- Email: [email protected]
Su1979 Detection of Gastric Cancer and Metaplasia in a High Risk Population in the USA
AGA Abstracts
pathway, including glutamine, glutamate, glycine and glutathione-S-S-glutathione. Signaling pathways that regulate glutamine metabolism, such as WNT/ß-catenin signaling, WNT target genes Cyclin D1, Axin2, Myc, Lgr5 and Cd44, p53 signaling, and mTOR signaling, were downregulated. The tricarboxylic acid cycle, including citrate, cis-aconitate, threonine and glycine, was also downregulated. However, glycolytic pathway, including glucose, glucose 6-phosphate, fructose 6-phosphate and lactate, and the central carbon metabolism in cancer (the Warburg effect signaling) were unchanged after VT. In humans, the targeted signaling pathways including WNT, mTOR, p53, neurotrophin, axon guidance, apoptosis, but not the Warburg effect signaling were activated in the tumor compared with the adjacent noncancerous tissue. Conclusions: Denervation-induced suppression of gastric tumorigenesis is probably mediated by the glutamine-dependent WNT/ß-catenin-mTOR signaling. The utility of this approach for the targeted treatment of glutamine-addicted/mTOR-dependent gastric cancer should be further investigated.
Su1979 Detection of Gastric Cancer and Metaplasia in a High Risk Population in the USA Niraj Jani, Ravi Kankotia, James L. Buxbaum, Alex Shindel, Ben Da, Daniel Cho, Elizabeth Dong, Mike Pepper, Didi Mwengela, Beverly Chen, Tova Sofer, Mario DinisRibeiro Introduction: Gastric cancer is rare in Western countries but is increasingly encountered in the Southwestern United States as a consequence of immigration patterns. The European Society for Gastrointestinal Endoscopy and Asian counterparts recognize gastric intestinal metaplasia as a precursor which merits surveillance by white light endoscopy and narrow band imaging. Aim: To develop a strategy to identify patients who need upper endoscopy to assess for gastric cancer and its precursor lesions in high risk populations. Methods: The Clinical Outcomes Research Initiative (CORI) indications associated with gastric disease were defined and characterized as high versus low risk for neoplasia. High risk indications included weight loss, gastric ulcer, epigastric pain, abnormal imaging, and iron deficiency anemia. Low risk indications included dyspepsia, reflux, recent upper gastrointestinal bleeding, fecal occult positive stools, and nausea. Consecutive procedures performed for these indications at our center (which has a Helicobacter Pylori prevalence of 67%) between March 2010 and March 2014 were individually reviewed to confirm histologic, clinical, and endoscopic findings. The primary endpoint was the confirmation of benign, premalignant, and malignant gastric findings and the primary predictor was the indication for endoscopy. Results: During the four years of the study 4034 patients underwent upper endoscopy for gastric indications. Among the underserved population 75% were Hispanic and 10% Asian. Endoscopy with biopsy was performed in 2518 (62%) patients and confirmed that 379 (9.4%) had gastric intestinal metaplasia (68% multifocal) and 162 gastric (4%) malignancies. Gastric intestinal metaplasia involved the antrum and/or body 96%% of cases. Neoplasia was found in the distal stomach in 84% of patients. Table 1 shows that current high risk indications did not predict which patients were found to have intestinal metaplasia compared to benign disease (p=0.34). High risk indications were associated with malignancy (p<0.001). Age was associated with both intestinal metaplasia (p<0.001) and malignancy (p=0.005). Poorly differentiated cancer was the most common type of gastric malignancy and patients were more likely to be female (p=0.005) and younger (p=0.11) than those with well differentiated adenocarcinoma. Conclusions: Populations with high Helicobacter pylori prevalence should undergo upper endoscopy for both low and high risk indications given the likelihood of intestinal metaplasia of the distal stomach. Poorly differentiated carcinoma may be a distinct entity and is the most frequent gastric neoplasm in the underserved Hispanic and Asian population of Los Angeles. Studies of screening and surveillance methods including narrow band imaging are needed in this population. Table 1: Clinical features and histology in 4039 patients with gastric symptoms*
