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Background Fecal immunochemical test (FIT) is worldwide strategy for colorectal cancer screening. The subjects with negative FIT still have the risk of an advanced colorectal neoplasia (AN), including adenoma with villous histology, high grade dysplasia or larger than 1 cm in size, or adenocarcinoma. The study determined the risk factors associated with AN in FIT-negative subjects. Methods The study included asymptomatic subjects who received health checkup colonoscopy and have provided FIT study within 6 months prior to colonoscopy. The risk factors to have AN in cases with negative FIT were analyzed. The numbers of colonoscopies needed to detect one AN were calculated for the subjects with different risk factors. Results There were 1411 cases, 85 with positive FIT and 1326 with negative FIT within 6 months before colonoscopy. In FIT positive and FIT negative cases, 45.9% and 34.6% were found to have colorectal adenoma, while 20.2% and 4.6% had AN, respectively. The univariate and multivariate logistic regression analyses showed that age more than 50 years old, male sex, smoking history and metabolic syndrome were the significant risk factors to have AN in the FIT negative cases. For cases with negative FIT to have these risk factors, the number of colonoscopies needed to detect one AN was 3.7, lower than 4.5 of the cases with positive FIT. Conclusion For the cases with negative FIT, colonoscopy screening should be considered for those male patients over 50 years old, with a history of smoking and metabolic syndrome to detect AN.

Background/Aims Endoscopic ultrasonography (EUS)-guided tissue acquisition requires a long learning curve. We aimed to compare the skill maturation curves between fine needle aspiration (FNA) and biopsy (FNB) for tissue acquisition. Methods The initial 60 procedures performed by the trainee endosonographer (30 FNA vs. 30 FNB) were consecutively enrolled. The difference in procedure performance was compared between the two groups. Learning curves were assessed. Twenty additional cases were subsequently enrolled to assess the consistency of performance in the FNB group. Results The FNB group acquired larger tissue samples (2.35 vs. 0.70 mm2; p

Background/Aims Since the use of dexlansoprazole in Asian subjects with gastroesophageal reflux disease (GERD) has not been adequately characterized, this study was conducted to evaluate the efficacy and safety of dexlansoprazole modified-release in Asian subjects with non-erosive reflux disease (NERD) and erosive esophagitis (EE). Methods In this phase 4, open-label, non-randomized, uncontrolled, multicenter, multi-country study sponsored by Takeda, subjects aged ≥ 20 years with persistent typical GERD symptoms for at least 6 months underwent endoscopy. Based on endoscopic findings, they were assigned to either dexlansoprazole modified-release 30 mg once-daily for 4 weeks (NERD group) or dexlansoprazole modified-release 60 mg once-daily for 8 weeks (EE group). The primary endpoint was the percentage of days that subjects did not experience any 24- hour heartburn or acid regurgitation. Results Of the 445 subjects screened from Hong Kong, South Korea, and Taiwan, 208 were enrolled in the NERD group (mean age: 53.6 years, male: 34.6%) and 88 in the EE group (mean age: 51.7 years, male: 55.7%). Over the treatment period, the median percentage of days that subjects did not experience any 24-hour heartburn or acid regurgitation was 26.9% and 65.5% in the NERD and EE groups, respectively; for nighttime heartburn or acid regurgitation the proportions were 59.3% and 83.3%, respectively. The treatment was well tolerated with low incidence of treatment-related adverse events in NERD and EE groups (6.7% and 5.7%, respectively). Conclusion In Asian patients with GERD, treatment with dexlansoprazole modified-release indicates a favorable efficacy and safety profile in relieving heartburn and acid regurgitation symptoms.

Background The Forrest classification is widely applied to guide endoscopic hemostasis for peptic ulcer bleeding. Accordingly, practice guidelines suggest medical treatment only for ulcer with a Forrest IIc lesion because it has low rebleeding risk even without endoscopic therapy, ranging from 0 to 13%. However, the risk ranges widely and it is unclear who is at risk of rebleeding with such a lesion. This study assessed whether the Rockall score, which evaluates patients holistically, could indicate the risk of recurrent bleeding among patients with a Forrest IIc lesion at the second-look endoscopy. Methods Patients who had peptic ulcer bleeding with Ia-IIb lesions received endoscopic hemostasis at the primary endoscopy, and they were enrolled if their Ia-IIb lesions had been fading to IIc at the second-look endoscopy after 48- to 72-h intravenous proton pump inhibitor (PPI) infusion. Primary outcomes were rebleeding during the 4th–14th day and 4th–28th day after the first bleeding episode. Results The prospective cohort study enrolled 140 patients, who were divided into a Rockall scores ≥ 6 group or a Rockall scores

