The effect of short-term proton pump inhibitor plus anti-ulcer drug on the healing of endoscopic submucosal dissection-derived artificial ulcer: a randomized controlled trial.

BACKGROUND/AIMS: Artificial ulcers remain a major complication after Endoscopic submucosal dissection (ESD). The development of more effective treatment regimen for this ulcer is required than the use of proton pump inhibitor (PPI) alone. METHODOLOGY: Patients with ESD-derived artificial ulcers were randomly assigned to two groups: a group of patients who received rabeprazole 20 mg daily for 8 weeks (PPI group) and a group of patients who received a combination of rebamipide 300 mg daily for 8 weeks and rabeprazole 20 mg dairy for the first 4 weeks (reb+PPI group). The area reduction ratio and healing status of ulcers were evaluated endoscopically on postoperative 7, 28 and 56 days. RESULTS: The overall ulcer area reduction ratio was higher in the reb+PPI group than in the PPI group, especially at an early stage. The ratio of progression to the H1 stage in the reb+PPI group was significantly higher than that in the PPI group, especially at an early stage. CONCLUSIONS: Treatment with 8 weeks of rebamipide plus the first 4 weeks of PPI demonstrated a reduction ratio of artificial ulcers superior to that with 8 weeks of PPI mono-therapy. This combination treatment is, therefore, one of the candidate treatment strategies against ESD-derived artificial ulcers.

Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium.

BACKGROUND: Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1. METHODS: Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP. RESULTS: Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia. CONCLUSIONS: Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.

Irsogladine maleate for the treatment of recurrent aphthous stomatitis in hepatitis C virus patients on pegylated-interferon and ribavirin: a pilot study.

BACKGROUND AND AIM: Aphthous stomatitis is one of the adverse effects associated with interferon (IFN) that forces dose reduction of IFN and there is no established therapy. This study was aimed to investigate whether irsogladine maleate, which enhances the functions of intercellular communication through the gap junctions, is effective for the treatment of aphthous stomatitis developed in hepatitis C virus (HCV) patients on pegylated-interferon (PEG-IFN) and ribavirin. METHODS: Nineteen patients with HCV were treated with PEG-IFN and ribavirin for 48 weeks. Ten out of 19 patients developed aphthous stomatitis during treatment with PEG-IFN and ribavirin. Within 1-2 weeks after development of aphthous stomatitis, 4 mg irsogladine maleate was orally administered daily to all patients and the therapeutic and adverse effects of irsogladine maleate were examined on every week. The degree of aphthous stomatitis was evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. RESULTS: Out of 10 patients, aphthous stomatitis was evaluated as grade 3 in three patients (30%) and grade 2 in seven patients (70%) by CTCAE. CTCAE grade was improved to 0 after 1 week in six patients, after 2 weeks in two patients, and after 3 weeks in two patients after the start of administration of irsogladine maleate. Aphthous stomatitis has not recurred in patients who had been on irsogladine maleate continuously during treatment of PEG-IFN and ribavirin. CONCLUSIONS: Irsogladine maleate is effective for the treatment of aphthous stomatitis developing during PEG-IFN and ribavirin administration in HCV patients.

Chronic ingestion of ethanol induces hepatocellular carcinoma in mice without additional hepatic insult.

BACKGROUND: Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury. METHODS: Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc. RESULTS: At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5-10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5-22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA. CONCLUSIONS: Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol.

Advanced ultrasonography technologies to assess the effects of radiofrequency ablation on hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is a curative therapy for hepatocellular carcinoma (HCC). In RFA, ultrasonography (US) is most commonly used to guide tumor puncture, while its effects are assessed using dynamic computed tomography or magnetic resonance. The differences in modalities used for RFA and assessment of its effects complicate RFA. We developed a method for assessing the effects of RFA on HCC by combining contrast-enhanced (CE) US and real-time virtual sonography with three-dimensional US data. PATIENTS AND METHODS: Before RFA, we performed a sweep scan of the target HCC nodule and the surrounding hepatic parenchyma to generate three-dimensional US data. After RFA, we synchronized multi-planar reconstruction images derived from stored three-dimensional US data with real-time US images on the same US monitor and performed CEUS and real-time virtual sonography. Using a marking function, we drew a sphere marker along the target HCC nodule contour on pre-treatment US- multi-planar reconstruction images so that the automatically synchronized sphere marker represented the original HCC nodule contour on post-treatment real-time CEUS images. Ablation was considered sufficient when an avascular area with a margin of several millimeters in all directions surrounded the sphere marker on CEUS. RESULTS: This method was feasible and useful for assessing therapeutic effects in 13 consecutive patients with HCC who underwent RFA. In 2 patients who underwent multiple sessions of RFA, HCC-nodule portions requiring additional RFA were easily identified on US images. CONCLUSIONS: This method using advanced US technologies will facilitate assessment of the effects of RFA on HCC.

