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Sa1738 Hepatocellular Growth Factor Increases Esophageal Epithelium Regeneration in an Experimental Ulcer Model in Rats
no study regarding this issue in Japan. To reveal the clinical features of NOACs-related upper gastrointestinal mucosal injury, we evaluate mucosal injury endoscopically between vitamin K anticoagulants (VKA) users and NOACs users. METHODS: Data were extracted from the records of subjects who underwent upper gastrointestinal endoscopy at our department between March 2011 and October 2014. Of the 21,824 subjects, we analyzed 516 subjects who took VKA (Warfarin) or NOACs (Rivaroxaban, Apixaban, Edoxaban, Dabigatran). Gastrointestinal mucosal injury was evaluated endoscopically according to the modified LANZA score (MLS). Statistical analyses were performed by Fisher's exact test. RESULTS: The results are shown in Table 1. Average MLS of Rivaroxaban users and Dabigatran users tended to be higher than that of Warfarin users. In contrast, average MLS of Apixaban users and Edoxaban users tend to be lower than that of Warfarin users. However these differences were not statistically significant. When we put score 1-5 together as an injury group, prevalence of gastrointestinal mucosal injury was statistically significantly lower in Apixaban users (20.0%) compared with Warfarin users (76.3%, p=0.01). CONCLUSION: Prevalence of gastrointestinal mucosal injury varies considerably among different NOACs. Although further consideration will be needed in large number to confirm this result, but this is the first study suggesting that Apixaban might have less adverse effect to upper gastrointestinal mucosa than Warfarin in Japanese. Table 1 : modified LANZA score in each anticoagulants group
Sa1738 Hepatocellular Growth Factor Increases Esophageal Epithelium Regeneration in an Experimental Ulcer Model in Rats Yuga Komaki, Shuji Kanmura, Tomoaki Makino, Yohei Ono, Fumisato Sasaki, Yuichiro Nasu, Shinichi Hashimoto, Hiroki Taguchi, Masatsugu Numata, Akihiro Moriuchi, Hirofumi Uto, Akio Ido Background and aim: Endoscopic submucosal dissection (ESD) is a safe and feasible treatment for early esophageal cancer. However, ESD may cause difficult-to-treat esophageal strictures, and it is therefore desirable to develop stricture prevention technologies. Hepatocyte growth factor (HGF) is known to regenerate a variety of epithelial cells. The aim of this study was to clarify the effects of recombinant human HGF (rh-HGF) for repairing esophageal mucosal damage and stenosis. Methods: Esophageal ulcers were induced by focal application of acetic acid in rats. Rats with ulcers were treated with osmotic pumps releasing rh-HGF (200 μg/day) or phosphate-buffered saline (PBS); pumps were implanted into the peritoneum for 7 days. The length and weight of the esophagus, ulcer size, histology, proliferation and apoptosis of epithelial cells, and rate of esophageal stenosis were investigated. We also checked the expression of fibrosis-associated genes (TGF-β, Col1a1, TIMP1, TIMP-2, Acta2, MMP-2, and MMP-9) by reverse transcription polymerase chain reaction (RT-PCR) of esophageal tissues on day 3 and on day 7 after ulcer induction in each treatment group. Results: Ulcer size and esophageal shortening on day 7 were significantly ameliorated in the rh-HGF-treated group compared to the PBS-treated group. Treatment with rh-HGF enhanced the proliferation of esophageal epithelial cells at the edges of ulcers and significantly increased the thickness of the ulcer margin epithelium by day 7, and also prevented esophageal stenosis. TIMP-1 and 2 and MMP-2 and 9 gene expressions were significantly suppressed in the lower esophagus, including the ulcerous area, by rh-HGF treatment. Conclusions: Rh-HGF promoted the repair of esophageal mucosal damage in rats. These results indicate that HGF controls esophageal stenosis by reducing fibrosis during esophageal ulcer repair.
