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Background/Aims There has been major progress in our understanding of the irritable bowel syndrome (IBS), and novel treatment classes have emerged. The Rome IV guidelines were published in 2016 and together with the growing body of Asian data on IBS, we felt it is timely to update the Asian IBS Consensus. Methods Key opinion leaders from Asian countries were organized into 4 teams to review 4 themes: symptoms and epidemiology, pathophysiology, diagnosis and investigations, and lifestyle modifications and treatments. The consensus development process was carried out by using a modified Delphi method. Results Thirty-seven statements were developed. Asian data substantiate the current global viewpoint that IBS is a disorder of gut-brain interaction. Socio-cultural and environmental factors in Asia appear to influence the greater overlap between IBS and upper gastrointestinal symptoms. New classes of treatments comprising low fermentable oligo-, di-, monosacharides, and polyols diet, probiotics, non-absorbable antibiotics, and secretagogues have good evidence base for their efficacy. Conclusions Our consensus is that all patients with functional gastrointestinal disorders should be evaluated comprehensively with a view to holistic management. Physicians should be encouraged to take a positive attitude to the treatment outcomes for IBS patients. (J Neurogastroenterol Motil 2019;25:343-362)

Generally, carbohydrate antigen 19-9 (CA 19-9) is not useful for screening pancreatic cancer in the asymptomatic general population. This study aimed to evaluate the utility of CA 19-9 level as a screening indicator of pancreatic cancer in asymptomatic patients with new-onset diabetes.We retrospectively reviewed the medical records of patients who visited our health promotion center for health check-ups without cancer related symptoms from January 2005 to January 2014, and were newly diagnosed with diabetes mellitus (DM) within 2 years before their visit.Of the 5111 asymptomatic patients with new-onset DM (2 years) selected for analyses, 87 (1.7%) eventually developed pancreatic cancer after the health check-up. In the subgroup of 322 patients with high total bilirubin levels (1.7 mg/dL) at the screening time, 42 (73.7%) of 57 patients with high CA 19-9 levels (37 IU/mL) had been diagnosed as pancreatic cancer during follow-up period and 12 (4.5%) of 265 patients with normal CA 19-9 levels had finally developed pancreatic cancer (OR = 16.3). In the subgroup of 4789 patients with normal bilirubin levels, pancreatic cancer had been detected in 20 (3.8%) of 522 patients with high CA 19-9 level, while only 13 (0.3%) in 4267 patients with normal CA 19-9 levels (OR = 12.6), respectively.CA 19-9 levels after a diagnosis of new-onset DM could be a useful biomarker of pancreatic cancer, especially in patients with high serum bilirubin.

Background and Aim Information on real world treatment experiences of patients with functional bowel disorders is lacking from Asia. This study aimed to describe the medication exposure and treatment satisfaction of patients presenting to gastroenterology clinics across a sampling of Asian cities. Methods From March 2011 to October 2013, adult patients presenting to hospital-based gastroenterology outpatient clinics in 11 cities across Asia, who fulfilled screening criteria for any functional gastrointestinal disorder, were asked to complete a validated culturally adapted translation of the Rome III diagnostic questionnaire, a checklist of medications received in the preceding 3 months and questions on treatment satisfaction. Results A total of 1376 patients (female 755, male 621, 41.36 ± 13.25 years) comprising irritable bowel (621, 45.1%), unspecified functional bowel disorder (372, 27.8%), functional constipation (202, 14.7%), functional bloating (144, 10.5%), and functional diarrhea (56, 4.1%) completed the study. Of 1105 patients with a previous consultation, 509 (46.1%) were dissatisfied with their treatment, with ineffective treatment being the commonest reason. Satisfaction with previous consultation was lowest by diagnosis for functional constipation (29.2%), and the most bothersome symptom was straining (37.5%). Of 1046 patients who had taken medications for their gastrointestinal symptoms in the last 3 months, 793 (75.8%) had received two or more drugs. For irritable bowel syndrome patients, treatment with proton pump inhibitors and antispasmodics was recorded in 57% and 31%, with overlapping epigastric pain and heartburn predicting proton pump inhibitors use. Conclusions More attention should be given to treatment gaps with regards to possible under-treatment with antispasmodics in irritable bowel syndrome and to critically evaluating the efficacy of constipation management.

Background/Aims Several specific foods are known to precipitate gastroesophageal reflux disease (GERD) symptoms and GERD patients are usually advised to avoid such foods. However, foods consumed daily are quite variable according to regions, cultures, etc. This study was done to elucidate the food items which induce typical GERD symptoms in Korean patients. Methods One hundred and twenty-six Korean patients with weekly typical GERD symptoms were asked to mark all food items that induced typical GERD symptoms from a list containing 152 typical foods consumed daily in Korea. All patients underwent upper gastrointestinal endoscopy followed by 24-hour ambulatory esophageal pH monitoring. The definition of “GERD” was if either of the 2 studies revealed evidence of GERD, and “possible GERD” if both studies were negative. Results One hundred and twenty-six cases (51 GERD and 75 possible GERD) were enrolled. In 19 (37.3%) of 51 GERD cases and in 17 (22.7%) of 75 possible GERD cases, foods inducing typical GERD symptoms were identified. In the GERD group (n = 19), frequent symptom-inducers were hot spicy stews, rice cakes, ramen noodles, fried foods, and topokki. In the possible GERD group (n = 17), frequent symptom-inducers were hot spicy stews, fried foods, doughnuts, breads, ramen noodles, coffee, pizza, topokki, rice cakes, champon noodles, and hotdogs. Conclusions In one-third of GERD patients, foods inducing typical symptoms were identified. Hot spicy stews, rice cakes, ramen noodles, fried foods, and topokki were the foods frequently inducing typical symptoms in Korea. The list of foods frequently inducing typical GERD symptoms needs to be modified based on their own local experiences. (J Neurogastroenterol Motil 2017;23:363-369)

ObjectiveFunctional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID.Design1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters.ResultsNine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence).ConclusionWe found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.