Association between functional promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene and ulcerative colitis in Japan.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. Two functional polymorphisms were identified in the promoter region of MIF gene. We attempted to clarify the associations between these polymorphisms and ulcerative colitis (UC). The study was performed in 111 patients with UC and 209 subjects without UC. We employed the PCR-SSCP method to detect gene polymorphisms. Overall, 5/5-CATT genotype was a decreased risk for the development of UC (OR, 0.51; 95% CI, 0.26-0.99). In addition, 7/7-CATT genotype was significantly associated with chronic continuous phenotype and distal colitis phenotype (OR, 5.49; 95% CI, 1.19-25.3, and OR, 6.10; 95% CI, 1.32-28.2, respectively), whereas 5/5-CATT genotype had an inhibitory effect on the development of UC after 20years of age (OR, 0.33; 95% CI, 0.14-0.82). On the other hand, G-173C polymorphism did not affect the susceptibility to and the phenotypes of UC. Our results suggested that tetranucleotide CATT repeat of MIF gene promoter may be associated with the development of UC and the severity of inflammation in patients with UC.

Usefulness of dual-phase 18F-FDG PET/CT for diagnosing small pancreatic tumors.

OBJECTIVES: The usefulness of dual-phase F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) for pancreatic tumors was investigated including numerous small tumors. METHODS: Consecutive 116 patients with solid pancreatic tumors were subjected. Maximum standard uptake values (SUVmax) at 1 and 2 hours after FDG injection were defined as early and delayed SUVmax, respectively. Receiver operating characteristic curve was used to determine the optimal cutoff value of early SUVmax. Diagnostic accuracy of dual-phase FDG PET/CT was compared with that of single phase. RESULTS: The mean ± SD tumor size was 25 ±12 mm in diameter. The level of early SUVmax and proportion of elevated SUVmax in delayed phase were significantly higher in malignancy than those in benignancy for less than 25 mm tumors (4.1 ± 2.6 vs 1.9 ± 0.5, P < 0.001; 89% vs 17%, P < 0.0001) although they did not reach statistical significance for greater than or equal to 25 mm tumors. When diagnostic criteria of dual-phase FDG PET/CT for less than 25 mm tumors were determined as (1) early SUVmax greater than or equal to 2.1 and/or (2) delayed SUVmax greater than early SUVmax, sensitivity, specificity, and over all accuracy of dual-phase FDG PET/CT were better than that of single phase for less than 25 mm tumor (93%, 83%, and 91% vs 79%, 83%, and 80%, respectively). CONCLUSIONS: Dual-phase FDG PET/CT might be useful for diagnosing small pancreatic tumors.

Potential use of point shear wave elastography for the pancreas: a single center prospective study.

AIM: Clinical use of point shear wave elastography for the liver has been established, however, few studies demonstrated its usefulness for the pancreas. A prospective study was conducted to clarify its feasibility for the pancreas and its usefulness for the identification of high risk group for pancreatic cancer. PATIENTS AND METHODS: Consecutive eighty-five patients underwent point shear wave elastography for the pancreas. The success rate of shear wave velocity (SWV) measurement, that is the number of successful measurements over total 10 measurements, was recorded. The SWV of the pancreas measured at non-tumorous area was compared between patients with and without pancreatic cancer. Factors associated with high SWV were determined by logistic regression model. RESULTS: Sixty patients were included, of these 18 had pancreatic cancer. The success rate of 100% was achieved at the head, the body and the tail of the pancreas in 80%, 83%, and 68% of the patients, respectively. The success rate of ≥80% was achieved in 100%, 100%, and 96% of the patients, respectively. Although mean SWV of the pancreas harboring pancreatic cancer tended to be higher compared with that of the pancreas without cancer (1.51 ± 0.45 m/s vs 1.43 ± 0.28 m/s), they did not reach statistical significance. Multivariate analysis showed that increased amount of alcohol intake was associated with high SWV. CONCLUSION: The SWV of the pancreas was measured with excellent success rate. However, tendency of higher SWV obtained from the pancreas harboring pancreatic cancer needed to be further investigated.

The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis.

Toll­like receptor activation intitially recruits the myeloid differentiation primary response gene (88) (MyD88) protein. A polymorphism *1244 A>G (rs7744) in the 3'­untranslated region of MyD88 has been identified. In the present study, the association of this polymorphism with ulcerative colitis (UC) was investigated. The population studied comprised 922 individuals, including patients with UC (UC cases) and without (controls). Genotyping of rs7744 was performed by PCR single-strand conformation polymorphism and the rs7744 G allele frequencies in the controls and UC cases were 32.8 and 43.5%, respectively (P<0.0001). The results showed that the genotype frequency of the AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls (P=0.0012 for both groups). The rs7744 minor allele variants were significantly associated with susceptibility to UC as indicated by dominant and recessive genetic models. The minor allele variants were associated with an increased risk for UC in the male individuals but not the female individuals. The rs7744 was also associated with a non­continuous phenotype of UC and steroid unused/independent UC. This minor allele homozygote was associated with the disease severity of UC, hospitalization and response to steroid treatment. The results of the present study provided evidence that MyD88 polymorphism rs7744 was significantly associated with the development of UC and that this polymorphism may be associated with the response to treatment therapies for UC.

