpendicularly because of the anatomical configuration of the stomach in nature. CONCLUSION: TN-EGD biopsied specimens obtained from the posterior aspect of the cardia exhibit limitations in both quality and quantity. When performing a biopsy using two directional TN-EGD, special attention should be paid to gastric lesions located on the posterior aspect of the cardia.

Cecal polypoid arteriovenous malformations removed by endoscopic biopsy.

Colonic arteriovenous malformation (AVM) is one of the causes of lower gastrointestinal bleeding. Unlike small vascular ectasia or angiodysplasia, colonic AVM tends to be solitary, large in size, and identified endoscopically as flat or elevated bright red lesion. Herein, we report a case of non-solitary and small cecal AVMs which were removed by endoscopic biopsy. A 66-yr-old woman was referred for routine gastrointestinal cancer screening. She was suffering from diabetes, hypertension, end-stage renal disease, and anemia of chronic disease. On colonoscopic finding, three semi-pedunculated polyps, less than 5 mm in size, were noticed near to the appendiceal orifice. Since the lesions revealed normal-looking epithelium with converging folds on the cecal base, lesions were diagnosed as inflammatory polyps on gross finding. Three biopsies were taken from each lesion. Bleeding from the biopsied site ceased spontaneously. Histopathologic evaluation demonstrated intramucosal hemorrhage and dilated submucosal vessels which were consistent with polypoid colonic AVMs.

Importance of the surrounding colonic mucosa in distinguishing between hyperplastic and adenomatous polyps during acetic acid chromoendoscopy.

AIM: To examine the characteristics of colonic polyps, where it is difficult to distinguish adenomatous polyps from hyperplastic polyps, with the aid of acetic acid chromoendoscopy. METHODS: Acetic acid spray was applied to colonic polyps smaller than 10 mm before complete excision. Endoscopic images were taken before and 15-30 s after the acetic acid spray. Both pre- and post-sprayed images were shown to 16 examiners, who were asked to interpret the lesions as either hyperplastic or adenomatous polyps. Regression analysis was performed to determine which factors were most likely related to diagnostic accuracy. RESULTS: In 50 cases tested by the 16 examiners, the overall accuracy was 62.4% (499/800). Regression analysis demonstrated that surrounding colonic mucosa was the only factor that was significantly related to accuracy in discriminating adenomatous from hyperplastic polyps (P < 0.001). Accuracy was higher for polyps with linear surrounding colonic mucosa than for those with nodular surrounding colonic mucosa (P < 0.001), but was not related to the shape, location, or size of the polyp. CONCLUSION: The accuracy of predicting histology is significantly related to the pattern of colonic mucosa surrounding the polyp. Making a histological diagnosis of colon polyps merely by acetic acid spray is helpful for colon polyps with linear, regularly patterned surrounding colonic mucosa, and less so for those with nodular, irregularly patterned surrounding colonic mucosa.

Presence of iron in colorectal adenomas and adenocarcinomas.

BACKGROUND/AIMS: Iron overload reportedly increases the risk of colorectal neoplasms, but the distribution of tissue iron in a colorectal neoplasm remains controversial. In this study, we attempted to determine the significance of tissue iron in colorectal adenomas and adenocarcinomas. METHODS: This study investigated 138 colorectal neoplasms (54 adenocarcinomas, 25 adenomas with high-grade dysplasia, and 59 adenomas with low-grade dysplasia) that were removed by surgical or endoscopic resection in Konkuk University Hospital between August 2005 and August 2006. Adjacent normal colon tissues and colorectal neoplasms were stained with Perls' Prussian blue to reveal ferric compounds. RESULTS: Positive Perls' staining was evident in 35.2% (19/54) of the adenocarcinomas and 22.6% (19/84) of the adenomas, and in only 2.2% (3/138) of the samples of adjacent normal colon tissue (p<0.001). Iron appears to reside exclusively in the stroma and outside the gland, rather than in the epithelial cells. Iron expression was strong in larger (p=0.004) and pedunculated (p<0.001) adenomas, and in all types of adenocarcinomas regardless of their size, shape, and location. CONCLUSIONS: The frequent presence of iron in the stroma of large adenomas, pedunculated adenomas, and adenocarcinomas indicates that iron deposition is a secondary phenomenon to intralesional hemorrhage rather than a consequence of epithelial-cell carcinogenesis.

Link between a preference for women colonoscopists and social status in Korean women.

BACKGROUND: Although the sex preference in women patients for their colonoscopist has been reported, the characteristics of these women have not been evaluated yet. OBJECTIVE: The aim of this study was to investigate the characteristics of women who have a specific preference for a man or a woman colonoscopist. DESIGN: Single-center prospective study. SETTING: Academic medical center, from October to November 2005. SUBJECTS: A total of 465 women who visited the Digestive Disease Center. METHODS: Subjects were asked to complete a self-administered questionnaire on the sex preference of the colonoscopist, employment status, and clinical symptoms. MAIN OUTCOME MEASUREMENTS: Factors related with sex preference for the colonoscopist. RESULTS: Only 358 subjects (77.0%) completed the questionnaire. Of these, 195 women (54.5%) had no preference, whereas 115 women (32.1%) preferred a woman colonoscopist and 48 women (13.4%) preferred a man colonoscopist. Subjects who preferred women colonoscopists were generally younger (P< .0001), more educated (P< .0001), single (P< .0001), and employed (P< .0001) than the other population. Neither the symptoms of functional dyspepsia nor irritable bowel syndrome were related with the sex preference of the colonoscopist. LIMITATIONS: A self-administered questionnaire study did not investigate specific physician interpersonal or communication styles. CONCLUSIONS: More than half of the women had no sex preference for their colonoscopist, and the sex preference for a specific sex was related to employment status, education level, age, and marital status. Such a sex-based preference in employed, highly educated young women predicts an increasing demand for women colonoscopists in the near future, particularly given the increasing social participation of women in these times of rapid industrialization.