Sa1741 The Antrum and Corpus mRNA and Small-RNA Profile of the Human Healthy Stomach Sergio Lario, Ana M. Aransay, Aintzane González Lahera, Juan José Lozano, Nuria Macias, Anna Brunet, Jose Luis Lavín, M. Elisa Quílez, Carles Pericay Pijaume, Antónia Montserrat, Mireia Miquel Planas, María José Ramírez-Lázaro, Xavier Calvet Background: Measuring mRNA and miRNAs in different pathophysiologic states is an important step in investigating the functions of miRNAs. Studies analyzing gene expression in normal human stomach tissue have focused on the whole organ without taking into account the distinct anatomic and physiologicalcharacteristics of the antrum and the corpus. Aim: To determine the mRNA, miRNA, and small-RNA profile of the normal human antrum and corpus. Methods: Tensubjects (6 male; mean age 52.1years) with strictly normal gastric histology were selected from among 410 consecutive patients referred for gastroscopy to evaluate dyspeptic symptoms. Selected patients were negative for H.pylori on rapid urease tests, urea breath tests, and histology. During gastroscopy, four additional biopsies were obtained, two from the corpus and two from the antrum. Total RNA was isolated from the two pooled biopsies of each tissue.We analyzed 5 paired biopsies (antrum- corpus), and 5 unpaired biopsies (2 antrum and 3 corpus) from 10 subjects. We used Illumina HT12 microarrays to determine gene expression (mRNA) and the TruSeq-SmallRNA Sample Prep Kit to determine small non-coding RNAs.Libraries were sequenced on an IlluminaHiScanSQ system. Single-end reads were mapped and analyzed using sRNAbench and R-edgeR. Results: Genes with the highest antrum-specificity were GAST, MUC17, SERPINB5, and REG4. Genes with the highest corpus-specificity genes were CHIA, PGA4, PGA3, and CHRD. A total of 214 miRNA species with more than 100 reads in all 15 libraries were found. Comparison of the expression profiles between antrum and corpus tissue revealed a total of 49 differentially expressed miRNAs (27 overexpressedand 22 downregulated)with a 2.5-fold (p<0.05). This miRNA signature was able to accurately separate the antrum from the corpus samples into two clusters.The remaining 165 miRNAs were expressed in both anatomic locations. The antrum and corpus expressed 180 small non-coding RNA species (nuclear, nucleolar, and ribosomal); we found no differences between their expression in the antrum and in the corpus. Conclusions: We provide an integrative view of the mRNA, miRNAs,and small non-coding RNAs in the antrum and corpus of normal subjects. Our data will help to optimize gene expression studies of the stomach and to improve understanding of changes associated with diseases of the stomach.
Sa1739 A Total of 379 Multiple White and Flat Elevated Lesions in the Gastric Fundus Are Induced by Acid Suppressive Agents and Long-Term Proton Pump Inhibitor Treatment Tomoari Kamada, Takahisa Murao, Motoyasu Osawa, Manabu Ishii, Minoru Fujita, Hiroshi Matsumoto, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Kazuhiko Inoue, Akiko Shiotani, Jiro Hata, Ken Haruma Background: The development of fundic gland polyps and foveolar hyperplastic polyps is a well-known event during long-term treatment with proton pump inhibitors (PPI). We have previously reported (at DDW 2011) a new type of gastric lesion that is related to PPI or H2-receptor antagonist (H2RA) treatment and that is endoscopically characterized by multiple white and flat elevated lesions located in the gastric fundus (MWFF). Aim: The aim of this study was to investigate the relationship between the development of MWFF and the long-term use of acid suppressive agents. Subjects and Methods: We retrospectively reviewed 379 patients who were endoscopically diagnosed with MWFF between January 1, 2009 and October 31, 2014 at our hospital. MWFF was defined as multiple white and flat elevated lesions with irregular margins that were located in the cardia, fornix, or corpus. Biopsy specimens were obtained from the lesions in 44 patients, fasting serum gastrin levels were evaluated in 59 patients, and Helicobacter pylori infection was evaluated in 60 patients. Hypergastrinemia was defined as gastrin levels >350 pg/mL. Results: The mean patient age was 69.8 years, and 263 (69.4%) of the 379 patients were women. Among the 379 patients, 272 (71.8%) had a history of current or previous PPI or H2RA treatment (H2RA: 47 patients, PPI: 225 patients). The common histological finding of the lesions was the straight and enlarged foveolar epithelium of the fundic gland without cystic dilatation. Among the patients whose gastrin levels were evaluated, the mean serum gastrin level was 319.8 pg/mL, and 19 (32.2%) patients had hypergastrinemia. Among the patients who were screened for H. pylori infection, the infection rate was 31.7% (19/60). Conclusions: Our results indicate that the development of MWFF is closely associated with long-term PPI treatment, and incremental increases in serum gastrin might be related to the development of this lesion. When this gastric lesion is identified during endoscopy, we should consider stopping the PPI treatment or reduce the dosage of the PPI.
