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T2065 Overexpression of the Receptor Tyrosine Kinase Epha4 Plays An Important Role in the Progression of Human Gastric Cancers
T2063
Male Predominance of Adenocarcinoma of Upper Gastrointestinal Tract Is Related to Intestinal Histological Subtype Not Tumour Location Mohammad H. Derakhshan, Sarah Liptrot, James Paul, Ian L. Brown, Kenneth E. McColl
Celecoxib Prevents Gastric Cancer in Helicobacter pylori-Infected Mice; Comparison with Nimesulide Ki-Baik Hahm, Dae Yong Kim, Ki-Taek Nam, Hyun W. Baik
Background: Upper gastrointestinal adenocarcinomas show an unexplained male predominance which is more apparent in the oesophagus than stomach. We have conducted a population-based study to determine whether the gender phenomenon is primarily related to the anatomical site or the histological subtype of the tumour. Method: The study was based upon 3270 gastric and oesophageal cancers recorded in West of Scotland cancer Registry, 1998-2002. 812 of these cases were randomly selected for detailed analysis. Their records were reviewed for histology and anatomical site of tumour using ICD-10 and ICD O-2. The Lauren histological subtype of adenocarcinoma was determined by reviewing 1204 original reports and 3241 biopsy and surgical slides. Results: 405 (51.5%) cancers originated from the non-cardia region of the stomach, 173 (22.0%) from the gastric cardia and 209 (26.6%) from the oesophagus. Regardless of anatomical subsite, the upper GI cancers were more common in males (502, 63.8%) than females (285, 36.2%). Regardless of anatomical site, the crude incidence rate of intestinal type upper GI adenocarcinoma was higher in males (23.86/ 105/y) versus females (9.00/ 105/y), giving M/F of 2.65. In contrast, the crude incidence rate of diffuse-type adenocarcinoma was similar in males and females (5.58 vs 5.20 /105/y) yielding M/F of 1.07. Male predominance was greatest in the oesophagus with M/F of 3.50, less in the cardia (M/F= 2.00) and least in the non-cardia cancer (M/F= 1.65). The relationship between tumour location and male predominance lost its significance in the multivariate analysis when histological subtype was added [OR (95%) = 1.37 (0.88 2.12)]. Multivariate analyses including histological subtype, tumour location and age indicated that the male predominance was related to the histological type rather than anatomical location. Intestinal type adenocarcinoma showed similar male predominance irrespective of its anatomical location (OR, 95% CI: 2.6, 1.78 - 3.9). Conclusion: Male predominance in upper GI adenocarcinomas is not a function of tumour location but rather related to histological subtype. The mechanism of the strong gender association with intestinal subtype requires elucidation.
Background: H. pylori infection can lead to gastric carcinogenesis through the overexpression of COX-2 and we had published that nimesulide protect against H. pylori-induced gastric tumorigenesis (Nam KT et al, Clin Cancer Res 10:8105, 2004). Aim: We investigated whether celecoxib, NSAID showing higher degree of selective COX-2 inhibition, might protect against this form of cancer more efficiently than nimesulide. Simultaneously, apoptosis inducing capability was compared between these two drugs. Methods: C57BL/6 mice were treated with the N-methyl-N-nitrosourea (MNU) and/or H. pylori. Celecoxib (500 ppm or 1000 ppm) or nimesulide (200 ppm) was mixed with feed pellets and administered for the duration of the experiment, respectively. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. Molecular mechanisms of cancer prevention were compared between celecoxib and nimesulide. In Vitro experiments with the human gastric cancer cell line AGS were also repeated to document the underlying mechanism of cancer prevention. Global changes in transcriptomes after celecoxib treatment were assayed with AffyMatrix Chip assay. Results: Gastric tumors developed in 72.7% of mice that were given both MNU and H. pylori, whereas less than only 11.1% developed gastric tumors when given either MNU or H. pylori alone, suggesting that H. pylori promoted carcinogeninduced gastric tumorigenesis. In mice treated with both MNU and H. pylori, celecoxib administration substantially reduced H. pylori-associated gastric tumorigenesis (20.0% in mice treated with 500 ppm of celecoxib and 10.0% in mice treated with 1,000 ppm of celecoxib) and nimesulide yielded tumor inhibition in 27.8%. In Vitro studies demonstrated that higher execution of apoptosis was noted in celecoxib treatment. Conclusion: COX-2 inhibitor prevented H. pylori-associated gastric carcinogenesis, higher selectivity, higher the effects of cancer prevention. T2064 Clinicopathological Characteristics and Prognosis of Young Age Gastric Cancer : Analysis of 3,362 Consecutive Gastric Cancer Patients Jun chul Park, Yong Chan Lee, Jie-Hyun Kim, Kyung Ho Song, Jae Jun Park, Yu Jin Kim, Sang Kil Lee, Woo jin Hyung, Sung Hoon Noh, Choong-Bai Kim, Jae Bock Chung Background/Aims:Several studies have reported controversial results about clinicopathological features and prognosis in