Su1977 Roles of Intestine Specific Homeobox (ISX) for Gastric Carcinogenesis and Cancer Growth Soichiro Sue, Wataru Shibata, Eri Kameta, Yasuaki Ishii, Takeshi Sato, Shin Maeda (Background) The inflammation amplifier, which is a chemokine inducer via an enhanced NF-κB pathway by positive-feedback loop with IL-6, is linked to cancer development. We have previously reported that intestine-specific homeobox (ISX) expressed in gastric mucosa infected with H.pylori, and inflammation-induced ISX may lead to gastric intestinal metaplasia and proliferative response of gastric epithelial cells, confirmed by stably-transfectant cells that expressed ISX (DDW 2014 AGA #268). Although, ISX regulates tumor growth and survival in hepatocellular carcinoma, the mechanisms linking inflammation-induced ISX and tumor formation/growth in stomach is not fully elucidated. In current study, we tried to elucidate the role of ISX in the regulation of gastric carcinogenesis and tumor growth in vitro and in vivo. (Materials and Methods) We performed immunohistochemical analysis to determine the expression of ISX in human early gastric cancer (n=30) and advanced gastric cancer (n=45) along with cancer-adjacent gastric tissue. We used stably-transfectant cells that expressed myc-tagged ISX in MKN45 human gastric cancer cells (stable-ISX). We performed spheroid colony formation assay and xenograft model by using stable-ISX MKN45 cells. (Results) In human early gastric cancer, 33% (10/30 cases) was positive for ISX protein expression, whereas, in human advanced gastric cancer, 42% (19/45 cases) was positive for ISX expression. ISX expression in adjacent gastric tissue was strongly correlated with ISX expression in advanced gastric cancer (Cramer's coefficient of association V=0.8025, p<0.001). Stable-ISX MKN45 gastric cancer cells showed more spheroid colony formation in serum-free media compared with control cells. In xenograft model, stable-ISX cells showed stronger tumorigenic ability than the control cells when infected cells subcutaneously of nude mice, determined by tumor volume and weight (stable vs control; 535±179g vs 333±167g, p<0.05). ISX expression in Stable-ISX derived tumor was confirmed by immunohistochemistry. (Conclusion) ISX expression in human gastric cancers was correlate well with its expression in adjacent gastric mucosa. Expression of ISX in gastric cancer cells accelerates cell proliferation and tumorigenic ability. Conclusively, ISX may play a key role in the association of gastric inflammation and carcinogenesis, as well as in gastric cancer growth. Su1978 Polymorphisms in the RELB Gene Identify a Haplotype Associated With Reduced Risk of Pangastric Atrophy Adrian O'Hara, Michael D. Burkitt, Daniel F. Carr, Ana Alfirevic, Andrew R. Moore, Senthil V. Murugesan, Islay Steele, Andrea Varro, D. M. Pritchard
*given small number (n=5) patients with dysplasia were excluded from statistical analysis
Gastric adenocarcinoma develops via a series of stereotypical preneoplastic stages. Members of the NF-κB family of transcription factors regulate inflammation and other cellular pathways involved in gastric carcinogenesis. Single nucleotide polymorphisms (SNPs) at loci encoding genes involved in the canonical NF-κB activation pathway including NFKBIA and NFKB1 are associated with altered gastric cancer risk. We previously demonstrated that germline Nfkb2 deletion protects mice from developing H. felis induced gastric preneoplasia. However, associations between SNPs affecting alternative pathway NF-κB signaling and gastric cancer have not previously been reported. To assess this, a cohort of 1400 adult patients attending for symptom directed diagnostic upper gastrointestinal endoscopy were genotyped for SNPs at loci thought to influence signaling in this pathway. Genomic DNA was extracted from whole blood. Gene selection in alternative pathway NF-κB signaling was based on biological plausibility. SNPs were identified from dbSNP using HapMap minor allele frequency data. Haploview was used to identify tag SNPs mapping 6 genes involved in alternative pathway NF-κB signaling. 50 SNPs were selected for analysis, each with a MAF of >5%, patients were genotyped using MALDI-TOF mass spectrometry (Sequenom® MassARRAY®). SNPs and patients with <90% call rates were excluded from further analysis. Association analyses for individual markers and haplotypes were carried out using Haploview with correction for multiple comparisons by permutation analysis and Benjamini-Hochberg false discovery rate (FDR). 1134 patients and 42 SNPs fulfilled our inclusion criteria. All 42 SNPS passed the Hardy-Weinberg threshold (p>0.001), and case control comparisons were carried out. In patients with gastric preneoplastic pathology (atrophic gastritis and/or intestinal metaplasia and/or dysplasia, n=207 vs control, n=274), a SNP in the NIK gene conferred an increased risk of pathology (OR 1.4, 95%CI = 1.02-1.88). After FDR and permutation analysis, this SNP did not retain statistical significance. In patients with pangastric atrophy (n=13) vs control (n=282), seven SNPs were observed to confer an altered risk (p<0.05 on individual testing), however these SNPs did not reach significance following permutation or FDR analyses. A RELB haplotype block was associated with an OR of 0.26 (95% CI = 0.1070.627, p=0.0014, corrected p=0.03) for developing pangastric atrophy. Identification of a RELB haplotype that may be associated with a reduced risk of developing pangastric atrophy provides further evidence of a role for the alternative NF-κB activation pathway in gastric carcinogenesis. These findings require validation in other cohorts of patients with preneoplastic gastric pathology, and identify the need to investigate how the identified RELB haplotype influences NF-κB signaling.