Sa1742 Pre-Pylorus Pseudomelanosis - "It Can Happen" Mohammad Bilal, Damanpreet K. Grewal, Kofi Clarke Introduction: Pseudomelanosis is a rare finding on upper endoscopy. It manifests as, discrete, flat, pigmented, dark mucosal lesions, with characteristic pathological findings, usually occurring in the duodenum. We report a case of Pseudomelanosis occurring in the pre pyloric region, a very rare site for an unusual condition. Case Presentation: A seventyseven year-old Caucasian-female with past medical history significant for hypertension, anemia of chronic disease, congestive heart failure, colorectal cancer status post partialcolectomy and a recently diagnosed adenocarcinoma of the lung, presented with hemoptysis and melena. Admission hemoglobin was 9.9 g/dl. Gastroenterology was consulted, and decision was made to pursue an upper endoscopy and colonoscopy for further investigation. Upper GI endoscopy showed segmental, dark pigmentation of mucosa in the antrum and pre-pyloric region [Figure 1], raising suspicion for melanosis or a melanoma. The colonoscopy was normal. Biopsy from the upper GI endoscopy showed granular pigmented material in
Sa1740 Upper Gastrointestinal Mucosal Injury in Japanese NOACs Users Yuji Shimada, Akihito Nagahara, Mariko Hojo, Daisuke Asaoka, Hitoshi Sasaki, Kentaro Izumi, Ippei Tanaka, Yuta Nakagawa, Tsutomu Takeda, Kohei Matsumoto, Hiroya Ueyama, Kenshi Matsumoto, Sumio Watanabe BACKGROUND AND AIMS: It is available to use non-vitamin K antagonist oral anticoagulants (NOACs) from 2011 in Japan. In terms of the gastrointestinal bleeding risk, previous studies have shown that the relative risk for gastrointestinal bleeding varies considerably among different NOACs. Its risk may be different in various races, however, there has been
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AGA Abstracts
AGA Abstracts
compared to that in H. pylori-negative patients (OR: 8.27, 95%CI: 4.04-16.92, p<0.01) and the administration of a potent acid inhibitor effectively prevented peptic ulcer (OR: 0.12, 95%CI: 0.06-0.25, p<0.01) regardless of LDA usage. In LDA users with the SLCO1B1 TT genotype, the risk of peptic ulcer tended to be high (ulcer [+] vs. ulcer [-] = 87.5% vs. 68.8%, p=0.06). For those with the UGT1A6 and CYP2C9*2, however, the risk wasn't increased. The peptic ulcer risk of SLCO1B1 TT genotype was also significantly higher than that of C allele carriers (C/T and C/C genotypes) in LDA users (OR: 3.18, 95%CI: 1.049.74, p=0.04). In Addition, the risk of peptic ulcer in patients with the TT genotype without a potent acid inhibitor tended to be higher than risk in C allele carriers (OR: 5.08, 95% CI: 0.89-28.96, p=0.06). Conclusions: We demonstrated that the TT genotype of SLCO1B1 increased the risk of peptic ulcer induced by LDA usage. Prophylactic use of acid inhibitors might therefore be an effective personalized treatment for preventing of gastric mucosal injury.
Sa1738 Hepatocellular Growth Factor Increases Esophageal Epithelium Regeneration in an Experimental Ulcer Model in Rats Yuga Komaki, Shuji Kanmura, Tomoaki Makino, Yohei Ono, Fumisato Sasaki, Yuichiro Nasu, Shinichi Hashimoto, Hiroki Taguchi, Masatsugu Numata, Akihiro Moriuchi, Hirofumi Uto, Akio Ido Background and aim: Endoscopic submucosal dissection (ESD) is a safe and feasible treatment for early esophageal cancer. However, ESD may cause difficult-to-treat esophageal strictures, and it is therefore desirable to develop stricture prevention technologies. Hepatocyte growth factor (HGF) is known to regenerate a variety of epithelial cells. The aim of this study was to clarify the effects of recombinant human HGF (rh-HGF) for repairing esophageal mucosal damage and stenosis. Methods: Esophageal ulcers were induced by focal application of acetic acid in rats. Rats with ulcers were treated with osmotic pumps releasing rh-HGF (200 μg/day) or phosphate-buffered saline (PBS); pumps were implanted into the peritoneum for 7 days. The length and weight of the esophagus, ulcer size, histology, proliferation and apoptosis of epithelial cells, and rate of esophageal stenosis were investigated. We also checked the expression of fibrosis-associated genes (TGF-β, Col1a1, TIMP1, TIMP-2, Acta2, MMP-2, and MMP-9) by reverse transcription polymerase chain reaction (RT-PCR) of esophageal tissues on day 3 and on day 7 after ulcer induction in each treatment group. Results: Ulcer size and esophageal shortening on day 7 were significantly ameliorated in the rh-HGF-treated group compared to the PBS-treated group. Treatment with rh-HGF enhanced the proliferation of esophageal epithelial cells at the edges of ulcers and significantly increased the thickness of the ulcer margin epithelium by day 7, and also prevented esophageal stenosis. TIMP-1 and 2 and MMP-2 and 9 gene expressions were significantly suppressed in the lower esophagus, including the ulcerous area, by rh-HGF treatment. Conclusions: Rh-HGF promoted the repair of esophageal mucosal damage in rats. These results indicate that HGF controls esophageal stenosis by reducing fibrosis during esophageal ulcer repair.