young age gastric cancer patients, probably due to variable definition and inhomogeneiety of patient population among studies. The aim of this study was to analyze the clinicopathological features and prognosis according to age in all stage gastric cancer. Methods: Between Jan.2000 and Dec.2005, a total 3,362 patients were diagnosed as gastric cancer in Severance hospital, Korea. We divided patients into three groups by age standard deviation (reference age points were 45 and 70); group 1 (≤45 years; 654 pts), group 2 (46 to 70 years; 2,317 pts) and group 3 (≥71 years; 391 pts). The patients were also classified according to treatment modalities; early gastric cancer (EGC) group treated by operation (1,400 pts) or endoscopic mucosal resection(152 pts), resectable advanced gastric cancer (AGC) group (1,619 pts) and unresectable AGC group (191 pts). Results: Female, upper third location and Linitis plastica were more frequent than other groups in group1(≤45 years). Group 1 patients are significantly associated with high proportion of poorly differentiated and signet ring cell carcinoma. CA19-9 level was much higher in young age gastric cancer patients (p>0.05). In EGC-group, the depressed endoscopic gross type is more frequent in group 1. In resectable AGC group, Bormann type IV and Lauren diffuse type were more common in group 1. The curative resection rate was significantly lower in young aged gastric cancer patients compared to others. Peritoneal metastasis was the most common case for unresectable in young age gastric cancer patients, and there was a higher proportion of unrespectable case in group1 compared to others (age>45yrs, p<0.05). In curatively resected patients, the 5 year survival rate was significantly better in group 1 than older group (p=0.0027). TNM stage, CA19-9 level and curative resection were significant prognostic factors by multivariate analysis. Conclusions: The clinicopathological features of young age gastric cancer patients(≤45 years) showed significantly higher preponderance for upper location, Linitis plastica gross type, diffuse histopathologic type and unresectability for curative resection compared to other aged gastric cancer patients. The prognostic factors were TNM stage, CA19-9 level and curative resection.
T2062 Comparison of Healing Rate of Artificial Ulcer After Endoscopic Submucosal Dissection in Relation to the Dose of Proton Pump Inhibitor. a Prospective Randomized Controlled Trial Seiji Kawano, Hiroyuki Okada, Keisuke Hori, Daisuke Tanioka, Masahide Kita, Takao Tsuzuki, Masafumi Inoue, Satoru Yagi, Ryuta Takenaka, Masayuki Uemura, Yoshiro Kawahara, Kazuhide Yamamoto Background: Proton pump inhibitor (PPI) and histamine2-receptor antagonist (H2RA) have similar effects on preventing bleeding and ulcer healing after conventional endoscopic mucosal resection. Two recent studies demonstrated the advantage of PPI as compared with H2RA for treatment of large artificial ulcers after endoscopic submucosal dissection (ESD), but the optimal duration and dose of PPI have not been clarified yet. Objective: To elucidate the optimal dose and duration of PPI for treatment of artificial ulcers after ESD by comparing the administration of 30mg with 15mg in terms of ulcer healing, prevention of bleeding, and QOL. Methods: A total of 84 patients who underwent ESD for gastric mucosal neoplasm between Jun 2006 and August 2007 at the University of Okayama Hospital were enrolled. All patients were given lansoprazole (30 mg) daily for 8 days, starting from the ESD day, and if there was no exposed vessel left in the ulcer bed after 8-day follow-up endoscopy, they were randomly assigned to either 30 mg group or 15 mg group and therapy was continued for 7 weeks. The study protocol was approved by the institutional review board and written consent was obtained from each patient prior to inclusion in the study. Results: Regarding the baseline characteristics of the patients, there were no significant differences in the factors between the two groups. Bleeding occurred in one patient of the 30mg group on day 11 after ESD and in one patient of the 15mg group on day 10. Finally, 39 of 42 patients in the 30mg group and 39 of 42 patients in the 15mg group successfully completed the protocol. The ulcer-healing rates after 4 weeks was 15% in the 30mg group and 8% in the 15mg group (not significant); 85% and 87% after 8 weeks, respectively (not significant). The stage of ulcers, the mean dimensions of ulcers on follow-up endoscopy (after 4 and 8 weeks), and the ulcer reduction ratio were not significantly different between the two groups. Moreover, the scores of the five symptom categories obtained from GSRS, and pH of the gastric juice were not significantly different between the two groups at the time of ESD and during follow-up. The cost of PPI in the 30mg group and 15mg group after completing 8week administration was 11698.4 yens and 7326.5 yens, respectively. Conclusions: The reduced dose of PPI after one week of ESD was equally effective in the treatment and superior in the cost reduction to continuing ordinary dose administration.