Backgrounds and Aims: Biliary intraepithelial neoplasia (BilIN) is a precursor of cholangiocarcinoma (CC) and it has been associated with several chronic inflammatory conditions. This study aimed to elucidate the prevalence of BilIN in CC and its clinicopathological significance. Methods: Medical records of 193 patients with histologically confirmed CC were analyzed. We reviewed the pathology findings of 48 patients who underwent curative surgery for CC. Results: Of the 48 patients analyzed, 34 and 14 patients had extrahepatic and intrahepatic CC respectively. BilIN was detected in 28 patients (58%) and showed a significantly higher prevalence in extrahepatic CC (75%) than in intrahepatic CC (21%; p < 0.001). In the subgroup of 34 patients with extrahepatic CC, 25 and 9 patients were BilIN positive and negative respectively. Poor differentiation and T3 stage were significantly more common in the BilIN-negative group than in the BilIN-positive group (p < 0.05). The expression of MUC5AC, p53, and loss of Smad4 showed no difference between BilIN-positive CC and in BilIN-negative CC, but the Ki-67 expression was significantly higher (p < 0.05). Conclusion: BilIN-positive CC showed less invasiveness than negative cases. The Ki-67 expression was significantly higher in BilIN-positive CC.

Although both corticosteroids and pentoxifylline are currently recommended drugs for the treatment of patients with severe alcoholic hepatitis, their effectiveness in reducing mortality remains unclear. In this systematic review, we aimed to evaluate the therapeutic and adverse effects of corticosteroids, pentoxifylline, and combination by using Cochrane methodology and therefore determine optimal treatment for severe alcoholic hepatitis.We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from their inauguration until October 2015. Combinations of the following keywords and controlled vocabularies were searched: alcoholic hepatitis, corticosteroid, and pentoxifylline.A total of 2639 patients from 25 studies were included. The treatment groups did not differ significantly in terms of overall mortality. Analysis of 1-month mortality revealed corticosteroid monotherapy reduced mortality compared with placebo (OR=0.58; 95% CI, 0.34-0.98; P=0.04), but pentoxifylline monotherapy did not. The mortality with dual therapy was similar to corticosteroid monotherapy (OR=0.91; 95% CI, 0.62-1.34; P=0.63). However, dual therapy decreased the incidences of hepatorenal syndrome or acute kidney injury (OR=0.47; 95% CI, 0.26-0.86; P=0.01) and the infection risk (OR=0.63; 95% CI, 0.41-0.97; P=0.04) significantly more than corticosteroid monotherapy did. None of the treatments conferred any medium-term or long-term survival benefits in the present study.Dual therapy was not inferior to corticosteroid monotherapy and could reduce the incidence of hepatorenal syndrome or acute kidney injury and risk of infection. Therefore, dual therapy might be considered in treatment of patients with severe alcoholic hepatitis.

Functional dysphagia and globus are symptoms frequently present in the general population. These are diagnosed after exclusion of other structural or major motility disorders of the esophagus. Underlying pathophysiology of these two conditions are still incompletely understood. At present time, effective management plan for both conditions is not satisfactory because of inadequate clinical research or experience. In this chapter, the currently available understanding on the diagnosis and clinical approach of these two conditions is reviewed. Structural causes need to be excluded using endoscopy with or without biopsy and barium swallow. Esophageal manometry and pH or pH-impedance monitoring are useful to demonstrate major esophageal motility disorders or pathologic gastroesophageal reflux. Laryngoscopy can be useful to exclude structural lesions in patients complaining of globus sensation. If the above investigations are not available, therapeutic trial with proton pump inhibitors can be tried. Reassurance and some supportive measures might be helpful in these patients.

Background and aim The aim of this study was to compare HOXB7 expression level between gastric cancer and non-cancerous gastric tissues. Additionally, the functional effects of HOXB7, including its pro-migration or invasion and anti-apoptosis roles, were evaluated in gastric cancer cells. Methods Both gene and protein expression levels of HOXB7 were examined in gastric cancer cell lines, and HOXB7 expression was compared between primary or metastatic gastric cancer tissues and chronic gastritis or intestinal metaplasia tissues. Functional studies included a wound healing assay, a Matrigel invasion assay, and an Annexin-V assay were performed, and Akt/PTEN activity was measured by western blotting. Results Both gene and protein expression levels of HOXB7 could be clearly detected in various gastric cancer cell lines except MKN-28 cell. HOXB7 expression was significantly higher in primary or metastatic gastric cancer tissues than in chronic gastritis or intestinal metaplasia tissues. HOXB7 knockdown led to inhibition of cell invasion and migration, had an apoptotic effect, downregulated phosphor-Akt, and upregulated PTEN in AGS and SNU-638 cells. Reinforced expression of HOXB7 caused the opposite effects in MKN-28 and MKN-45 cells. Conclusion Our study suggests that HOXB7 has an oncogenic role in gastric cancer, which might be related to the modulation of Akt/PTEN activity to induce cell migration/invasion and anti-apoptotic effects.

OBJECTIVES We evaluated the value of carbohydrate antigen 19-9 (CA 19-9) as a pancreatic cancer (PC) screening tool in an asymptomatic new-onset diabetic patients. METHODS Medical records of asymptomatic patients newly diagnosed with diabetes mellitus (DM) were reviewed retrospectively at our hospital from January 2004 to January 2013. RESULTS In total, 2363 asymptomatic diabetic patients with CA 19-9 measurements were enrolled. Of them, 68 (2.9%) were diagnosed with PC. In the 1719 patients who had CA 19-9 measured within 1 year after the DM diagnosis, a total of 51 (3.0 %) patients developed PC and the odds ratio (OR) of PC according to higher CA 19-9 than normal upper limit, 37 IU/mL was 5.57 (P < 0.001). In 248 patients checked CA 19-9 between 1 and 2 years after DM diagnosis, PC was detected in 9 (3.6%) cases and OR of high CA 19-9 was 4.51 (P = 0.019). However, beyond 2 years, the OR for PC showed no statistical significance. The patients with high CA 19-9 levels tended to have more advanced-stage disease. CONCLUSIONS Early check-up of CA 19-9 could be a useful marker for screening for PC in asymptomatic patients with new-onset DM in the first 2 years.