Aims/Introduction Helicobacter pylori infection is associated with insulin resistance and glycemia in non‐diabetes. However, the relationship between H. pylori infection and glycemia in diabetes remains inconclusive. Therefore, we explored the effect of H. pylori infection status and its eradication on glycemic control and antidiabetic therapy in type 2 diabetes patients. Materials and Methods A total of 549 diabetes patients were recruited for sequential two‐step approach (immunoglobulin G [IgG] serology followed by 13C‐urea breath test [UBT]) to discriminate “active” (IgG+ and UBT+) from “non‐active” (UBT− or IgG−) H. pylori infection, and “past” (IgG+ but UBT−) from “never/remote” (IgG−) infection. The differences in hemoglobin A1c (A1C) and antidiabetic regimens between groups were compared. In the “active” infection group, the differences in A1C changes between participants with and without 10‐day eradication therapy were compared after 3 months. Results Despite no between‐group difference in A1C, the “active” infection group (n = 208) had significantly more prescriptions of oral antidiabetic drug classes (2.1 ± 1.1 vs 1.8 ± 1.1, P = 0.004) and higher percentages of sulfonylurea use (67.3% vs 50.4%, P

ObjectiveA global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC).Methods28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed.ResultsConsensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of ‘the point of no return’. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori.ConclusionEvidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori. Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.

This study investigated the compositional differences in fecal microbiota between children with and without H. pylori infection and tested whether probiotics-containing yogurt and bacterial eradication improve H. pylori-related dysbiosis. Ten H. pylori-infected children and 10 controls ingested probiotics-containing yogurt for 4 weeks. Ten-day triple therapy plus yogurt was given to the infected children on the 4th week. Fecal samples were collected at enrollment, after yogurt ingestion, and 4 weeks after successful H. pylori eradication for cytokines and microbiota analysis using ELISA and metagenomic sequencing of the V4 region of the 16S rRNA gene, respectively. The results showed H. pylori-infected children had significantly higher levels of fecal TGF-&beta, 1 than those who were not infected. Eight of 295 significantly altered OTUs in the H. pylori-infected children were identified. Among them, the abundance of F. prausnitzii was significantly lower in the H. pylori-infected children, and then increased after yogurt ingestion and successful bacterial eradication. We further confirmed probiotics promoted F. prausnitzii growth in vitro and in ex vivo using real-time PCR. Moreover, F. prausnitzii supernatant significantly ameliorated lipopolysaccharide-induced IL-8 in HT-29 cells. In conclusions, Probiotics-containing yogurt ingestion and H. pylori eradication can restore the decrease of fecal F. prausnitzii in H. pylori-infected children.

H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7–14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p

BackgroundThis study aimed to investigate the correlation between primary tumor volume and cancer failure patterns in esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT) and examine whether increasing radiation dose can improve the outcome.MethodsWe retrospectively reviewed 124 patients with stage III ESCC treated by definitive CCRT. The primary tumor volume calculated from the radiotherapy planning computed tomography scans was correlated to treatment response, time to disease progression, and overall survival. We further analyzed whether a higher radiation dose correlated with better disease control and patient survival.ResultsPatients with poor CCRT response had a larger primary tumor volume than those with good response (97.9 vs 64.3 cm3, P = 0.032). The optimal cutoff value to predict CCRT response was 55.3 cm3. Large primary tumor volume (≥ 55.3 cm3) correlated with shorter time to tumor progression in the esophagus (13.6 vs 48.6 months, P = 0.033) compared with small tumor volume (< 55.3 cm3). For the large esophageal tumors (≥ 55.3 cm3), radiation dose > 60 gray significantly prolonged the time to tumor progression in esophagus (20.3 vs 10.1 months, P = 0.036) and overall survival (12.2 vs 8.0 months, P = 0.030), compared with dose ≤ 60 gray. In contrast, higher radiation dose did not benefit local disease control or overall survival in the small esophageal tumors (< 55.3 cm3).ConclusionLarge primary tumor volume correlates with poor local control and overall survival in ESCC treated with definitive CCRT. Radiation dose > 60 gray can improve the outcomes in patients with large primary tumor. Further prospective dose escalation trials are warranted.