T2065 Overexpression of the Receptor Tyrosine Kinase Epha4 Plays An Important Role in the Progression of Human Gastric Cancers Nobuki Miyamoto, Hiroyuki Yamamoto, Chie Miyamoto, Tadateru Maehata, Katsuhiko Nosho, Hiroaki Taniguchi, Kentaro Yamashita, Yasushi Adachi, Yoshiaki Arimura, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura Altered expression of the genes for Eph receptors and ephrin ligands has been recognized to play an important role in human cancer. Compared with other Eph receptor family members, EphA4 is distinguished by its ability to bind to both type A ephrins and most type B ephrins, and the interaction with fibroblast growth factor receptor (FGFR) signal pathway. Using reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assay, we analyzed the expression and role of EphA4 in gastric cancer, in relation to clinicopathological characteristics and the expression of FGFR1 and ephrin ligands. Overexpression of EphA4 mRNA expression was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Overexpression of EphA4 analyzed by immunohistochemistry was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression at protein level was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of
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EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. Our results suggest that overexpression of EphA4 plays an important role in gastric cancer. EphA4 could be an attractive target for molecular therapy by a therapeutic antibody and/or by small molecules targeting its kinase activities.
were detected during the observation period. The incidence for cardia type I-III adenocarcinoma tended to decrease from 1982 to 2006 from 5.07 to 4.16/100 000. The incidence rates for noncardia gastric adenocarcinoma strongly (P < 0.001) decreased from 1982 to 2006 from 6.61 to 2.83/100 000 (Figure). Conclusions: As in other Western countries, the incidence of noncardia gastric cancer strongly decreased within the last 25 years in Central Switzerland. In contrast to other Western countries, cardia type I-III adenocarcinoma did not increase in the last 25 years.
T2066 Endoscopic Mucosal Resection for Undifferentiated Intramucosal Gastric Cancer: Different Indications Between Signet Ring Cell Carcinoma and Poorly Differentiated Adenocarcinoma Hoi Jin Kim, Jae J Kim, Eun Ran Kim, Dong Hyun Sinn, Young-Ho Kim, Jun Haeng Lee, Dong Kyung Chang, Poong-lyul Rhee, Jong Chul Rhee Background) Small undifferentiated gastric cancer limited to the mucosal layer has been proposed as an extended indication for endoscopic mucosal resection (EMR). However, there is limited data about the difference of lymph node metastasis (LNM) in different histological subtypes between intramucosal signet ring cell carcinoma (SRC) and poorly differentiated adenocarcinoma (PDC). The aim of this study was to identify risk factors of the LNM and to suggest appropriate indications for EMR for undifferentiated intramucosal cancers. Method) We reviewed medical records of 2128 patients with intramucosal gastric cancers treated with gastrectomy and regional lymph node dissection at the Samsung Medical Center from 1994 to 2005. Clinicopathological factors related to LNM for intramucosal SRC and PDC were evaluated in comparison to differentiated intramucosal gastric cancers (DAC). Results) Out of 2128 intramucosal gastric cancers, 9 of 1243 (0.7%) cases of DAC, 20 of 594 (3.4%) cases of SRC and 18 of 291 (6.2%) cases of PDC had LNM. LNM increased significantly in SRC (OR=4.18 95% CI: 1.64-10.6) and PDC (OR=12.4 95% CI: 4.83-32.1) compared to DAC as determined by multivariate analysis. Tumor size (OR =3.36, 95% CI: 1.07-10.5) and lymphovascular invasion (OR=13.6 95% CI: 4.65-40.1) were other significant risk factors associated with LNM. None of 175 SRCs less than 20 mm in size (95% CI: 02.09) and none of 21 PDCs less than 10 mm in size (95% CI: 0-16.11) without lymphovascular invasion had LNM. Conclusion) Histological subtype, tumor size and lymphovascular invasion are risk factors of LNM in undifferentiated intramucosal gastric cancers. Intramucosal SRC has an intermediate LNM risk between the differentiated type and PDC. SRCs less than 20 mm and PDCs less than 10 mm in size without lymphovascular invasion are possible candidates for EMR.
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Role of Ciap2 in Gastric Cancer Zesong Li, Liang Qiao, Yun Dai, Bing Zou, Juan Ma, HuiYao Lan, Benjamin C.Y. Wong BACKGROUND AND OBJECTIVES cIAP2 is a member of the IAP family and is overexpressed in most cancer tissues. Expression of cIAP2 can be induced by gastric carcinogen H. pylori. Therefore enhanced expression of cIAP2 may be related to gastric carcinogenesis. We aimed to investigate the feasibility of targeting cIAP2 in gastric cancer therapy. METHODS AND MATERIALS 12 pairs of human gastric cancer tissues and matched non-cancerous tissues were used to extract total RNA by Trizol method. Whole tissue lysates were prepared by using RIPA lysis buffer. Expressions of cIAP2 were detected by RT-PCR and Western blot analysis. Gastric cancer BGC-7901 cells were transfected with specific siRNA against cIAP2 for 48 h, and the effect of siRNA-cIAP2 on cell proliferation was detected by standard WST-1 assay. Apoptosis was detected by TUNEL staining and quantitated by flow cytometry. RESULTS Over 70% of gastric cancer tissues expressed higher levels of cIAP2 compared to non-cancerous gastric tissues at both mRNA and protein levels. Over-expression of cIAP2 was also confirmed by immunohistochemical staining which cIAP2 is strongly expressed in most gastric cancer tissues, whereas in normal gastric tissues, cIAP2 is expressed in gastric epithelium with weak to medium intensity. Knocking down of cIAP2 in BGC-7901 cells by siRNA-cIAP2 resulted in a 30% decrease in cell proliferation and a 20% increase in apoptosis as revealed by flow cytometry. CONCLUSION cIAP2 may be a potential target for gastric cancer therapy. Further studies are under way to investigate the efficacy of cIAP downregulation in gastric cancer In Vivo.