Melanocytic nevus is the benign proliferation of melanocytes. The most common location of melanocytic nevus is the skin of the extremities; however, there are few case reports of melanocytic nevus at the rectal mucosa. No prior case of malignant melanoma from melanocytic nevus at the rectal mucosa has been reported; therefore, it is unclear whether resection should be performed or close observation is sufficient. However, the potential malignant transformation of melanocytic nevus should be considered, including melanocytic nevus on the rectum. Melanocytic nevus of the skin can be removed by surgical excision; however, due to rare incidence on the mucosa of the gastrointestinal tract, the optimal treatment for rectal melanocytic nevus remains controversial. Here, we report the first case of melanocytic nevus on the rectal mucosa that was removed by endoscopic submucosal dissection. This case report provides useful information about the optimal management of rectal melanocytic nevus.

Background and Aims Endoscopic resection has been performed for treatment of GI stromal tumors (GISTs) in the upper GI tract. However, the therapeutic roles of the endoscopic procedure remain debatable. We aimed in this retrospective study to evaluate the feasibility and long-term follow-up results of endoscopic resection of GISTs in the upper GI tract, compared with surgery. Methods Between March 2005 and August 2014, 130 cases of GIST in the upper GI tract were resected. We compared baseline characteristics and clinical outcomes including R0 resection rate and recurrence rate between the endoscopy group (n = 90) and surgery group (n = 40). Results The most common location of GIST was the stomach body in the endoscopy group, whereas it was the duodenum in the surgery group ( P = .001). Tumor size was significantly smaller (2.3 vs 5.1 cm; P P P P = .001), and 50.0% of resected tumors belonged to a very low–risk group in the endoscopy group, whereas 35.0% and 30.0% belonged to low-risk and high-risk in the surgery group ( P = .001). However, during 45.5 months of follow-up, the recurrence rate was not significantly different between the 2 groups (2.2% vs 5.0%; P = .586). Conclusions Endoscopic resection might be an alternative therapeutic modality for GISTs in the upper GI tract in selective cases.

AIMS Pancreatic cystic neoplasms (PCN) with malignant potential are thought to be less aggressive than ordinary ductal adenocarcinoma, even in the setting of malignant transformation. Therefore, deciding whether or not to carry out surgery is very difficult, especially in elderly and asymptomatic patients, because of the high risk of perioperative morbidities. The aim of the present study was to examine clinical outcomes of PCN patients aged 65 years or older. METHODS This retrospective analysis included patients with incidentally detected PCN with follow-up durations >1 year. Patients diagnosed with obvious simple cysts, pseudocysts or pancreatic cancer and patients with a history of pancreatic disease were excluded from the study. RESULTS The present study included 201 patients (older group 104 patients ≥65 years; younger group 97 patients

A recent study reported that plumbagin downregulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various antitumor effects in multiple myeloma cells. We aimed in this in vitro study to demonstrate the inhibition of JAK2/STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in the MKN-28 gastric cancer cell line. We performed western blot analysis to measure SHP1, phosphor-JAK2/STAT3 level, and observed that plumbagin induced SHP1 expression and simultaneously downregulated phosphor-JAK2/STAT3 in MKN-28 cells, with negative SHP1 expression. This effect was consistent when JAK2/STAT3 signaling was activated by interleukin-6 (IL-6), and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor. Furthermore, plumbagin significantly reduced gene expression of cyclin D1, vascular endothelial growth factor (VEGF)-1, Bcl-xL, survivin and matrix metalloproteinase-9 (MMP-9), known target products of STAT3 activation in gastric carcinogenesis by reverse transcription-polymerase chain reaction (RT-PCR). Several functional studies such as water soluble tetrazolium salt-1 (WST-1) assay, wound closure assay, Matrigel invasion assay and Annexin V assay were also performed, and we validated the functional effect of plumbagin for inhibition of cell proliferation, migration and invasion, and induction of apoptosis. Collectively, our findings suggest that plumbagin is a potential regulator of cellular growth, migration, invasion and apoptosis by inhibiting both constitutive and inducible STAT3 activity through induction of SHP1 in gastric cancer cells.

Background/Aims Prothrombin induced by vitamin K deficiency or antagonist II (PIVKA-II) is a widely used diagnostic marker for hepatocellular carcinoma (HCC). We evaluated the correlation between alcoholic liver disease (ALD) and serum PIVKA-II levels in chronic liver disease (CLD) patients. Methods We retrospectively reviewed the medical records of 2,528 CLD patients without HCC. Among these patients, 76 exhibited serum high PIVKA-II levels of >125 mAU/mL (group 1). We categorized 76 control patients matched by age, sex, and the presence of liver cirrhosis from the remaining patients who were negative for serum PIVKA-II (group 2). Results Group 1 revealed increased antibiotic usage (23.7% vs 2.6%, p

Background/Aims The development-processes by regional socio-cultural adaptation of an Enhanced Asian Rome III questionnaire (EAR3Q), a cultural adaptation of the Rome III diagnostic questionnaire (R3DQ), and its translation-validation in Asian languages are presented. As English is not the first language for most Asians, translation-validation of EAR3Q is essential. Hence, we aimed to culturally adapt the R3DQ to develop EAR3Q and linguistically validate it to show that the EAR3Q is able to allocate diagnosis according to Rome III criteria. Methods After EAR3Q was developed by Asian experts by consensus, it was translated into Chinese, Hindi-Telugu, Indonesian, Korean, and Thai, following Rome Foundation guidelines; these were then validated on native subjects (healthy [n = 60], and patients with irritable bowel syndrome [n = 59], functional dyspepsia [n = 53] and functional constipation [n = 61]) diagnosed by clinicians using Rome III criteria, negative alarm features and investigations. Results Experts noted words for constipation, bloating, fullness and heartburn, posed difficulty. The English back-translated questionnaires demonstrated concordance with the original EAR3Q. Sensitivity and specificity of the questionnaires were high enough to diagnose respective functional gastrointestinal disorders (gold standard: clinical diagnoses) in most except Korean and Indonesian languages. Questionnaires often uncovered overlapping functional gastrointestinal disorders. Test-retest agreement (kappa) values of the translated questionnaires were high (0.700–1.000) except in Korean (0.300–0.500) and Indonesian (0.100–0.400) languages at the initial and 2-week follow-up visit. Conclusions Though Chinese, Hindi and Telugu translations were performed well, Korean and Indonesian versions were not. Questionnaires often uncovered overlapping FGIDs, which were quite common.