Although most H. pylori infectors are asymptomatic, some may develop serious disease, such as gastric adenocarcinoma, gastric high-grade B cell lymphoma and peptic ulcer disease. Epidemiological and basic studies have provided evidence that infection with H. pylori carrying specific virulence factors can lead to more severe outcome. The virulence factors that are associated with gastric adenocarcinoma development include the presence, expression intensity and types of cytotoxin-associated gene A (CagA, especially EPIYA-D type and multiple copies of EPIYA-C) and type IV secretion system (CagL polymorphism) responsible for its translocation into the host cells, the genotypes of vacuolating cytotoxin A (vacA, s1/i1/m1 type), and expression intensity of blood group antigen binding adhesin (BabA, low-producer or chimeric with BabB). The presence of CagA is also related to gastric high-grade B cell lymphoma occurrence. Peptic ulcer disease is closely associated with cagA-genopositive, vacA s1/m1 genotype, babA2-genopositive (encodes BabA protein), presence of duodenal ulcer promoting gene cluster (dupA cluster) and induced by contact with epithelium gene A1 (iceA1), and expression status of outer inflammatory protein (OipA). The prevalence of these virulence factors is diverse among H. pylori isolated from different geographic areas and ethnic groups, which may explain the differences in disease incidences. For example, in East Asia where gastric cancer incidence is highest worldwide, almost all H. pylori isolates were cagA genopositive, vacA s1/i1/m1 and BabA-expressing. Therefore, selection of appropriate virulence markers and testing methods are important when using them to determine risk of diseases. This review summarizes the evidences of H. pylori virulence factors in relation with gastroduodenal diseases and discusses the geographic differences and appropriate methods of analyzing these virulence markers.

Background Helicobacter pylori infection is known to alter growth-related hormones and affect growth in young children. However, it is still unknown whether maternal H. pylori infection has an impact on the levels of cord blood growth-related hormones and whether this can predict intrauterine growth restriction and poor physical and neurodevelopmental outcomes in children. This study aimed to examine associations between maternal H. pylori infection and pregnancy-related adverse events, fetal growth and early childhood development. Methods In this prospective cohort study, we recruited singleton pregnant women without major medical illnesses from January 2014 to January 2015. Seropositivity for H. pylori was defined as > 12 U/ml of anti-H. pylori IgG in maternal serum. Demographic data and pregnancy-related medical issues of the cohort were documented. Cord blood levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), insulin, and ghrelin were determined using ELISA. The growth of the included neonates was monitored annually for up to 3 years, and cognitive development was assessed using the comprehensive developmental inventory for infants and toddlers (CDIIT) test 3 years after birth. Results Of the 106 enrolled women, 25 (23.6%) were H. pylori-seropositive. Maternal H. pylori seropositivity was correlated with a higher risk of developing gestational hypertension (GH) (12% vs. 1.2%, p = 0.04) and lower cord blood levels of IGF-1 (p = 0.02) and IGFBP-3 (p = 0.02) compared with the seronegative women. No significant impacts on birth weight, childhood growth and cognitive development were found to be correlated with maternal H. pylori seropositivity during pregnancy. Conclusions Maternal H. pylori infection during pregnancy was more likely to lead to the development of GH, but was not correlated with fetal and childhood growth and development. In addition to close monitoring of hypertension, H. pylori eradication can be considered for mothers with H. pylori infection.

Background/Purpose: The prevalence of Gastroesophageal reflux disease (GERD) is increasing worldwide, including Asia. Although several consensus reports have been published, little is known regarding the adherence of the physicians on the consensus of GERD. We aimed to survey the agreements and adherence of physicians to the Taiwan GERD consensus before and after the continual medical education (CME) courses. Methods: Two-hundred and twenty-seven physicians, including 81 fellows of gastroenterology, 135 qualified gastroenterologists, and 11 non-gastroenterologist attending physicians were invited to the CME course. Their agreements and adherence to the statements before and after the CME course were assessed by the pre-defined questionnaire with the aid of electronic keypads. The adherence rate before and after the CME course were compared by the McNemar test to indicate the changes in their willingness to follow the statements in clinical practice. Results: The rates of agreement of the 227 participating physicians were uniformly greater than 80% for all of the 22 statements. However, the adherence rates were lower than 80% in 16 statements before the CME intervention. The adherence rates were significantly (p

Background/purpose: Peptic ulcer bleeding remains a deadly disease, and a simple indicator of long-term outcomes is crucial. This study validated whether hypoalbuminemia and its related factors in patients with peptic ulcer bleeding can indicate long-term mortality and rebleeding under proton pump inhibitor use. Methods: The prospective cohort study enrolled 426 patients with peptic ulcer bleeding who had high risk stigmata at endoscopy and had received endoscopic hemostasis. They were divided into 79 patients in the hypoalbuminemia group (Hypo-AG, serum albumin

Background Patients with high Rockall scores have increased risk of rebleeding and mortality within 30 days after peptic ulcer bleeding, but long-term outcomes deserve follow-up after cessation of proton-pump inhibitors (PPIs). Aim To validate whether patients with high Rockall scores have more recurrent ulcer bleeding in a 3.5-year longitudinal cohort. Methods Between August, 2011 and July, 2014, 368 patients with peptic ulcer bleeding were prospectively enrolled after endoscopic hemostasis to receive PPIs for at least 8 to 16 weeks. These subjects were categorized into either a Rockall scores ≥6 group (n=257) or a Rockall scores