Prospective Analysis of Metachronous Early Gastric Cancer in High Risk Patients After H. pylori Eradication Akiko Shiotani, Noriya Uedo, Tomoari Kamada, Hiroyasu Iishi, Masaharu Tatsuta, Minoru Fujita, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Ken Haruma Background: It has been reported that H. pylori eradication reduced the risk for development of gastric cnacer in the subgroup without precancerous lesions. We previously reported that residual inflammation and no improvement of atrophy after eradication were more frequently detected in the cancer group than in the controls (Int J Cancer 2007;15:1182). Aim: We evaluated the development of new malignant lesions in the patients with prior medical endoscopic treatment after eradication to determine a prediction marker of second cancerogenesis. Methods: Histology was evaluated using two specimens from each sample site, the antrum greater curve and corpus greater and lesser curves. Serum pepsinogen (PG) I and II were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results: Eightysix patients were enrolled and 76 patients had been successfully treated for H. pylori and followed up more than 2 years (average observation period 27 months, range 24-60 months). Metachronous gastric cancers developed in eight (10.5%) patients. All cases were men, and an average size of tumors was 6.5mm (3~12mm, superficial depressed type (IIc) 6 lesions and superficial elevated type (IIa) 2 lesions). Serum PG I and I/II ratio before eradication were significantly lower (PG I 18 vs 44, p=0.008; I/II ratio 0.9 vs 1.4, p=0.03) in the group that developed cancer compared to the group that did not. Atrophy at corpus lesser curve was severe in the all cancer cases; the frequency of sever atrophy was higher in the group that developed cancer compared to the group that did not (100% vs 51%, p=0.04). Conclusions: Prevention of cancer will likely require H. pylori eradication prior to the development of atrophy. The cancer risk post eradication relates to the extent and severity of atrophy. Studies are needed to identify the parameters dictating surveillance intervals and duration after H. pylori eradication in those with H. pylori -induced gastric atrophy.
T2070 The Promoter Polymorphism of Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Gene Affects the Aberrant Promoter Methylation of Tumor-Related Genes in Gastric Epithelium Tomiyasu Arisawa, Tomomitsu Tahara, Tomoyuki Shibata, Masakatsu Nakamura, MItsuo Nagasaka, Yoshio Kamiya, Hiroshi Fujita, Daisuke Yoshioka, Masaaki Okubo, Yuko Arima, Hiroaki Shimazaki, Ichiro Hirata, Hiroshi Nakano
T2068
[Background and Aim] Aberrant promoter methylation is an important mechanism for gene silencing. Generated reactive oxygens may contribute to this CpG island methylation. Nrf2 is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene (G-686A, G-684A and C650A) and the CpG island methylation in non-cancerous gastric mucosa. [Methods] The study was performed in 85 subjects [46 without gastric malignancies (non-GC group) and 39 with gastric cancer (GC group)]. The promoter methylation status of the p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by Methylation-Specific-Polymerase Chain Reaction (MSP). The Nrf2 gene genotypes were determined by the PCR-SSCP method. [Results] In all 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16 and none for p21. The frequency of methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95%CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was largely higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95%CI, 1.26-8.59; p=0.015, and OR, 0.38; 95%CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95%CI, 1.14-7.36; p=0.026, and OR, 0.33; 95%CI, 0.13-0.88; p=0.027, respectively). There was no significant association between C-650A polymorphism and the DNA aberrant methylation. [Conclusions] Our
Incidence Rates of Esophageal and Gastric Carcinoma in Central Switzerland Within the Last 25 Years: There Is No Increase of the Incidence of Adenocarcinoma of the Gastroesophageal Junction Adrian Schmassmann, Marie-Gabrielle Oldendorf, Jan-Olaf Gebbers Background: A strong increase of adenocarcinoma incidence rates of the gastroesophageal junction has been reported in several other Western countries. The goal of this study was to examine subsite-specific and histology-specific esophageal and gastric carcinoma incidence patterns among the Central Swiss population within the last 25 years. Methods: Data on newly diagnosed esophageal and gastric carcinoma during 1982-2006 were obtained from the Cancer Registry of the Department of Pathology Lucerne, representing a catch population of about 700 000. Age, gender, tumor localization, histology, and incidence rates were assessed. Results: Between 1982-2006, there were (1) 344 patients with esophageal squamous cell carcinoma, (2) 669 patients with cardia type I-III adenocarcinoma, (3) 1061 patients with noncardia adenocarcinoma, and (4) 147 patients with gastric adenocarcinoma of unclear localization. The male-female sex ratio was 5.3 for esophageal squamous cell carcinoma, 3.1 for cardia type I-III, and 1.3 for noncardia gastric carcinoma, respectively. The mean age of diagnosis for all esophageal and gastric cancers was between 67-70 years. The average incidence for epithelial squamous cell carcinoma was 2.2/100 000; no significant changes