Sa1741 The Antrum and Corpus mRNA and Small-RNA Profile of the Human Healthy Stomach Sergio Lario, Ana M. Aransay, Aintzane González Lahera, Juan José Lozano, Nuria Macias, Anna Brunet, Jose Luis Lavín, M. Elisa Quílez, Carles Pericay Pijaume, Antónia Montserrat, Mireia Miquel Planas, María José Ramírez-Lázaro, Xavier Calvet Background: Measuring mRNA and miRNAs in different pathophysiologic states is an important step in investigating the functions of miRNAs. Studies analyzing gene expression in normal human stomach tissue have focused on the whole organ without taking into account the distinct anatomic and physiologicalcharacteristics of the antrum and the corpus. Aim: To determine the mRNA, miRNA, and small-RNA profile of the normal human antrum and corpus. Methods: Tensubjects (6 male; mean age 52.1years) with strictly normal gastric histology were selected from among 410 consecutive patients referred for gastroscopy to evaluate dyspeptic symptoms. Selected patients were negative for H.pylori on rapid urease tests, urea breath tests, and histology. During gastroscopy, four additional biopsies were obtained, two from the corpus and two from the antrum. Total RNA was isolated from the two pooled biopsies of each tissue.We analyzed 5 paired biopsies (antrum- corpus), and 5 unpaired biopsies (2 antrum and 3 corpus) from 10 subjects. We used Illumina HT12 microarrays to determine gene expression (mRNA) and the TruSeq-SmallRNA Sample Prep Kit to determine small non-coding RNAs.Libraries were sequenced on an IlluminaHiScanSQ system. Single-end reads were mapped and analyzed using sRNAbench and R-edgeR. Results: Genes with the highest antrum-specificity were GAST, MUC17, SERPINB5, and REG4. Genes with the highest corpus-specificity genes were CHIA, PGA4, PGA3, and CHRD. A total of 214 miRNA species with more than 100 reads in all 15 libraries were found. Comparison of the expression profiles between antrum and corpus tissue revealed a total of 49 differentially expressed miRNAs (27 overexpressedand 22 downregulated)with a 2.5-fold (p<0.05). This miRNA signature was able to accurately separate the antrum from the corpus samples into two clusters.The remaining 165 miRNAs were expressed in both anatomic locations. The antrum and corpus expressed 180 small non-coding RNA species (nuclear, nucleolar, and ribosomal); we found no differences between their expression in the antrum and in the corpus. Conclusions: We provide an integrative view of the mRNA, miRNAs,and small non-coding RNAs in the antrum and corpus of normal subjects. Our data will help to optimize gene expression studies of the stomach and to improve understanding of changes associated with diseases of the stomach.