This study investigated whether levofloxacin-containing concomitant therapy can effectively eradicate Helicobacter pylori infection in patients with type 2 diabetes mellitus (T2DM).A total of 797 T2DM patients were screened for anti-H. pylori IgG antibodies, and the presence of H. pylori infection was confirmed byThe H. pylori eradication rates with concomitant therapy were higher than sequential therapy in both intention-to-treat (96.4% versus 81.4%, p = 0.012) and per-protocol (100% versus 85.4%, p = 0.006) analysis. The adverse effects in both groups were similarly mild. In the patients who received sequential therapy, clarithromycin resistance was significantly associated with eradication failure (p = 0.02). There were no significant differences in the antibiotic-resistant rates to amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin between the patients with and without T2DM.Ten days of levofloxacin-containing concomitant therapy is an effective and well-tolerated treatment to eradicate H. pylori infection for T2DM patients. Key messages Ten days of levofloxacin-containing concomitant therapy is well tolerated and superior to clarithromycin-containing sequential therapy for first-line H. pylori eradication in patients with type 2 diabetes. Clarithromycin resistance to H. pylori is the main factor associated with eradication failure in clarithromycin-containing sequential therapy in diabetic patients.

Background The index of hemoglobin (IHb) has not been applied in colonoscopy to correlate the histological features of colon polyps. This study tested whether the net change of IHb values between polyp and normal mucosa correlates with the pathological features of colon polyps. Patients and methods This study consecutively enrolled patients who underwent colonoscopy during September 2011–August 2012 in a single tertiary referral colorectal unit. Endoscopic pictures and IHb values of each part of the colon were taken at the levels of cecum, ascending colon, transverse colon, sigmoid colon, and rectum. The net change of IHb values was calculated as follows: IHb value of colon polyp minus that of the surrounding mucosa. Results A total of 117 patients (32 with hyperplastic polyp, 5 with sessile serrated adenoma, 53 with tubular adenoma, 10 with villotubular adenoma, and 3 with adenocarcinoma) were recruited. The net change of IHb values increased in following order: hyperplastic polyp, tubular adenoma, sessile serrated adenoma, villotubular adenoma, and adenocarcinoma (−3.8 ± 6.3, −1.2 ± 1.7, −1.2 ± 5.7, 2.9 ± 8.1, and 12.7 ± 9.3, respectively; p

Background Antimicrobial resistance of Helicobacter pylori reduces the eradication rate. This study aimed to investigate changes in antimicrobial susceptibility of H pylori isolated from children in Taiwan in the past two decades. Methods This study enrolled children receiving esophagogastroduodenoscopy for upper gastrointestinal diseases in a national tertiary referring hospital from 1998 to 2018. H pylori infection was diagnosed by culture. The minimal inhibitory concentrations (MICs) of antibiotics were tested using the E test. The antibiotic resistance rates and MICs of amoxicillin, clarithromycin, metronidazole, levofloxacin, and tetracycline were compared between 1998-2008 and 2009-2018. Results A total of 70 Helicobacter pylori isolates (29 from 1998 to 2008 and 41 from 2009 to 2018) were identified. The esophagogastroduodenoscopy findings included duodenal ulcers (n = 31), gastric ulcers (n = 9), and gastritis (n = 30). The overall antimicrobial resistance rates of clarithromycin and metronidazole were 22.9% and 21.4%, respectively. The dual resistance rate of clarithromycin and metronidazole was 10%. Resistance rates of levofloxacin and amoxicillin were 8.3% and 2.9%, respectively. None of the isolates were resistant to tetracycline. Compared with the isolates from 1998 to 2008, those from 2009 to 2018 had higher MICs and resistance rates of clarithromycin (26.8% vs 17.2%, P = 0.35) and metronidazole (26.8% vs 13.8%, P = 0.19), but not levofloxacin (9.8% vs 5.3%, P = 1.0) or coresistance to clarithromycin and metronidazole (12.2% vs 6.9%, P = 0.69). Conclusions The antimicrobial resistance rates of pediatric H pylori isolates to clarithromycin and metronidazole increased during the past decade. The selection of antimicrobial agents other than clarithromycin and metronidazole is crucial to increase pediatric H pylori eradication rates.