Background/aims The use of self-expandable metallic stents (SEMS) is an established palliative treatment for malignant stenosis in the gastrointestinal tract; therefore, its application to benign stenosis is expected to be beneficial because of the more gradual and sustained dilatation in the stenotic portion. We aimed in this prospective observational study to evaluate the efficacy and safety of temporary SEMS placement in benign pyloric stenosis. Methods Twenty-two patients with benign stenosis of the prepylorus, pylorus, and duodenal bulb were enrolled and underwent SEMS placement. We assessed symptom improvement, defined as an increase of at least 1 degree in the gastric-outlet-obstruction scoring system after stent insertion. Results No major complications were observed during the procedures. After stent placement, early symptom improvement was achieved in 18 of 22 patients (81.8%). During the follow-up period (mean 10.2 months), the stents remained in place successfully for 6 to 8 weeks in seven patients (31.8%). Among the 15 patients (62.5%) with stent migration, seven (46.6%) showed continued symptomatic improvement without recurrence of obstructive symptoms. Conclusions Despite the symptomatic improvement, temporary SEMS placement is premature as an effective therapeutic tool for benign pyloric stenosis unless a novel stent is developed to prevent migration.

Background/Aims: To investigate the incidence of cholangiocarcinoma in patients with hepatolithiasis with or without previous resection of liver. Methods: From 2002 to 2009, we retrospectively reviewed 117 patients who were diagnosed and treated for hepatolithiasis in Korea University Guro Hospital. Among the 117 patients, 55 patients who were lost during follow-up were excluded, and 62 patients were eligible for analysis. The hepatic resection group (n=25) included patients who underwent left hemihepatectomy (n=2); left lateral segmentectomy (n=10); left lobectomy (n=9); right lobectomy (n=3); or wedge resection (n=1). The nonhepatic resection group (n=37) included transhepatic cholangiographic lithotomy and endoscopic retrograde cholangiopancreatography-treated patients. The mean follow-up period was 47 months. Results: The incidence of cholangiocarcinoma while patients were followed for hepatolithiasis was 12.9% (8/62) (hepatic resection group, three cases [12%] vs nonhepatic resection group, five cases [13.5%]; p=1.000). The mean follow-up period was 53 months (47±11 months) until the diagnosis of cholangiocarcinoma. Conclusions: There was no difference in the incidence of cholangiocarcinoma according to previous liver resections. Patients with hepatolithiasis should be carefully followed up for detection of cholangiocarcinoma even after a previous liver resection. (Gut Liver 2013;7:475479)

Background/Aims Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. Similar to asthma, EoE can induce irreversible structural changes in the esophagus as a result of chronic and persistent eosinophilic inflammation. The aim of this study was to analyse changes in symptoms, eosinophil counts and endoscopic findings after treatment. Methods Nine patients with EoE (6 men and 3 women; mean age, 36.44 years) were diagnosed with EoE based on typical symptoms, endoscopic abnormalities and infiltration of the esophageal epithelium with ≥ 15 eosinophils/high-power field. The average endoscopic follow-up period was 10 months, ranging from 1 to 25 months. Symptoms and endoscopic and pathological findings at initial observation and follow-up were evaluated. Results Seven of the 9 patients had dysphagia symptoms, which improved in 4 of 6 patients who were treated with proton pump inhibitor. Two patients were unresponsive to proton pump inhibitor and another 2 patients were treated with corticosteroid, which led to symptomatic relief. In 8 patients, esophageal eosinophilia was improved histologically at follow-up after treatment. Six of the 9 patients had typical endoscopic findings of EoE at initial examination. Despite treatment, these findings remained in 5 of the 6 patients at follow-up endoscopy. Conclusions After treatment, the symptoms and eosinophil counts were temporarily improved, but the endoscopic findings of EoE were generally not improved. This indicates that deformity of esophageal structure due to eosinophilic inflammation might be irreversible despite proper management.

Recent studies revealed that long-term intake of proton pump inhibitor (PPI) increases the risk of vertebral or hip fracture; however, the exact mechanism for this is not known. To evaluate the effect of long-term PPI therapy on bone turnover, we analyzed the signaling pathway involved in osteoclast differentiation and bone resorption/formation markers using ovariectomized rats. Six-week-old Sprague-Dawley (S-D) rats were ovariectomized, and two weeks later they were divided into four groups (group A, normal diet + placebo; group B, low calcium diet + placebo; group C, normal diet + PPI; and group D, low calcium diet + PPI). Omeprazole, at a concentration of 30 mg/kg, was administered orally for eight weeks and the rats were sacrificed when they were 16 weeks old. The relative expression levels of the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, c-Fos, nuclear factor of activated T cells c1 (NFATc1) and osteocalcin in femoral bone marrow cells were compared, and serum C-terminal cross-linking telopeptide of type I (CTX-1) levels were determined. The relative ratio of RANKL/OPG was increased in group D, and gene expression levels of c-Fos and NFATc1 were upregulated in groups B and D, which are involved in differentiation and activation of osteoclasts. Furthermore, expression levels of osteocalcin, a bone formation marker, were decreased and levels of serum CTX-1, a bone resorption marker, were increased in group D. Taken together, a low calcium diet and PPI administration are thought to collaborate in order to alter osteoclast activity and bone resorption signaling.