AGA Abstracts
Su1980 Diabetes and Dislipidemia Increase Significantly the Risk of Gastric Intestinal Metaplasia: A Prospective Study Tomás Navarro-Rodriguez, Ricardo C. Barbuti, Jaime N. Eisig, Ricardo A. Dib, Eduardo F. Abrantes, Karina B. Ribeiro, Luiz Fernando L. Reis, André L. Montagnini Introduction: Chronic gastric inflammation and intestinal metaplasia (IM) are known risks for gastric cancer. Other risk factors have been recently linked to this type of neoplasia, one of these is diabetes. In order to better understand the relation between diabetes and gastric cancer, we have performed a cohort of dyspeptic patients. Patients and methods: Between 2010 and 2012, 399 patients with dyspeptic symptoms were submitted to an upper digestive endoscopy. Patients with chronic gastritis and/or IM, were enrolled in a repeated endoscopy protocol. Clinical commorbidities were registered. Results: Expressed in tables 1 and 2. Conclusions: Diabetes increases the risk of gastric intestinal metaplasia with an OR = 3.2 (table 1). When diabetes is associated with dislipidemia the risk is even higher OR = 7.2 (table 2). Our results identified a possible high risk population for gastric cancer. Patients with these clinical conditions should be carefully followed. Table 1: Association between diabetes and IM.
p = 0.013 (Fischer exact test), OR = 3,2 (IC 95% 1.1 - 8.4)
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pathway, including glutamine, glutamate, glycine and glutathione-S-S-glutathione. Signaling pathways that regulate glutamine metabolism, such as WNT/ß-catenin signaling, WNT target genes Cyclin D1, Axin2, Myc, Lgr5 and Cd44, p53 signaling, and mTOR signaling, were downregulated. The tricarboxylic acid cycle, including citrate, cis-aconitate, threonine and glycine, was also downregulated. However, glycolytic pathway, including glucose, glucose 6-phosphate, fructose 6-phosphate and lactate, and the central carbon metabolism in cancer (the Warburg effect signaling) were unchanged after VT. In humans, the targeted signaling pathways including WNT, mTOR, p53, neurotrophin, axon guidance, apoptosis, but not the Warburg effect signaling were activated in the tumor compared with the adjacent noncancerous tissue. Conclusions: Denervation-induced suppression of gastric tumorigenesis is probably mediated by the glutamine-dependent WNT/ß-catenin-mTOR signaling. The utility of this approach for the targeted treatment of glutamine-addicted/mTOR-dependent gastric cancer should be further investigated.