Background: Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer in Asia and demonstrates poor survival rates following a therapeutic regimen. Methods: Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and treatment failure in cancers. Therefore, identification and characterization of CSCs may help to improve clinical outcomes for ESCC patients. Tumor sphere formation assay are performed to isolate cancer stem-like ESCC cells. QRT-PCR, tumor initiation, metastasis, CCRT treatment are used to evaluate ESCC cells’ stemness properties in vitro and in vivo. Results: The authors’ data demonstrates that cancer stem-like ESCC cells harbored stemness characteristics including self-renewal, differentiation, and transdifferentiation, and possess tumor initiation, metastasis, and treatment inefficiency properties. For the identification of useful biomarkers of cancer stem-like ESCC cells, the authors further identified that CLDN4 was upregulated in cancer stem-like ESCC cells when compared with bulk cancer cells. High-CLDN4 cells harbored stemness and cisplatin/concurrent chemoradiation therapy (CCRT) resistance properties and a high level of CLDN4 was correlated with poor prognosis and poor CCRT response in ESCC patients. Importantly, thiamine tetrahydrofurfuryl disulfide (TTFD) decreased CLDN4 and attenuated stemness in ESCC cells, and TTFD combined with CCRT improved CCRT response in vivo. Conclusions: CLDN4 was suggested as prognostic and a CCRT response indicator for ESCC patients. TTFD combined with CCRT has potential to improve ESCC patient’s clinical outcomes in the future.

ObjectiveTo establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO).DesignIn this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs).ResultsIn the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI –3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI –1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI –4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI –5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI –8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI –9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively.ConclusionOur findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms.Trial registration numberNCT02388724.

Background H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59. Methods One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing. Results The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1–6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 (P

Background: H. pylori infection with triple-drug resistance to clarithromycin, metronidazole, and levofloxacin (TR) limits the success of rescue therapy. This study identified the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. Methods: We consecutively enrolled 430 patients with at least one-course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with a positive 13C-urea breath test after the 1st rescue therapy were retreated with a cross-over 2nd rescue therapy. Findings: The MTBP regimen had higher eradication success than the ATBP regimen for the 1st rescue therapy of TRH. pylori (intent-to-treat [ITT] analysis: 70.3 vs. 46.9%, p=0.048; per protocol [PP] analysis: 78.8% vs. 51.7%, p=0.025). For the MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p

// Yu-Chuan Huang 1 , Chung-Ta Lee 5, * , Jenq-Chang Lee 7, * , Yao-Wen Liu 8 , Ying-Jen Chen 3 , Joseph T. Tseng 1, 2 , Jui-Wen Kang 6 , Bor-Shyang Sheu 6 , Bo-Wen Lin 7 , Liang-Yi Hung 1, 2, 4, 9 1 Institute of Bioinformatics and Biosignal Transduction, National Cheng-Kung University, Tainan 70101, Taiwan 2 Department of Biotechnology and Bioindustry Sciences, National Cheng-Kung University, Tainan 70101, Taiwan 3 Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 70101, Taiwan 4 Center for Infectious Disease and Signal Transduction Research, College of Medicine, National Cheng-Kung University, Tainan 70101, Taiwan 5 Department of Pathology, National Cheng-Kung University Hospital, Tainan 70403, Taiwan 6 Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan 70403, Taiwan 7 Department of Surgery, National Cheng-Kung University Hospital, Tainan 70403, Taiwan 8 Department of Pathology, Kuo General Hospital, Tainan 70054, Taiwan 9 Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan * These authors contributed equally to this work Correspondence to: Liang-Yi Hung, email: lyhung@mail.ncku.edu.tw Bo-Wen Lin, email: wen276@gmail.com Keywords: miR-137, Aurora-A, COX2, colorectal cancer, epigenetic regulation Received: May 14, 2016 Accepted: October 12, 2016 Published: October 18, 2016 ABSTRACT MicorRNA-137 is silenced in human colorectal cancer tissues and colon polyps. Our study showed that the decreased expression of miR-137 is significantly different in various types of polyp which maintain different potentials to lead to CRC development. The expression of miR-137 gradually decreases during the process of colorectal carcinogenesis. Receiver operating characteristic curve (ROC) analysis indicates that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the predisposition of colorectal carcinogenesis. By cell model and xenograft animal model, the enforced expression of miR-137 in colorectal cancer cells can inhibit cell proliferation and tumor formation, induce G2/M arrest, and lead to apoptosis. The expression pattern of miR-137 and Aurora-A or PTGS2 is negatively correlated in human colorectal cancer tissues and colon polyps. Those effects induced by overexpressed miR-137 can be rescued by the overexpression of Aurora-A. In summary, our study suggests that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the tendency toward to CRC formation through the impaired inhibitory effect of Aurora-A. The investigation of the regulatory mechanism of miR-137 -mediated Aurora-A inhibition may shed new light on the early prognosis of cancer therapy for CRC in the future.

Prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, and the chemoradiotherapy (CRT) applied to ESCC patients often failed. Therefore, development of biomarkers to predict CRT response is immensely important for choosing the best treatment strategy of an individual patient. The methylation array and pyrosequencing methylation assay were performed in pre-treatment endoscopic biopsies to identify probes with differential CpG methylation levels between good and poor CRT responders in a cohort of 12 ESCC patients. Receiver operating characteristic curves and multivariate logistic regressions were conducted to build the risk score equation of selected CpG probes in another cohort of 91 ESCC patients to predict CRT response. Kaplan–Meier analysis was used to estimate progression-free survival or time-to-progression of patients predicted with good and poor CRT responses. Nine differentially methylated CpG probes were identified to be associated with CRT response. A risk score equation comprising six CpG probes located in IFNGR2, KCNK4, NOTCH4, NPY, PAX6, and SOX17 genes were built. The risk score was derived from the sum of each probe multiplied by its corresponding coefficient. Such a risk score has a good prediction performance in discriminating poor CRT responders from good responders (AUC: 0.930). Moreover, poor CRT responders predicted by risk score significantly had poorer prognosis in terms of shorter progression-free survival and time-to-progression (p = 0.004–0.008). We established a proof-of-concept CRT response prediction panel consisting of six-CpG methylation biomarkers in identifying ESCC patients who are at high risk of CRT failure and need intensive care.

// Cheng-Han Lin 1, 9, * , Chen-Hsun Tsai 2, * , Ching-Tung Yeh 1 , Jui-Lin Liang 1, 3 , Wan-Chun Hung 1 , Forn-Chia Lin 4 , Wei-Lun Chang 1, 5 , Hao-Yi Li 1 , Yun-Chin Yao 6 , Tai-I Hsu 2 , Yu-Cheng Lee 2 , Yi-Ching Wang 7 , Bor-Shyang Sheu 1, 5 , Wu-Wei Lai 8 , Marcus J. Calkins 1 , Michael Hsiao 9 , Pei-Jung Lu 1, 2 1 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan 2 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan 3 Department of General Surgery, Chi-Mei Medical Center, Liouying, Tainan 736, Taiwan 4 Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan 704, Taiwan 5 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan 6 Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan 704, Taiwan 7 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan 8 Department of Surgery Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan 9 Genomics Research Center, Academia Sinica, Taipei 115, Taiwan * These authors contributed equally to this work Correspondence to: Michael Hsiao, email: mhsiao@gate.sinica.edu.tw Pei-Jung Lu, email: pjlu2190@mail.ncku.edu.tw Keywords: miR-193a-5p, ERBB2, CCRT, esophageal squamous cell carcinoma, indicator Received: October 16, 2015 Accepted: March 31, 2016 Published: May 18, 2016 ABSTRACT Concurrent chemoradiation therapy (CCRT) is the predominant treatment in esophageal cancer, however resistance to therapy and tumor recurrence are exceedingly common. Elevated ERBB2/Her2 may be at least partially responsible for both the high rates of recurrence and resistance to CCRT. This receptor tyrosine kinase is upregulated in 10–20% of esophageal squamous cell carcinoma (ESCC) tissues, and amplification of ERBB2 has been correlated with poor prognosis in esophageal cancer. Tissues from 131 ESCC patients, along with cell and animal models of the disease were used to probe the underlying mechanisms by which ERBB2 upregulation occurs and causes negative outcomes in ESCC. We found that overexpression of ERBB2 inhibited radiosensitivity in vitro . Furthermore, miR-193a-5p reduced ERBB2 expression by directly targeting the 3’UTR. Increased miR-193a-5p enhanced radiosensitivity and inhibited tumorigenesis in vitro and in vivo . Additionally, low miR-193a-5p expression correlated with poor prognosis in ESCC patients, and ESCC patients with good CCRT response exhibited higher miR-193a-5p expression. Our data suggest that patients with high miR-193a-5p will likely benefit from CCRT treatment alone, however a combination of CCRT with Herceptin may be beneficial for patients with low miR-193a-5p expression.

Patients with esophageal squamous cell carcinomas (ESCCs) have poor survival and high recurrence rate, but lack a prognostic biomarker. Disabled-2 (DAB2) is a crucial tumor suppressor, but its roles in ESCCs are uncertain. We investigated whether low DAB2 expression in ESCCs could lead into tumor progression and poor prognosis. Our results found patients with low-DAB2 expression ESCCs had significantly larger tumor size, deeper tumor invasion depth, lymph node metastasis, worse survival, and higher recurrence rate (P