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Male Predominance of Adenocarcinoma of Upper Gastrointestinal Tract Is Related to Intestinal Histological Subtype Not Tumour Location Mohammad H. Derakhshan, Sarah Liptrot, James Paul, Ian L. Brown, Kenneth E. McColl
Celecoxib Prevents Gastric Cancer in Helicobacter pylori-Infected Mice; Comparison with Nimesulide Ki-Baik Hahm, Dae Yong Kim, Ki-Taek Nam, Hyun W. Baik
Background: Upper gastrointestinal adenocarcinomas show an unexplained male predominance which is more apparent in the oesophagus than stomach. We have conducted a population-based study to determine whether the gender phenomenon is primarily related to the anatomical site or the histological subtype of the tumour. Method: The study was based upon 3270 gastric and oesophageal cancers recorded in West of Scotland cancer Registry, 1998-2002. 812 of these cases were randomly selected for detailed analysis. Their records were reviewed for histology and anatomical site of tumour using ICD-10 and ICD O-2. The Lauren histological subtype of adenocarcinoma was determined by reviewing 1204 original reports and 3241 biopsy and surgical slides. Results: 405 (51.5%) cancers originated from the non-cardia region of the stomach, 173 (22.0%) from the gastric cardia and 209 (26.6%) from the oesophagus. Regardless of anatomical subsite, the upper GI cancers were more common in males (502, 63.8%) than females (285, 36.2%). Regardless of anatomical site, the crude incidence rate of intestinal type upper GI adenocarcinoma was higher in males (23.86/ 105/y) versus females (9.00/ 105/y), giving M/F of 2.65. In contrast, the crude incidence rate of diffuse-type adenocarcinoma was similar in males and females (5.58 vs 5.20 /105/y) yielding M/F of 1.07. Male predominance was greatest in the oesophagus with M/F of 3.50, less in the cardia (M/F= 2.00) and least in the non-cardia cancer (M/F= 1.65). The relationship between tumour location and male predominance lost its significance in the multivariate analysis when histological subtype was added [OR (95%) = 1.37 (0.88 2.12)]. Multivariate analyses including histological subtype, tumour location and age indicated that the male predominance was related to the histological type rather than anatomical location. Intestinal type adenocarcinoma showed similar male predominance irrespective of its anatomical location (OR, 95% CI: 2.6, 1.78 - 3.9). Conclusion: Male predominance in upper GI adenocarcinomas is not a function of tumour location but rather related to histological subtype. The mechanism of the strong gender association with intestinal subtype requires elucidation.
Background: H. pylori infection can lead to gastric carcinogenesis through the overexpression of COX-2 and we had published that nimesulide protect against H. pylori-induced gastric tumorigenesis (Nam KT et al, Clin Cancer Res 10:8105, 2004). Aim: We investigated whether celecoxib, NSAID showing higher degree of selective COX-2 inhibition, might protect against this form of cancer more efficiently than nimesulide. Simultaneously, apoptosis inducing capability was compared between these two drugs. Methods: C57BL/6 mice were treated with the N-methyl-N-nitrosourea (MNU) and/or H. pylori. Celecoxib (500 ppm or 1000 ppm) or nimesulide (200 ppm) was mixed with feed pellets and administered for the duration of the experiment, respectively. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. Molecular mechanisms of cancer prevention were compared between celecoxib and nimesulide. In Vitro experiments with the human gastric cancer cell line AGS were also repeated to document the underlying mechanism of cancer prevention. Global changes in transcriptomes after celecoxib treatment were assayed with AffyMatrix Chip assay. Results: Gastric tumors developed in 72.7% of mice that were given both MNU and H. pylori, whereas less than only 11.1% developed gastric tumors when given either MNU or H. pylori alone, suggesting that H. pylori promoted carcinogeninduced gastric tumorigenesis. In mice treated with both MNU and H. pylori, celecoxib administration substantially reduced H. pylori-associated gastric tumorigenesis (20.0% in mice treated with 500 ppm of celecoxib and 10.0% in mice treated with 1,000 ppm of celecoxib) and nimesulide yielded tumor inhibition in 27.8%. In Vitro studies demonstrated that higher execution of apoptosis was noted in celecoxib treatment. Conclusion: COX-2 inhibitor prevented H. pylori-associated gastric carcinogenesis, higher selectivity, higher the effects of cancer prevention. T2064 Clinicopathological Characteristics and Prognosis of Young Age Gastric Cancer : Analysis of 3,362 Consecutive Gastric Cancer Patients Jun chul Park, Yong Chan Lee, Jie-Hyun Kim, Kyung Ho Song, Jae Jun Park, Yu Jin Kim, Sang Kil Lee, Woo jin Hyung, Sung Hoon Noh, Choong-Bai Kim, Jae Bock Chung Background/Aims:Several studies have reported controversial results about