Su1979 Detection of Gastric Cancer and Metaplasia in a High Risk Population in the USA Niraj Jani, Ravi Kankotia, James L. Buxbaum, Alex Shindel, Ben Da, Daniel Cho, Elizabeth Dong, Mike Pepper, Didi Mwengela, Beverly Chen, Tova Sofer, Mario DinisRibeiro Introduction: Gastric cancer is rare in Western countries but is increasingly encountered in the Southwestern United States as a consequence of immigration patterns. The European Society for Gastrointestinal Endoscopy and Asian counterparts recognize gastric intestinal metaplasia as a precursor which merits surveillance by white light endoscopy and narrow band imaging. Aim: To develop a strategy to identify patients who need upper endoscopy to assess for gastric cancer and its precursor lesions in high risk populations. Methods: The Clinical Outcomes Research Initiative (CORI) indications associated with gastric disease were defined and characterized as high versus low risk for neoplasia. High risk indications included weight loss, gastric ulcer, epigastric pain, abnormal imaging, and iron deficiency anemia. Low risk indications included dyspepsia, reflux, recent upper gastrointestinal bleeding, fecal occult positive stools, and nausea. Consecutive procedures performed for these indications at our center (which has a Helicobacter Pylori prevalence of 67%) between March 2010 and March 2014 were individually reviewed to confirm histologic, clinical, and endoscopic findings. The primary endpoint was the confirmation of benign, premalignant, and malignant gastric findings and the primary predictor was the indication for endoscopy. Results: During the four years of the study 4034 patients underwent upper endoscopy for gastric indications. Among the underserved population 75% were Hispanic and 10% Asian. Endoscopy with biopsy was performed in 2518 (62%) patients and confirmed that 379 (9.4%) had gastric intestinal metaplasia (68% multifocal) and 162 gastric (4%) malignancies. Gastric intestinal metaplasia involved the antrum and/or body 96%% of cases. Neoplasia was found in the distal stomach in 84% of patients. Table 1 shows that current high risk indications did not predict which patients were found to have intestinal metaplasia compared to benign disease (p=0.34). High risk indications were associated with malignancy (p<0.001). Age was associated with both intestinal metaplasia (p<0.001) and malignancy (p=0.005). Poorly differentiated cancer was the most common type of gastric malignancy and patients were more likely to be female (p=0.005) and younger (p=0.11) than those with well differentiated adenocarcinoma. Conclusions: Populations with high Helicobacter pylori prevalence should undergo upper endoscopy for both low and high risk indications given the likelihood of intestinal metaplasia of the distal stomach. Poorly differentiated carcinoma may be a distinct entity and is the most frequent gastric neoplasm in the underserved Hispanic and Asian population of Los Angeles. Studies of screening and surveillance methods including narrow band imaging are needed in this population. Table 1: Clinical features and histology in 4039 patients with gastric symptoms*
Su1977 Roles of Intestine Specific Homeobox (ISX) for Gastric Carcinogenesis and Cancer Growth Soichiro Sue, Wataru Shibata, Eri Kameta, Yasuaki Ishii, Takeshi Sato, Shin Maeda (Background) The inflammation amplifier, which is a chemokine inducer via an enhanced NF-κB pathway by positive-feedback loop with IL-6, is linked to cancer development. We have previously reported that intestine-specific homeobox (ISX) expressed in gastric mucosa infected with H.pylori, and inflammation-induced ISX may lead to gastric intestinal metaplasia and proliferative response of gastric epithelial cells, confirmed by stably-transfectant cells that expressed ISX (DDW 2014 AGA #268). Although, ISX regulates tumor growth and survival in hepatocellular carcinoma, the mechanisms linking inflammation-induced ISX and tumor formation/growth in stomach is not fully elucidated. In current study, we tried to elucidate the role of ISX in the regulation of gastric carcinogenesis and tumor growth in vitro and in vivo. (Materials and Methods) We performed immunohistochemical analysis to determine the expression of ISX in human early gastric cancer (n=30) and advanced gastric cancer (n=45) along with cancer-adjacent gastric tissue. We used stably-transfectant cells that expressed myc-tagged ISX in MKN45 human gastric cancer cells (stable-ISX). We performed spheroid colony formation assay and xenograft model by using stable-ISX MKN45 cells. (Results) In human early gastric cancer, 33% (10/30 cases) was positive for ISX protein expression, whereas, in human advanced gastric cancer, 42% (19/45 cases) was positive for ISX expression. ISX expression in adjacent gastric tissue was strongly correlated with ISX expression in advanced gastric cancer (Cramer's coefficient of association V=0.8025, p<0.001). Stable-ISX MKN45 gastric cancer cells showed more spheroid colony formation in serum-free media compared with control cells. In xenograft model, stable-ISX cells showed stronger tumorigenic ability than the control cells when infected cells subcutaneously