Background and study aims: The need for routine second-look endoscopy in cases of peptic ulcer bleeding remains uncertain. We investigated risk factors related to the need for second-look endoscopy after endoscopic hemostasis and proton pump inhibitor (PPI) infusion. Patients and methods: We prospectively enrolled 316 patients with peptic ulcer bleeding after endoscopic hemostasis. Second-look endoscopy was scheduled after 72-hour PPI infusion (Day-3 subgroup) or one day early (Day-2 subgroup). If early rebleeding developed within 3 days, emergent second-look endoscopy was conducted. Risk factors for early rebleeding (use of E2nd score to predict the need for early second-look endoscopy) and persistent major stigmata in the Day-3 subgroup (use of R2nd score to predict the need for routine second-look endoscopy) were analyzed using univariable and multivariable regression. Results: Excluding 10 of 316 patients with early rebleeding, the rate of persistent major stigmata was lower in the Day-3 subgroup than in the Day-2 subgroup (4.8 % vs. 15.4 %, P = 0.002). Endoscopic epinephrine-injection monotherapy and hypoalbuminemia

A number of clinical guidelines on nutrition therapy in cancer patients have been published by national and international societies; however, most of the reviewed data focused on gastrointestinal cancer or non-cancerous abdominal surgery. To collate the corresponding data for esophageal cancer (EC), a consensus panel was convened to aid specialists from different disciplines, who are involved in the clinical nutrition care of EC patients. The literature was searched using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the ISI Web of Knowledge. We searched for the best evidence pertaining to nutrition therapy in the case of EC. The panel summarized the findings in 3 sections of this consensus statement, based on which, after the diagnosis of EC, an initial distinction is made between the patients, as follows: (1) Assessment; (2) Therapy in patients with resectable disease; patients receiving chemotherapy or chemoradiotherapy prior to resection, and patients with unresectable disease, requiring chemoradiotherapy or palliative therapy; and (3) Formula. The resulting consensus statement reflects the opinions of a multidisciplinary group of experts, and a review of the current literature, and outlines the essential aspects of nutrition therapy in the case of EC. The statements are: Patients with EC are among one of the highest risk to have malnutrition. Patient generated suggestive global assessment is correlated with performance status and prognosis. Nutrition assessment for patients with EC at the diagnosis, prior to definitive therapy and change of treatment strategy are suggested and the timing interval can be two weeks during the treatment period, and one month while the patient is stable. Patients identified as high risk of malnutrition should be considered for preoperative nutritional support (tube feeding) for at least 7-10 days. Various routes for tube feedings are available after esophagectomy with similar nutrition support benefits. Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and self-expanding metal stent (SEMS) or jejunal tube. Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides benefits of maintaining weight, decreasing toxicity, and preventing treatment interruption. Tube feeding or SEMS can offer nutrition support in patients with unresectable esophageal cancer, but SEMS is not recommended for those with neoadjuvant chemoradiation before surgery. Enteral immunonutrition may preserve lean body mass and attenuates stress response after esophagectomy. Administration of glutamine may decrease the severity of chemotherapy induced mucositis. Enteral immunonutrition achieves greater nutrition status or maintains immune functions during concurrent chemoradiation.

A consensus on the management of Helicobacter pylori has been developed. We aimed to assess whether dissemination through continuing medical education (CME) could enhance the adoption of this consensus among clinicians and to explore potential barriers to acceptance.Four CME courses were held to disseminate the consensus. Adoption surveys were performed to evaluate participants' behavior in the past and their commitment to adopt the consensus in future clinical practice after CME. The gaps and barriers to adoption were also surveyed.A total of 240 physicians had attended the CME courses and received surveys with the 22 statements/substatements of the consensus. Before CME, adoption was good in six, fair in ten, and poor in six. After CME, 21 statements had either an initial90% adoption or improvement to good or fair (P 0.001), but one still had poor even though it showed improvement (P = 0.02). Although commitment was good or fair after CME, there was a20% gap between "commitment" and "no barrier" to adoption for 11 statements, ten of which had a main barrier of financial incentives. Among the statements with fair or poor commitment after CME, less commitment to adoption and more barriers related to financial incentives were pronounced in clinicians serving in regional/district hospitals or clinics compared to those serving in medical centers.Continuing medical education may improve the adoption of the H. pylori consensus. The financial incentives were shown to be a main barrier to adoption of the consensus and should be improved.