Decreasing prevalence of Helicobacter pylori infection: a 9-year observational study.

BACKGROUND/AIMS: Detailed information is still lacking on the trends of changes in Helicobacter pylori infection. The aim of the study was to investigate how the prevalence of H. pylori infection varied with gender and age during the past 9 years. METHODOLOGY: A total of 8646 subjects who submitted to a rapid urease test were included. The prevalence of H. pylori infection according to age and gender was analyzed. RESULTS: H. pylori infection was noted in 3747 cases (43.3%) of all cases. The infection rate was 50.0% in 1997, but declined gradually down to 40.6% in 2005 (P < 0.001). The rate of H. pylori infection reached a peak at the age of 30-39 years and decreased thereafter in men while it reached a peak at the age of 40-49 years in women (P < 0.001). The prevalence was higher in men than in women before the age 50 years (P < 0.001) while there was no difference after the age 50 years (P = 0.28) in any of the years studied. CONCLUSIONS: H. pylori infection has gradually decreased over the past decade, and there is a gender-related difference in the prevalence of H. pylori infection manifesting as a lower rate of infection in young women and an earlier plateau of infection rate in men.

Sonic hedgehog expression in gastric cancer and gastric adenoma.

Hedgehog protein is essential to gastrointestinal tract development, and disruption of the hedgehog signaling pathway is associated with gastrointestinal tumorigenesis. Here, we analyzed the degree of hedgehog expression in gastric cancer and precancerous tissue. From August 2005 to May 2006, 52 gastric cancers and 16 gastric adenomas were obtained from surgically or endoscopically resected specimens. Immunohistochemical staining using sonic hedgehog (Shh) antibody was performed in cancerous and noncancerous tissue portions. Hedgehog expression was assessed based on the summed scores of the intensity and proportion of Shh staining. According to Lauren's classification, Shh expression was stronger in the intestinal type than in the diffuse type (p<0.001). Although Shh expression was not related to the location, size, metastatic status, or mucin phenotype of the gastric cancer, the expression was stronger in the tubular type of gastric cancer than in the mucinous and signet-ring cell types (p=0.001). Shh expression was stronger in gastric adenoma than in the diffuse-type gastric cancer (p<0.001), but revealed no difference with that of the intestinal-type gastric cancer (p=0.30). Shh expression was strongest in all types of intestinal metaplasia of noncancerous tissues. Shh expression is related to the intestinal type of gastric cancer. The stronger Shh expression in intestinal metaplasia and gastric adenoma indicates that hedgehog protein is involved at an early phase of gastric carcinogenesis.

Plasma adiponectin and insulin resistance in Korean type 2 diabetes mellitus.

Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-alpha, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75 gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r= -0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r= 0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.

Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines.

The various treatments for advanced gastric cancer have limitations and induce only marginal survival benefit. HER-2/neu protein is overexpressed in several types of human cancers and its amplification is associated with poor prognosis. Recombinant humanized anti-HER-2/neu antibody (trastuzumab) not only inhibits the proliferation of HER-2/neu overexpressing tumor cells but also augments the cytotoxicity of concomitant chemotherapeutic agents in metastatic breast cancer. In this study, we evaluated the growth inhibitory effects of trastuzumab in gastric cancer cells. HER-2/neu protein was evaluated by immunohistochemical analysis in seven gastric cancer cell lines. MTT assay was performed to evaluate the growth inhibitory effects of trastuzumab and three chemotherapeutic agents, doxorubicin, cisplatin and paclitaxel, both alone and in combinations. The changes of cell cycle after trastuzumab treatment were analyzed by flow cytometry. Four of the cell lines, YCC-2 with strong positivity of HER-2/neu expression, NCI-N87 with moderate positivity, YCC-3 with weak positivity, and SK-BR-3 as a positive control, were selected. After in vitro MTT assay for 1-day and 5 consecutive days' treatment of trastuzumab at various concentrations, growth inhibition was not observed in any cancer cell lines. However, there was variable dose-dependent sensitivity to doxorubicin, cisplatin and paclitaxel. YCC-2 and SK-BR-3 cancer cells were more sensitive to three chemotherapeutic drugs, constantly (P<0.05). The combination of 5 consecutive days' treatment of trastuzumab with 1-day doxorubicin treatment showed significant growth inhibition only in YCC-2 and NCI-N87 gastric cancer cells. After 1-day trastuzumab treatment, the S-phase fraction was decreased by 52 and 70% in YCC-2 and SK-BR-3, respectively. In conclusion, the expressions of HER-2/neu protein in gastric cancer cells are variable, and concomitant treatments of trastuzumab with doxorubicin increase cytotoxicity. This suggests that trastuzumab-based biologic therapy with chemotherapeutic agents can be applied in gastric cancer treatment.