Subepithepial tumors (SETs) in esophagus are mostly benign and causes no specific symptoms, however, resection should be considered in case of large tumors leading to troublesome symptoms such as dysphagia or rapidly growing tumor. Endoscopioc submucosal dissection (ESD) has been performed for therapeutic resection of esophageal epithepial lesions or even SETs, however, post-procedureal stricture is a major concern. Recently, a novel endoscopic approach using submucosal space, namely submucosal tunneling, is considered as a good alternative option for endoscopic resection of esophageal lesions. This approach can preserve mucosal integrity and use it as a coverage flap, which prevents serious late complications such as stricture in esophagus. Here, we report two cases of large esophageal SETswhich were endoscopically resected by two different approaches: the first one by conventional ESD, and the second one by submucosal tunneling approach. The former eventually resulted in significant stricture at esophagus, thus repeatitive balloon dilation was needed. However, the latter had no serious late complications including stricture. This case report clealy provides the advantage of submucosal tunneling over conventional ESD in the treatment of esophageal SETs, and the promising therapeutic value of this new approach is expected.

Information on real world treatment experiences of patients with functional bowel disorders is lacking from Asia. This study aimed to describe the medication exposure and treatment satisfaction of patients presenting to gastroenterology clinics across a sampling of Asian cities.From March 2011 to October 2013, adult patients presenting to hospital-based gastroenterology outpatient clinics in 11 cities across Asia, who fulfilled screening criteria for any functional gastrointestinal disorder, were asked to complete a validated culturally adapted translation of the Rome III diagnostic questionnaire, a checklist of medications received in the preceding 3 months and questions on treatment satisfaction.A total of 1376 patients (female 755, male 621, 41.36 ± 13.25 years) comprising irritable bowel (621, 45.1%), unspecified functional bowel disorder (372, 27.8%), functional constipation (202, 14.7%), functional bloating (144, 10.5%), and functional diarrhea (56, 4.1%) completed the study. Of 1105 patients with a previous consultation, 509 (46.1%) were dissatisfied with their treatment, with ineffective treatment being the commonest reason. Satisfaction with previous consultation was lowest by diagnosis for functional constipation (29.2%), and the most bothersome symptom was straining (37.5%). Of 1046 patients who had taken medications for their gastrointestinal symptoms in the last 3 months, 793 (75.8%) had received two or more drugs. For irritable bowel syndrome patients, treatment with proton pump inhibitors and antispasmodics was recorded in 57% and 31%, with overlapping epigastric pain and heartburn predicting proton pump inhibitors use.More attention should be given to treatment gaps with regards to possible under-treatment with antispasmodics in irritable bowel syndrome and to critically evaluating the efficacy of constipation management.

S-isomer (S) pantoprazole is known to be more effective and less dependent on cytochrome 2C19 than R-isomer (R)-pantoprazole.The purpose of this study was to compare the efficacy and safety of S-pantoprazole 20 mg versus pantoprazole 40 mg for treatment of reflux esophagitis.This multi-center, double-blind, randomized trial enrolled patients with endoscopically documented reflux esophagitis. Patients were assigned to receive either 20 mg S-pantoprazole or 40 mg pantoprazole once daily for 4 weeks. Endoscopy and symptoms were assessed after 4 weeks of treatment. In patients whose reflux esophagitis was not resolved at 4 weeks, treatment was extended to 8 weeks and symptoms were reassessed. Heartburn, chest pain, acid regurgitation, globus, and overall symptoms were rated. The primary efficacy endpoint was healing of esophagitis, and secondary endpoints were symptomatic and endoscopic improvement.Sixty-seven patients in the S-pantoprazole group (52 male, mean age 51 years) and 62 in the pantoprazole group (61 male, mean age 50 years) were analyzed per protocol. The healing rate of reflux esophagitis was 85 % at 4 weeks and 94 % at 8 weeks in the S-pantoprazole group, which did not differ from those in the pantoprazole group (84 and 97 %, respectively). After treatment, individual and overall gastroesophageal reflux disease (GERD) symptoms and esophagitis improved compared with baseline inflammation in both groups. Intergroup differences in symptoms and endoscopic healing were not significant.The efficacy and safety of 20 mg S-pantoprazole were comparable to those of 40 mg pantoprazole for treatment of reflux esophagitis and symptomatic improvement of GERD.

OBJECTIVE: This study was aimed to evaluate the prevalence of eosinophilic esophagitis (EoE) among patients with esophageal or upper gastrointestinal (UGI) symptoms. METHODS: Patients with esophageal or UGI symptoms including dysphagia food impaction, acid regurgitation, heartburn, chest pain, epigastric pain, nausea and/or vomiting were prospectively collected. The enrolled patients responded to a symptomatic questionnaire and underwent an esophagogastroduodenoscopy and esophageal biopsies. Supportive endoscopic findings of EoE (ring-like appearance, liner furrows, whitish papules, shearing or friability) were recorded. EoE was diagnosed if patients had chronic UGI or esophageal symptoms, the esophageal biopsy showed ≥15 eosinophils/high-power field and were unresponsive to 2–3 weeks of proton pump inhibitors. RESULTS: A total of 122 patients were enrolled and supportive endoscopic findings were found in 31 (25.4%) patients [whitish papules: 19 (15.6%), ring-like appearance: 8 (6.6%), linear furrows: 5 (4.1%)]. One patient had a simultaneous ring-like appearance and linear furrows. EoE was diagnosed in 8 (6.6%) patients and supportive endoscopic findings and past history of gastroesophageal reflux disease, allergic rhinitis and atopic dermatitis were more common in EoE positive than EoE negative patients. The diagnostic yield of endoscopic findings was 40.0% (2/5) in linear furrows, 25.0% (2/8) in ring-like appearance and 15.8% (3/19) in whitish papules. CONCLUSION: Prevalence of EoE among patients with esophageal or UGI symptoms was 6.6%. Linear furrows and ring-like appearance had a relatively high diagnostic value.