Influence of IL17A polymorphisms (rs2275913 and rs3748067) on the susceptibility to ulcerative colitis.

Interleukin-17A plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We investigated the association between ulcerative colitis (UC) and polymorphisms of IL17A, rs2275913 (-197 G > A), and rs3748067 (*1249 C > T). The study was performed in 475 healthy subjects (controls) and 202 with UC (UC cases), including 113 controls and 64 UC cases from previous study. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. The minor allele frequency of rs2275913 was significantly higher but that of rs3748067 was significantly lower in UC cases than controls. The rs2275913 minor homozygote (AA) had an increased risk of the development of UC, whereas rs3748067 minor carrier (CT + TT) had decreased risks for the development of UC. When compared with LR group (rs2275913 GG + GA with rs3748067 CT + TT), HR group (rs2275913 AA with rs3748067 CC) had a more increased risk of the development of UC (OR, 3.38; p = 0.0007). The polymorphisms of IL17A were associated with the noncontinuous and pancolitis phenotypes of UC. Our results suggest that IL17A polymorphisms (both rs2275913 and rs3748067) influence the susceptibility to and pathophysiological features of UC, coordinately.

Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects.

BACKGROUND: Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS (sensory-neuron specific), encoded by SCN10A, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and SCN10A non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C). METHODS: The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms. RESULTS: The 3218 CC homozygotes had a reduced risk for the development of FD [odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402-0.864; p = 0.0067]. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD (p = 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448-0.853; p = 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS (p = 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in Helicobacter pylori-negative subjects (OR 0.463; 95 % CI 0279-0.9768; p = 0.0029). CONCLUSION: We conclude that genetic polymorphisms of SCN10A are closely associated with FD (both EPS and PDS), especially in H. pylori-negative subjects, in Japanese.

Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer.

In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.

Three ileus cases associated with the use of dipeptidyl peptidase-4 inhibitors in diabetic patients.

Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic drugs that increase incretin hormone levels to enhance blood sugar level-dependent insulinotropic effects, suppress glucagon action, and reduce bowel motility. These incretin effects are ideal for blood sugar control. However, the safety profile of DPP-4 inhibitors is not yet established. Herein, we present three cases of ileus, considered to be closely related to the use of DPP-4 inhibitors, in diabetic patients. Each of the three patients exhibited some risk of a deficiency in bowel movement; the onset of ileus was within 40 days after strengthened inhibition of DPP-4. The use of a DPP-4 inhibitor could be safe, although the cases presented herein enable us to inform the scientific community to some of the potential adverse effects of the use of DPP-4 inhibitors in select populations.

Effects of -1018G>A polymorphism of HRH2 (rs2607474) on the severity of gastric mucosal atrophy.

BACKGROUND AND AIM: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy. METHODS: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR-SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score higher or equal to 2 and metaplasia score higher or equal to1 were classified into the severe atrophic gastritis group (SA group). RESULTS: The -1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier. CONCLUSIONS: Our results suggest that HRH2 -1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects.

Genetic polymorphism of pri-microRNA 325, targeting SLC6A4 3'-UTR, is closely associated with the risk of functional dyspepsia in Japan.

BACKGROUND: The role of genetics in the susceptibility to functional dyspepsia (FD) remains unclear. We attempted to clarify the association between FD and polymorphisms in SLC6A4. In addition, rs5981521 (C>T) in the pri-microRNA 325 (pri-miR-325) coding region was also investigated. METHODS: The study was performed in 395 subjects (172 with no upper abdominal symptoms and 223 with FD, including medication-resistant FD). We employed a polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method to detect gene polymorphisms. RESULTS: Neither SLC6A4 -185 A>C nor *463 G>T was associated with susceptibility to FD. The number of rs5981521 T alleles was significantly correlated with an increased risk for FD (odds ratio [OR] 1.45, 95 % confidence interval [CI] 1.05-1.98; p = 0.022) and the TT homozygote was more closely associated with the risk for FD (OR 3.01, 95 % CI 1.41-6.42; p = 0.0043). The TT homozygote also had significantly increased risks for both the epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) subtypes of FD (OR 3.04, 95 % CI 1.25-7.42; p = 0.014 and OR 3.05, 95 % CI 1.14-8.13; p = 0.026, respectively). In addition, Helicobacter pylori-negative TT homozygotes had a greater risk for FD (OR 8.37, 95 % CI 1.78-39.5; p = 0.0072). In subjects with the SLC6A4 5'-untranslated region (UTR) wild homozygote, the number of rs5981521 T alleles was significantly correlated to an increased risk for FD (OR 1.45, 95 % CI 1.03-2.04, p = 0.033). Of note, in subjects who were SLC6A4 3'-UTR mutant carriers, the number of rs5981521 T alleles was also significantly correlated with an increased risk for FD (OR 2.07, 95 % CI 1.08-3.98; p = 0.029). CONCLUSIONS: Our results suggest that the genetic polymorphism pri-miR-325 is associated with FD and interacts with SLC6A4 polymorphisms in increasing susceptibility to FD in Japanese.