Sa1739 A Total of 379 Multiple White and Flat Elevated Lesions in the Gastric Fundus Are Induced by Acid Suppressive Agents and Long-Term Proton Pump Inhibitor Treatment Tomoari Kamada, Takahisa Murao, Motoyasu Osawa, Manabu Ishii, Minoru Fujita, Hiroshi Matsumoto, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Kazuhiko Inoue, Akiko Shiotani, Jiro Hata, Ken Haruma Background: The development of fundic gland polyps and foveolar hyperplastic polyps is a well-known event during long-term treatment with proton pump inhibitors (PPI). We have previously reported (at DDW 2011) a new type of gastric lesion that is related to PPI or H2-receptor antagonist (H2RA) treatment and that is endoscopically characterized by multiple white and flat elevated lesions located in the gastric fundus (MWFF). Aim: The aim of this study was to investigate the relationship between the development of MWFF and the long-term use of acid suppressive agents. Subjects and Methods: We retrospectively reviewed 379 patients who were endoscopically diagnosed with MWFF between January 1, 2009 and October 31, 2014 at our hospital. MWFF was defined as multiple white and flat elevated lesions with irregular margins that were located in the cardia, fornix, or corpus. Biopsy specimens were obtained from the lesions in 44 patients, fasting serum gastrin levels were evaluated in 59 patients, and Helicobacter pylori infection was evaluated in 60 patients. Hypergastrinemia was defined as gastrin levels >350 pg/mL. Results: The mean patient age was 69.8 years, and 263 (69.4%) of the 379 patients were women. Among the 379 patients, 272 (71.8%) had a history of current or previous PPI or H2RA treatment (H2RA: 47 patients, PPI: 225 patients). The common histological finding of the lesions was the straight and enlarged foveolar epithelium of the fundic gland without cystic dilatation. Among the patients whose gastrin levels were evaluated, the mean serum gastrin level was 319.8 pg/mL, and 19 (32.2%) patients had hypergastrinemia. Among the patients who were screened for H. pylori infection, the infection rate was 31.7% (19/60). Conclusions: Our results indicate that the development of MWFF is closely associated with long-term PPI treatment, and incremental increases in serum gastrin might be related to the development of this lesion. When this gastric lesion is identified during endoscopy, we should consider stopping the PPI treatment or reduce the dosage of the PPI.
Sa1742 Pre-Pylorus Pseudomelanosis - "It Can Happen" Mohammad Bilal, Damanpreet K. Grewal, Kofi Clarke Introduction: Pseudomelanosis is a rare finding on upper endoscopy. It manifests as, discrete, flat, pigmented, dark mucosal lesions, with characteristic pathological findings, usually occurring in the duodenum. We report a case of Pseudomelanosis occurring in the pre pyloric region, a very rare site for an unusual condition. Case Presentation: A seventyseven year-old Caucasian-female with past medical history significant for hypertension, anemia of chronic disease, congestive heart failure, colorectal cancer status post partialcolectomy and a recently diagnosed adenocarcinoma of the lung, presented with hemoptysis and melena. Admission hemoglobin was 9.9 g/dl. Gastroenterology was consulted, and decision was made to pursue an upper endoscopy and colonoscopy for further investigation. Upper GI endoscopy showed segmental, dark pigmentation of mucosa in the antrum and pre-pyloric region [Figure 1], raising suspicion for melanosis or a melanoma. The colonoscopy was normal. Biopsy from the upper GI endoscopy showed granular pigmented material in
Sa1740 Upper Gastrointestinal Mucosal Injury in Japanese NOACs Users Yuji Shimada, Akihito Nagahara, Mariko Hojo, Daisuke Asaoka, Hitoshi Sasaki, Kentaro Izumi, Ippei Tanaka, Yuta Nakagawa, Tsutomu Takeda, Kohei Matsumoto, Hiroya Ueyama, Kenshi Matsumoto, Sumio Watanabe BACKGROUND AND AIMS: It is available to use non-vitamin K antagonist oral anticoagulants (NOACs) from 2011 in Japan. In terms of the gastrointestinal bleeding risk, previous studies have shown that the relative risk for gastrointestinal bleeding varies considerably among different NOACs. Its risk may be different in various races, however, there has been
S-319
AGA Abstracts
AGA Abstracts
compared to that in H. pylori-negative patients (OR: 8.27, 95%CI: 4.04-16.92, p<0.01) and the administration of a potent acid inhibitor effectively prevented peptic ulcer (OR: 0.12, 95%CI: 0.06-0.25, p<0.01) regardless of LDA usage. In LDA users with the SLCO1B1 TT genotype, the risk of peptic ulcer tended to be high (ulcer [+] vs. ulcer [-] = 87.5% vs. 68.8%, p=0.06). For those with the UGT1A6 and CYP2C9*2, however, the risk wasn't increased. The peptic ulcer risk of SLCO1B1 TT genotype was also significantly higher than that of C allele carriers (C/T and C/C genotypes) in LDA users (OR: 3.18, 95%CI: 1.049.74, p=0.04). In Addition, the risk of peptic ulcer in patients with the TT genotype without a potent acid inhibitor tended to be higher than risk in C allele carriers (OR: 5.08, 95% CI: 0.89-28.96, p=0.06). Conclusions: We demonstrated that the TT genotype of SLCO1B1 increased the risk of peptic ulcer induced by LDA usage. Prophylactic use of acid inhibitors might therefore be an effective personalized treatment for preventing of gastric mucosal injury.