Background/Aims Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared to the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia. Methods Consensus team members were selected from Asian experts and consensus development was carried out using a modified Delphi method. Consensus teams collected published papers on functional dyspepsia especially from Asia and developed candidate consensus statements based on the generated clinical questions. At the first face-to-face meeting, each statement was reviewed and e-mail voting was done twice. At the second face-to-face meeting, final voting on each statement was done using keypad voting system. A grade of evidence and a strength of recommendation were applied to each statement according to the method of the GRADE Working Group. Results Twenty-nine consensus statements were finalized, including 7 for definition and diagnosis, 5 for epidemiology, 9 for pathophysiology and 8 for management. Algorithms for diagnosis and management of functional dyspepsia were added. Conclusions This consensus developed by Asian experts shows distinctive features of functional dyspepsia in Asia and will provide a guide to the diagnosis and management of functional dyspepsia for Asian primary care physicians.

Background and Aim: Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared with the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia. Methods: Consensus team members were selected from Asian experts and consensus development was carried out by using a modified Delphi method. Consensus teams collected published papers on functional dyspepsia especially from Asia and developed candidate consensus statements based on the generated clinical questions. At the first face-to-face meeting, each statement was reviewed and e-mail voting was done twice. At the second face-to-face meeting, final voting on each statement was done using a keypad voting system. A grade of evidence and strength of recommendation were applied to each statement according to the method of the GRADE Working Group. Results: Twenty-nine consensus statements were finalized, including seven for definition and diagnosis, five for epidemiology, nine for pathophysiology, and eight for management. Algorithms for diagnosis and management of functional dyspepsia were added. Conclusions: This consensus developed by Asian experts shows distinctive features of functional dyspepsia in Asia and will provide a guide to the diagnosis and management of functional dyspepsia for Asian primary care physicians.

The relationship between hiatal hernias and gastroesophageal reflux disease (GERD) has been greatly debated over the past decades, with the importance of hiatal hernias first being overemphasized and then later being nearly neglected. It is now understood that both the anatomical (hiatal hernia) and the physiological (lower esophageal sphincter) features of the gastroesophageal junction play important, but independent, roles in the pathogenesis of GERD, constituting the widely accepted "two-sphincter hypothesis." The gastroesophageal junction is an anatomically complex area with an inherent antireflux barrier function. However, the gastroesophageal junction becomes incompetent and esophageal acid clearance is compromised in patients with hiatal hernia, which facilitates the development of GERD. Of the different types of hiatal hernias (types I, II, III, and IV), type I (sliding) hiatal hernias are closely associated with GERD. Because GERD may lead to reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma, a better understanding of this association is warranted. Hiatal hernias can be diagnosed radiographically, endoscopically or manometrically, with each modality having its own limitations, especially in the diagnosis of hiatal hernias less than 2 cm in length. In the future, high resolution manometry should be a promising method for accurately assessing the association between hiatal hernias and GERD. The treatment of a hiatal hernia is similar to the management of GERD and should be reserved for those with symptoms attributable to this condition. Surgery should be considered for those patients with refractory symptoms and for those who develop complications, such as recurrent bleeding, ulcerations or strictures.

Background The 5-HT3 receptor antagonists are known to be effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS), but not widely used yet. The aim of this study was to compare the efficacy and safety of ramosetron, a 5-HT3 receptor antagonist, and mebeverine in male patients with IBS with diarrhea (IBS-D). Methods This study was performed in a multicenter, randomized, open-label design. Data of 343 male patients with IBS-D who were randomized to either a 4-week treatment of ramosetron 5 μg once daily or a 4-week treatment of mebeverine 135 mg three times daily were analyzed by the intent-to-treat analysis. The primary efficacy parameter was the proportion of patients with adequate relief of IBS symptoms at the last week of treatment. The secondary endpoints were changes in each symptom score and the safety profiles. Key Results The responder rates for global IBS symptoms, abdominal pain/discomfort and abnormal bowel habits in the ramosetron and mebeverine groups significantly increased during the treatment period. The severity scores of abdominal pain/discomfort and urgency, the stool form score, and the stool frequency in both treatment arms were significantly reduced, compared with the baselines. There were no significant differences in the responder rates (37%vs 38% on ITT analysis) and adverse event profiles between the ramosetron and mebeverine groups. Neither severe constipation nor ischemic colitis was reported by ramosetron-treated patients. Conclusions & Inferences Ramosetron 5 μg once daily is as effective as mebeverine three times daily in male patients with IBS-D.

Background/Aims Patients with type II diabetes mellitus (DM) were known to have higher prevalence of gastroesophageal reflux disease (GERD). Recent studies have shown that neuropathy has positive role on the development of GERD in type II DM, although its pathogenesis has not been fully understood yet. The aim of this study was to investigate whether neuropathy really contribute to the development of GERD and typical GERD symptoms in patients with type II DM in Korea. Methods One hundred and nineteen patients with type II DM who had given informed consents were enrolled. All patients underwent electromyography to check the presence of peripheral neuropathy, face-to-face interview to evaluate their typical GERD symptoms and esophagogastroduodenoscopy to look for the presence of erosive esophagitis. Ninety-five patients were finally included for this study and they were divided according to the presence or absence of the peripheral neuropathy. Results The mean age of 95 patients was 59.3 ± 9.1 years and the mean disease duration of DM was 9.3 ± 5.9 years. Typical GERD symptoms were similarly found in both groups with and without peripheral neuropathy (23.6% vs 22.8%, P = 0.921). Erosive esophagitis was more prevalent in patients with neuropathy than in those without neuropathy (31.5% vs 10.5%, P = 0.022). Conclusions In patients with type II DM, peripheral neuropathy is an independent risk factor for the erosive esophagitis. However, peripheral neuropathy did not contribute to the presence of the typical GERD symptoms.