clinicopathological features and prognosis in young age gastric cancer patients, probably due to variable definition and inhomogeneiety of patient population among studies. The aim of this study was to analyze the clinicopathological features and prognosis according to age in all stage gastric cancer. Methods: Between Jan.2000 and Dec.2005, a total 3,362 patients were diagnosed as gastric cancer in Severance hospital, Korea. We divided patients into three groups by age standard deviation (reference age points were 45 and 70); group 1 (≤45 years; 654 pts), group 2 (46 to 70 years; 2,317 pts) and group 3 (≥71 years; 391 pts). The patients were also classified according to treatment modalities; early gastric cancer (EGC) group treated by operation (1,400 pts) or endoscopic mucosal resection(152 pts), resectable advanced gastric cancer (AGC) group (1,619 pts) and unresectable AGC group (191 pts). Results: Female, upper third location and Linitis plastica were more frequent than other groups in group1(≤45 years). Group 1 patients are significantly associated with high proportion of poorly differentiated and signet ring cell carcinoma. CA19-9 level was much higher in young age gastric cancer patients (p>0.05). In EGC-group, the depressed endoscopic gross type is more frequent in group 1. In resectable AGC group, Bormann type IV and Lauren diffuse type were more common in group 1. The curative resection rate was significantly lower in young aged gastric cancer patients compared to others. Peritoneal metastasis was the most common case for unresectable in young age gastric cancer patients, and there was a higher proportion of unrespectable case in group1 compared to others (age>45yrs, p<0.05). In curatively resected patients, the 5 year survival rate was significantly better in group 1 than older group (p=0.0027). TNM stage, CA19-9 level and curative resection were significant prognostic factors by multivariate analysis. Conclusions: The clinicopathological features of young age gastric cancer patients(≤45 years) showed significantly higher preponderance for upper location, Linitis plastica gross type, diffuse histopathologic type and unresectability for curative resection compared to other aged gastric cancer patients. The prognostic factors were TNM stage, CA19-9 level and curative resection.
T2062 Comparison of Healing Rate of Artificial Ulcer After Endoscopic Submucosal Dissection in Relation to the Dose of Proton Pump Inhibitor. a Prospective Randomized Controlled Trial Seiji Kawano, Hiroyuki Okada, Keisuke Hori, Daisuke Tanioka, Masahide Kita, Takao Tsuzuki, Masafumi Inoue, Satoru Yagi, Ryuta Takenaka, Masayuki Uemura, Yoshiro Kawahara, Kazuhide Yamamoto Background: Proton pump inhibitor (PPI) and histamine2-receptor antagonist (H2RA) have similar effects on preventing bleeding and ulcer healing after conventional endoscopic mucosal resection. Two recent studies demonstrated the advantage of PPI as compared with H2RA for treatment of large artificial ulcers after endoscopic submucosal dissection (ESD), but the optimal duration and dose of PPI have not been clarified yet. Objective: To elucidate the optimal dose and duration of PPI for treatment of artificial ulcers after ESD by comparing the administration of 30mg with 15mg in terms of ulcer healing, prevention of bleeding, and QOL. Methods: A total of 84 patients who underwent ESD for gastric mucosal neoplasm between Jun 2006 and August 2007 at the University of Okayama Hospital were enrolled. All patients were given lansoprazole (30 mg) daily for 8 days, starting from the ESD day, and if there was no exposed vessel left in the ulcer bed after 8-day follow-up endoscopy, they were randomly assigned to either 30 mg group or 15 mg group and therapy was continued for 7 weeks. The study protocol was approved by the institutional review board and written consent was obtained from each patient prior to inclusion in the study. Results: Regarding the baseline characteristics of the patients, there were no significant differences in the factors between the two groups. Bleeding occurred in one patient of the 30mg group on day 11 after ESD and in one patient of the 15mg group on day 10. Finally, 39 of 42 patients in the 30mg group and 39 of 42 patients in the 15mg group successfully completed the protocol. The ulcer-healing rates after 4 weeks was 15% in the 30mg group and 8% in the 15mg group (not significant); 85% and 87% after 8 weeks, respectively (not significant). The stage of ulcers, the mean dimensions of ulcers on follow-up endoscopy (after 4 and 8 weeks), and the ulcer reduction ratio were not significantly different between the two groups. Moreover, the scores of the five symptom categories obtained from GSRS, and pH of the gastric juice were not significantly different between the two groups at the time of ESD and during follow-up. The cost of PPI in the 30mg group and 15mg group after completing 8week administration was 11698.4 yens and 7326.5 yens, respectively. Conclusions: The reduced dose of PPI after one week of ESD was equally effective in the treatment and superior in the cost reduction to continuing ordinary dose administration.