of nude mice, determined by tumor volume and weight (stable vs control; 535±179g vs 333±167g, p<0.05). ISX expression in Stable-ISX derived tumor was confirmed by immunohistochemistry. (Conclusion) ISX expression in human gastric cancers was correlate well with its expression in adjacent gastric mucosa. Expression of ISX in gastric cancer cells accelerates cell proliferation and tumorigenic ability. Conclusively, ISX may play a key role in the association of gastric inflammation and carcinogenesis, as well as in gastric cancer growth. Su1978 Polymorphisms in the RELB Gene Identify a Haplotype Associated With Reduced Risk of Pangastric Atrophy Adrian O'Hara, Michael D. Burkitt, Daniel F. Carr, Ana Alfirevic, Andrew R. Moore, Senthil V. Murugesan, Islay Steele, Andrea Varro, D. M. Pritchard
*given small number (n=5) patients with dysplasia were excluded from statistical analysis
Gastric adenocarcinoma develops via a series of stereotypical preneoplastic stages. Members of the NF-κB family of transcription factors regulate inflammation and other cellular pathways involved in gastric carcinogenesis. Single nucleotide polymorphisms (SNPs) at loci encoding genes involved in the canonical NF-κB activation pathway including NFKBIA and NFKB1 are associated with altered gastric cancer risk. We previously demonstrated that germline Nfkb2 deletion protects mice from developing H. felis induced gastric preneoplasia. However, associations between SNPs affecting alternative pathway NF-κB signaling and gastric cancer have not previously been reported. To assess this, a cohort of 1400 adult patients attending for symptom directed diagnostic upper gastrointestinal endoscopy were genotyped for SNPs at loci thought to influence signaling in this pathway. Genomic DNA was extracted from whole blood. Gene selection in alternative pathway NF-κB signaling was based on biological plausibility. SNPs were identified from dbSNP using HapMap minor allele frequency data. Haploview was used to identify tag SNPs mapping 6 genes involved in alternative pathway NF-κB signaling. 50 SNPs were selected for analysis, each with a MAF of >5%, patients were genotyped using MALDI-TOF mass spectrometry (Sequenom® MassARRAY®). SNPs and patients with <90% call rates were excluded from further analysis. Association analyses for individual markers and haplotypes were carried out using Haploview with correction for multiple comparisons by permutation analysis and Benjamini-Hochberg false discovery rate (FDR). 1134 patients and 42 SNPs fulfilled our inclusion criteria. All 42 SNPS passed the Hardy-Weinberg threshold (p>0.001), and case control comparisons were carried out. In patients with gastric preneoplastic pathology (atrophic gastritis and/or intestinal metaplasia and/or dysplasia, n=207 vs control, n=274), a SNP in the NIK gene conferred an increased risk of pathology (OR 1.4, 95%CI = 1.02-1.88). After FDR and permutation analysis, this SNP did not retain statistical significance. In patients with pangastric atrophy (n=13) vs control (n=282), seven SNPs were observed to confer an altered risk (p<0.05 on individual testing), however these SNPs did not reach significance following permutation or FDR analyses. A RELB haplotype block was associated with an OR of 0.26 (95% CI = 0.1070.627, p=0.0014, corrected p=0.03) for developing pangastric atrophy. Identification of a RELB haplotype that may be associated with a reduced risk of developing pangastric atrophy provides further evidence of a role for the alternative NF-κB activation pathway in gastric carcinogenesis. These findings require validation in other cohorts of patients with preneoplastic gastric pathology, and identify the need to investigate how the identified RELB haplotype influences NF-κB signaling.
AGA Abstracts
Su1980 Diabetes and Dislipidemia Increase Significantly the Risk of Gastric Intestinal Metaplasia: A Prospective Study Tomás Navarro-Rodriguez, Ricardo C. Barbuti, Jaime N. Eisig, Ricardo A. Dib, Eduardo F. Abrantes, Karina B. Ribeiro, Luiz Fernando L. Reis, André L. Montagnini Introduction: Chronic gastric inflammation and intestinal metaplasia (IM) are known risks for gastric cancer. Other risk factors have been recently linked to this type of neoplasia, one of these is diabetes. In order to better understand the relation between diabetes and gastric cancer, we have performed a cohort of dyspeptic patients. Patients and methods: Between 2010 and 2012, 399 patients with dyspeptic symptoms were submitted to an upper digestive endoscopy. Patients with chronic gastritis and/or IM, were enrolled in a repeated endoscopy protocol. Clinical commorbidities were registered. Results: Expressed in tables 1 and 2. Conclusions: Diabetes increases the risk of gastric intestinal metaplasia with an OR = 3.2 (table 1). When diabetes is associated with dislipidemia the risk is even higher OR = 7.2 (table 2). Our results identified a possible high risk population for gastric cancer. Patients with these clinical conditions should be carefully followed. Table 1: Association between diabetes and IM.
p = 0.013 (Fischer exact test), OR = 3,2 (IC 95% 1.1 - 8.4)
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