Irritable bowel syndrome (IBS) is a complex disorder characterized by abdominal symptoms including chronic abdominal pain or discomfort and altered bowel habits. The etiology of IBS is multifactorial, as abnormal gut motility, visceral hypersensitivity, disturbed neural function of the brain-gut axis and an abnormal autonomic nervous system are all implicated in disease progression. Based on recent experimental and clinical studies, it has been suggested that additional etiological factors including low-grade inflammation, altered gut microbiota and alteration in the gut immune system play important roles in the pathogenesis of IBS. Therefore, therapeutic restoration of altered intestinal microbiota may be an ideal treatment for IBS. Probiotics are live organisms that are believed to cause no harm and result in health benefits for the host. Clinical efficacy of probiotics has been shown in the treatment or prevention of some gastrointestinal inflammation-associated disorders including traveler's diarrhea, antibiotics-associated diarrhea, pouchitis of the restorative ileal pouch and necrotizing enterocolitis. The molecular mechanisms, as cause of IBS pathogenesis, affected by altered gut microbiota and gut inflammation-immunity are reviewed. The effect of probiotics on the gut inflammation-immune systems and the results from clinical trials of probiotics for the treatment of IBS are also summarized.

Invasive gastric Candida infection in patient with co-morbidity can cause stenotic change if it is developed at anatomically narrowing portion, such as distal antrum, pylorus, or duodenal bulb. However, proper management of benign stenosis by diffuse gastric Candidasis is still under controversy and palliative bypass surgery has several shortcomings because high risk operative group may be included in this case. Palliative placement of self-expandable metallic stent has been settled as a standard management of malignant gastric pyloric obstruction and it is expected to be applied in benign stenotic lesions due to its gradual dilation effect. We described a case of stenosis by diffuse gastric Candidasis at anastomosis of subtotal gastrectomy, which was managed by temporary placement of self-expandable metallic stent.

The long-term clinical course, including the development of hepatocellular carcinoma (HCC) after hepatic B surface antigen (HBsAg) seroclearance is not established. We discovered that the incidence of HCC and the risk factors for HCC in chronic hepatitis B (CHB) patients after HBsAg seroclearance.During 28 years, 96 CHB patients with HBsAg seroclearance were retrospectively reviewed. These patients continued to undergo HCC surveillance. The median follow-up time from initial visit was 166.5 months (range, 7 to 321 mo).The mean age at the initial visit and at the time of seroclearance was 39.2 ± 10.6 years and 46.4 ± 9.9 years, respectively. The mean age at the time of HBsAg seroclearance was significantly lower (P=0.03) in patients with spontaneous HBsAg seroclearance than patients with treatment-associated HBsAg seroclearance. During a median of 56 months (range, 7 to 238 mo) of follow-up after HBsAg seroclearance, 6 (6.5%) patients developed HCC. The mean age at the time of developing HCC was 55.8 ± 10.3 years. On univariate analysis, the evidence of liver cirrhosis from the time of HBsAg seroclearance and age more than 45 years at the time of HBsAg seroclearance were significant risk factors for HCC development. In multivariate analysis, the evidence of liver cirrhosis at HBsAg seroclearance was the only significant risk factor for HCC development.HCC can develop after HBsAg seroclearance in patients with known cirrhosis. Patients who achieved HBsAg seroclearance at older age (45) may have undiagnosed cirrhosis and hence remain at risk for HCC. HCC surveillance should be carried out for both of those patient populations.

Background/Aim: We investigated changes in hepatitis B surface antigen (HBsAg) level and its correlation with clinical outcomes in treatment-naive chronic hepatitis B (CHB) patients undergoing entecavir therapy. Patients and Methods: Among 51 hepatitis B e antigen (HBeAg)-positive treatment-naive CHB patients receiving entecavir for more than 1 year, 28 were enrolled. HBsAg levels were measured at baseline, 6 months, and 12 months after treatment using the Architect HBsAg QT assay (Abbott, dynamic; range: 0.05 to 125,000 IU/mL). Serum alanine aminotransferase, HBeAg, anti-HBe, and hepatitis B virus (HBV) DNA (Cobas Taqman: low detection limit 1.84 log 10 copies/mL) were measured at baseline and every 3 months. The HBsAg response was defined as an HBsAg level that decreased more than 1 log 10 IU/mL from baseline level at 12 months after entecavir treatment. Results: Twenty-eight patients were treated for a median period of 21 months (range: 18 to 24mo). Serum HBsAg level showed a mean of 4.0, 3.7, and 3.6 log 10 IU/mL at pretreatment, 6, and 12 months, respectively, and declined significantly (P < 0.001). Serum HBV DNA level showed a mean of 8.1, 3.1, and 2.4 log 10 copies/mL at pretreatment, 6, and 12 months, respectively, and declined significantly (P < 0.001). The decline in HBsAg level was significantly correlated with that of the HBV DNA level at 12 months from baseline (γ=0.391, P=0.044). Five patients showed an HBsAg response, and cumulative incidence of HBeAg loss at 1 year after entecavir treatment was 80% versus 30% in patients with an HBsAg response and those without, respectively (P=0.034). Conclusions: Monitoring changes in quantitative HBsAg level could be a useful parameter for assessing the response to entecavir therapy in HBeAg-positive treatment-naive CHB patients.

Adefovir dipivoxil (ADV) is commonly used as an antiviral agent in the treatment of chronic hepatitis B or human immunodeficiency virus infection. Nephrotoxicity has been shown to occur at daily dosages of 60-120 mg. Fanconi's syndrome is a generalized dysfunction of the renal proximal tubular cells, which is usually accompanied by complications. Here we report a case of Fanconi's syndrome in a chronic hepatitis B patient who had been treated with a prolonged regimen of ADV at 10 mg/day. A 47-year-old man complained of severe back and chest-wall pain. He had chronic hepatitis B and had been treated with ADV at a daily dose of 10 mg for 38 months. He was hospitalized because of severe bone pain, and laboratory and radiologic findings suggested a diagnosis of Fanconi's syndrome with osteomalacia. After discontinuation of the ADV, he recovered and was discharged from hospital. His laboratory findings had normalized within 2 weeks. This case indicates that Fanconi's syndrome can be acquired by a chronic hepatitis B patient taking ADV at a conventional dosage of 10 mg/day. Therefore, patients treated with long-term ADV should be checked regularly for the occurrence of ADV-induced Fanconi's syndrome.