T2065 Overexpression of the Receptor Tyrosine Kinase Epha4 Plays An Important Role in the Progression of Human Gastric Cancers Nobuki Miyamoto, Hiroyuki Yamamoto, Chie Miyamoto, Tadateru Maehata, Katsuhiko Nosho, Hiroaki Taniguchi, Kentaro Yamashita, Yasushi Adachi, Yoshiaki Arimura, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura Altered expression of the genes for Eph receptors and ephrin ligands has been recognized to play an important role in human cancer. Compared with other Eph receptor family members, EphA4 is distinguished by its ability to bind to both type A ephrins and most type B ephrins, and the interaction with fibroblast growth factor receptor (FGFR) signal pathway. Using reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assay, we analyzed the expression and role of EphA4 in gastric cancer, in relation to clinicopathological characteristics and the expression of FGFR1 and ephrin ligands. Overexpression of EphA4 mRNA expression was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Overexpression of EphA4 analyzed by immunohistochemistry was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression at protein level was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of
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AGA Abstracts
EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. Our results suggest that overexpression of EphA4 plays an important role in gastric cancer. EphA4 could be an attractive target for molecular therapy by a therapeutic antibody and/or by small molecules targeting its kinase activities.
were detected during the observation period. The incidence for cardia type I-III adenocarcinoma tended to decrease from 1982 to 2006 from 5.07 to 4.16/100 000. The incidence rates for noncardia gastric adenocarcinoma strongly (P < 0.001) decreased from 1982 to 2006 from 6.61 to 2.83/100 000 (Figure). Conclusions: As in other Western countries, the incidence of noncardia gastric cancer strongly decreased within the last 25 years in Central Switzerland. In contrast to other Western countries, cardia type I-III adenocarcinoma did not increase in the last 25 years.
T2066 Endoscopic Mucosal Resection for Undifferentiated Intramucosal Gastric Cancer: Different Indications Between Signet Ring Cell Carcinoma and Poorly Differentiated Adenocarcinoma Hoi Jin Kim, Jae J Kim, Eun Ran Kim, Dong Hyun Sinn, Young-Ho Kim, Jun Haeng Lee, Dong Kyung Chang, Poong-lyul Rhee, Jong Chul Rhee Background) Small undifferentiated gastric cancer limited to the mucosal layer has been proposed as an extended indication for endoscopic mucosal resection (EMR). However, there is limited data about the difference of lymph node metastasis (LNM) in different histological subtypes between intramucosal signet ring cell carcinoma (SRC) and poorly differentiated adenocarcinoma (PDC). The aim of this study was to identify risk factors of the LNM and to suggest appropriate indications for EMR for undifferentiated intramucosal cancers. Method) We reviewed medical records of 2128 patients with intramucosal gastric cancers treated with gastrectomy and regional lymph node dissection at the Samsung Medical Center from 1994 to 2005. Clinicopathological factors related to LNM for intramucosal SRC and PDC were evaluated in comparison to differentiated intramucosal gastric cancers (DAC). Results) Out of 2128 intramucosal gastric cancers, 9 of 1243 (0.7%) cases of DAC, 20 of 594 (3.4%) cases of SRC and 18 of 291 (6.2%) cases of PDC had LNM. LNM increased significantly in SRC (OR=4.18 95% CI: 1.64-10.6) and PDC (OR=12.4 95% CI: 4.83-32.1) compared to DAC as determined by multivariate analysis. Tumor size (OR =3.36, 95% CI: 1.07-10.5) and lymphovascular invasion (OR=13.6 95% CI: 4.65-40.1) were other significant risk factors associated with LNM. None of 175 SRCs less than 20 mm in size (95% CI: 02.09) and none of 21 PDCs less than 10 mm in size (95% CI: 0-16.11) without lymphovascular invasion had LNM. Conclusion) Histological subtype, tumor size and lymphovascular invasion are risk factors of LNM in undifferentiated intramucosal gastric cancers. Intramucosal SRC has an intermediate LNM risk between the differentiated type and PDC. SRCs less than 20 mm and PDCs less than 10 mm in size without lymphovascular invasion are possible candidates for EMR.
T2069
T2067
Role of Ciap2 in Gastric Cancer Zesong Li, Liang Qiao, Yun Dai, Bing Zou, Juan Ma, HuiYao Lan, Benjamin C.Y. Wong BACKGROUND AND OBJECTIVES cIAP2 is a member of the IAP family and is overexpressed in most cancer tissues. Expression of cIAP2 can be induced by gastric carcinogen H. pylori. Therefore enhanced expression of cIAP2 may be related to gastric carcinogenesis. We aimed to investigate the feasibility of targeting cIAP2 in gastric cancer therapy. METHODS AND MATERIALS 12 pairs of human gastric cancer tissues and matched non-cancerous tissues were used to extract total RNA by Trizol method. Whole tissue lysates were prepared by using RIPA lysis buffer. Expressions of cIAP2 were detected by RT-PCR and Western blot analysis. Gastric cancer BGC-7901 cells were transfected with specific siRNA against cIAP2 for 48 h, and the effect of siRNA-cIAP2 on cell proliferation was detected by standard WST-1 assay. Apoptosis was detected by TUNEL staining and quantitated by flow cytometry. RESULTS Over 70% of gastric cancer tissues expressed higher levels of cIAP2 compared to non-cancerous gastric tissues at both mRNA and protein levels. Over-expression of cIAP2 was also confirmed by immunohistochemical staining which cIAP2 is strongly expressed in most gastric cancer tissues, whereas in normal gastric tissues, cIAP2 is expressed in gastric epithelium with weak to medium intensity. Knocking down of cIAP2 in BGC-7901 cells by siRNA-cIAP2 resulted in a 30% decrease in cell proliferation and a 20% increase in apoptosis as revealed by flow cytometry. CONCLUSION cIAP2 may be a potential target for gastric cancer therapy. Further studies are under way to investigate the efficacy of cIAP downregulation in gastric cancer In Vivo.
Prospective Analysis of Metachronous Early Gastric Cancer in High Risk Patients After H. pylori Eradication Akiko Shiotani, Noriya Uedo, Tomoari Kamada, Hiroyasu Iishi, Masaharu Tatsuta, Minoru Fujita, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Ken Haruma Background: It has been reported that H. pylori eradication reduced the risk for development of gastric cnacer in the subgroup without precancerous lesions. We previously reported that residual inflammation and no improvement of atrophy after eradication were more frequently detected in the cancer group than in the controls (Int J Cancer 2007;15:1182). Aim: We evaluated the development of new malignant lesions in the patients with prior medical endoscopic treatment after eradication to determine a prediction marker of second cancerogenesis. Methods: Histology was evaluated using two specimens from each sample site, the antrum greater curve and corpus greater and lesser curves. Serum pepsinogen (PG) I and II were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results: Eightysix patients were enrolled and 76 patients had been successfully treated for H. pylori and followed up more than 2 years (average observation period 27 months, range 24-60 months). Metachronous gastric cancers developed in eight (10.5%) patients. All cases were men, and an average size of tumors was 6.5mm (3~12mm, superficial depressed type (IIc) 6 lesions and superficial elevated type (IIa) 2 lesions). Serum PG I and I/II ratio before eradication were significantly lower (PG I 18 vs 44, p=0.008; I/II ratio 0.9 vs 1.4, p=0.03) in the group that developed cancer compared to the group that did not. Atrophy at corpus lesser curve was severe in the all cancer cases; the frequency of sever atrophy was higher in the group that developed cancer compared to the group that did not (100% vs 51%, p=0.04). Conclusions: Prevention of cancer will likely require H. pylori eradication prior to the development of atrophy. The cancer risk post eradication relates to the extent and severity of atrophy. Studies are needed to identify the parameters dictating surveillance intervals and duration after H. pylori eradication in those with H. pylori -induced gastric atrophy.
T2070 The Promoter Polymorphism of Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Gene Affects the Aberrant Promoter Methylation of Tumor-Related Genes in Gastric Epithelium Tomiyasu Arisawa, Tomomitsu Tahara, Tomoyuki Shibata, Masakatsu Nakamura, MItsuo Nagasaka, Yoshio Kamiya, Hiroshi Fujita, Daisuke Yoshioka, Masaaki Okubo, Yuko Arima, Hiroaki Shimazaki, Ichiro Hirata, Hiroshi Nakano
T2068
[Background and Aim] Aberrant promoter methylation is an important mechanism for gene silencing. Generated reactive oxygens may contribute to this CpG island methylation. Nrf2 is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene (G-686A, G-684A and C650A) and the CpG island methylation in non-cancerous gastric mucosa. [Methods] The study was performed in 85 subjects [46 without gastric malignancies (non-GC group) and 39 with gastric cancer (GC group)]. The promoter methylation status of the p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by Methylation-Specific-Polymerase Chain Reaction (MSP). The Nrf2 gene genotypes were determined by the PCR-SSCP method. [Results] In all 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16 and none for p21. The frequency of methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95%CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was largely higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95%CI, 1.26-8.59; p=0.015, and OR, 0.38; 95%CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95%CI, 1.14-7.36; p=0.026, and OR, 0.33; 95%CI, 0.13-0.88; p=0.027, respectively). There was no significant association between C-650A polymorphism and the DNA aberrant methylation. [Conclusions] Our
Incidence Rates of Esophageal and Gastric Carcinoma in Central Switzerland Within the Last 25 Years: There Is No Increase of the Incidence of Adenocarcinoma of the Gastroesophageal Junction Adrian Schmassmann, Marie-Gabrielle Oldendorf, Jan-Olaf Gebbers Background: A strong increase of adenocarcinoma incidence rates of the gastroesophageal junction has been reported in several other Western countries. The goal of this study was to examine subsite-specific and histology-specific esophageal and gastric carcinoma incidence patterns among the Central Swiss population within the last 25 years. Methods: Data on newly diagnosed esophageal and gastric carcinoma during 1982-2006 were obtained from the Cancer Registry of the Department of Pathology Lucerne, representing a catch population of about 700 000. Age, gender, tumor localization, histology, and incidence rates were assessed. Results: Between 1982-2006, there were (1) 344 patients with esophageal squamous cell carcinoma, (2) 669 patients with cardia type I-III adenocarcinoma, (3) 1061 patients with noncardia adenocarcinoma, and (4) 147 patients with gastric adenocarcinoma of unclear localization. The male-female sex ratio was 5.3 for esophageal squamous cell carcinoma, 3.1 for cardia type I-III, and 1.3 for noncardia gastric carcinoma, respectively. The mean age of diagnosis for all esophageal and gastric cancers was between 67-70 years. The average incidence for epithelial squamous cell carcinoma was 2.2/100 000; no significant changes
AGA Abstracts
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