Background and Aims: Many of the ideas on irritable bowel syndrome (IBS) are derived from studies conducted in Western societies. Their relevance to Asian societies has not been critically examined. Our objectives were to bring to attention important data from Asian studies, articulate the experience and views of our Asian experts, and provide a relevant guide on this poorly understood condition for doctors and scientists working in Asia. Methods: A multinational group of physicians from Asia with special interest in IBS raised statements on IBS pertaining to symptoms, diagnosis, epidemiology, infection, pathophysiology, motility, management, and diet. A modified Delphi approach was employed to present and grade the quality of evidence, and determine the level of agreement. Results: We observed that bloating and symptoms associated with meals were prominent complaints among our IBS patients. In the majority of our countries, we did not observe a female predominance. In some Asian populations, the intestinal transit times in healthy and IBS patients appear to be faster than those reported in the West. High consultation rates were observed, particularly in the more affluent countries. There was only weak evidence to support the perception that psychological distress determines health-care seeking. Dietary factors, in particular, chili consumption and the high prevalence of lactose malabsorption, were perceived to be aggravating factors, but the evidence was weak. Conclusions: This detailed compilation of studies from different parts of Asia, draws attention to Asian patients' experiences of IBS.

Background: Sphingolipids play a very important role in cell membrane formation, signal transduction and plasma lipoprotein metabolism. The first rate-limiting step in the sphingolipid biosynthetic pathway is catalyzed by serine palmitoyltransferase (SPT), and myriocin is a potent and specific inhibitor of SPT. We investigated the impact of SPT inhibition on cholesterol gallstone formation in C57BL/6J mice. Methods: Three groups of eight-week-old C57BL/6J mice were utilized. Each group consisted of 20 mice; group A, B, and C were fed normal chow, lithogenic diet with vehicle, and lithogenic diet with myriocin (0.3mg/kg), respectively, for 6 weeks. All of the mice were sacrificed at the end of the study. The ceramide activities in both the serum and bile were assessed by HPLC analysis and the total cholesterol and triglyceride level in the plasma were assayed by enzymatic methods. Protein expression of ERK, JNK and p38 in the extracted gallbladder were determined by Western-blot analysis. Results: Myriocin treatment caused a significant decrease in the rate of cholesterol gallstone formation. The lithogenic diet mice (group B) showed the highest ceramide activities in both the serum and bile among all the tested groups and there was significant suppression of the ceramide activities in both the serum and bile of the myriocin-treated mice (group C, p

Introduction Hiatal hernia (HH) is a well-known contributory factor of gastroesophageal reflux disease (GERD). However, studies on the clinical significance of simple small HH are lacking. We conducted a study to clarify the clinical significance of short segment HH (SSHH) in relation to GERD. Methods 4,592 consecutive cases (male/female: 2,076/2,516, median age: 49 years) examined with diagnostic esophagogastroduodenoscopy for the first time were enrolled. During the insertion of endoscope, presence of HH was determined and the length was measured, if present. The relationships between gender, age, presence of erosive esophagitis, and columnar-lined esophagus (CLE) and the lengths of HH were analyzed. Results Among 4,592 cases, HH was present in 428 cases (9.3%); SSHH was found in 255 cases (5.6%) and long segment HH (LSHH) in 173 cases (3.8%). HH was more frequent among males and patients with LSHH tended to be older. Erosive esophagitis was observed in 4.8%, 22.0%, and 37.0% of no HH, SSHH, and LSHH group, respectively (p

Endoscopic histoacryl injection (EHI) is reported to be an effective treatment modality for bleeding gastric varices (GVs) but controversial as a prophylactic treatment for non-bleeding GVs because efficacy and safety have yet to be determined. The aim of this study was to evaluate safety and long-term outcomes of prophylactic EHI for non-bleeding GVs with a high risk of bleeding.Thirty-three patients (23 males/10 females, mean age 56.6 years old) with a high risk of gastric variceal bleeding (large tumorous (27), red color sign (14) or rapidly growing in size (1)) underwent EHI. According to the grade of GVs, 25 patients belonged to F3, seven to F2, and one to F1. In terms of the locations of GVs, four patients belonged to type IGV1, 21 to type GOV2, and eight to type GOV1.Obliteration of GVs was achieved in all of the treated patients. Twenty-three patients required one session and ten needed more than two sessions to obliterate their GVs. A mean volume of histoacryl used per session was 2.0 ml. Complications related to the procedure included immediate bleeding in two patients and bacteremia in one patient. The mean duration of follow-up was 12.2 months and eradication of GVs was achieved in 21 (95%) of 22 patients who were followed-up more than 3 months. Index GVs recurred in three of 21 patients (14%) and re-bleeding in index GVs after EHI occurred in two of 26 patients (8%).Prophylactic EHI can be a promising procedure for eradication of non-bleeding GVs in case with a high risk of bleeding.

The purpose of this study is to determine the long-term relapse rate and associated risk factors in HBeAg-positive chronic hepatitis B (CHB) patients who had maintained virologic response (VR) for 1 year after lamivudine (LMV) discontinuation. We enrolled 55 treatment-naive HBeAg-positive CHB patients who achieved and maintained VR until 1 year after LMV discontinuation. Delayed relapse was defined as an elevation of HBV DNA after sustained VR for 1 year. During follow-up, 16 of 55 patients (29%) showed delayed relapse. Beginning 1 year after LMV discontinuation, the cumulative rates of relapse after 2 and 4 years were 29 and 44%, respectively. In multivariate analysis, age (P = 0.029) and >2,000 copies/ml HBV DNA 3 months after LMV discontinuation (P = 0.047) were significant predictors of delayed relapse. Delayed relapse is not infrequent, even in patients who maintain VR for 1 year after LMV discontinuation. Therefore, LMV maintenance therapy might be considered in HBeAg-positive CHB patients who achieve VR.