Background and Aim We assessed the feasibility of combined endoscopic ultrasound and computed tomography on response evaluation in patients with esophageal squamous cell carcinoma treated by definitive chemoradiotherapy, and the impact of response on prognosis. Methods Sixty patients treated by definitive chemoradiotherapy were followed by miniprobe endoscopic ultrasound and computed tomography. The post-treatment esophageal wall thickness was measured by miniprobe endoscopic ultrasound. Metastatic tumors were evaluated by computed tomography. The correlation between post-treatment image findings and prognosis was evaluated. Results Twenty-four patients (40%) had esophageal stricture after chemoradiotherapy, which limited complete evaluation by endoscopy. Miniprobe successfully penetrated all strictures to measure post-treatment esophageal wall thickness. Both post-treatment esophageal wall thickness 30 months, 16.8 months and 7.1 months, respectively (P

BACKGROUND Tolerance to the early acquisition of Helicobacter pylori is suggested because of a biased ratio of regulatory to effector T cells in a mice model. This study investigated whether the CD4CD25 regulatory T (Treg) and CD4+CD25- effector T (Teff) cell responses after H. pylori exposure determine H. pylori susceptibility in children. METHODS Treg and Teff cells from peripheral blood mononuclear cells (PBMCs) of H. pylori-infected and non-infected children were incubated with H. pylori protein. The cytokine levels and fraction of FOXP3+ to T cells were measured. FOXP3 expression was assessed by Western blotting and immunohistochemistry of gastric biopsies from dyspeptic children. RESULTS The fraction of FOXP3+ to CD4+CD25 high cells in PBMCs, FOXP3-positive staining and translation level in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). The translation levels of TGF-β1 in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). After H. pylori challenge, H. pylori-infected children had a positive net-change in TGF-β1 from Treg cells, and a negative net-change of IFN-γ from Teff cells. Paradoxically, the non-infected controls had a negative net-change in TGF-β1 from Treg cells, and a positive net-change of IFN-γ from Teff cells. CONCLUSIONS The host response of Treg cells with increases in FOXP3 and TGF-β1 combined with a reduction in IFN-γ by Teff cells may contribute to H. pylori susceptibility in children.

Background Helicobacter pylori infection increases the risk of gastric cancer. The study aimed to compare cost-effectiveness ratios of H. pylori test-and-treat programs to prevent gastric cancer in Taiwan, referring to the nationwide reimbursement database and expected years of life lost. Materials and Methods During 1998–2009, there were 12,857 females and 24,945 males with gastric adenocarcinoma in Taiwan National Cancer Registry. They were followed up to 2010 and linked to the reimbursement database of National Health Insurance and the national mortality registry to determine lifetime health expenditures and expected years of life lost. Cost-effectiveness ratios of H. pylori test-and-treat programs for prevention of gastric adenocarcinoma were compared between screenings with 13C-urea breath test and with anti-H. pylori IgG. Results The test-and-treat program with anti-H. pylori IgG to prevent gastric adenocarcinoma had lower incremental cost-effectiveness ratios than that with 13C-urea breath test in both sexes (females: 244 vs 1071 US dollars/life-year; males: 312 vs 1431 US dollars/life-year). Cost saving would be achieved in an endemic area where H. pylori prevalence was >73.5%, or by selecting subpopulations with high absolute risk reduction rates of cancer after eradication. Moreover, expected years of life lost of gastric adenocarcinoma were higher and the incremental cost-effectiveness ratios of test-and-treat programs were more cost-effective in young adults (30–69 y/o) than in elders (≥70 y/o). Conclusions The test-and-treat program with anti-H. pylori IgG shall be cost-effective to prevent gastric adenocarcinoma in a high endemic area, especially beginning at 30 years of age when H. pylori prevalence rates become stabilized.

Background Both H. pylori infection and diabetes increase the risk of gastric cancer. This study investigated whether patients with type 2 diabetes mellitus (T2DM) and H. pylori infection had more severe corpus gastric inflammation and higher prevalence of precancerous lesions than non-diabetic controls. Methods A total of 797 patients with type 2 diabetes mellitus were screened for H. pylori, of whom 264 had H. pylori infection. Of these patients, 129 received esophagogastroduodenoscopy to obtain topographic gastric specimens for gastric histology according to the modified Updated Sydney System, corpus-predominant gastritis index (CGI), Operative Link on Gastritis Assessment, and Operative Link on Gastric Intestinal Metaplasia Assessment. Non-diabetic dyspeptic patients who had H. pylori infection confirmed by esophagogastroduodenoscopy were enrolled as controls. Results The male as well as total T2DM patients had higher acute/chronic inflammatory and lymphoid follicle scores in the corpus than non-diabetic controls (p

Background Corpus-predominant gastritis index (CGI) is an early histological marker to identify Helicobacter pylori-infected gastric cancer relatives at risk of cancer. This study validated whether CGI is more prevalent in H. pylori-infected nonulcer dyspepsia (NUD) subjects than in duodenal ulcer (DU) controls and whether it is reversible after H. pylori eradication or is correlated with noninvasive biomarkers. Materials and Methods In this longitudinal cohort study, 573 H. pylori-infected subjects were enrolled, including 349 NUD and 224 DU. Gastric specimens were provided to assess CGI, spasmolyic polypeptide-expressing metaplasia (SPEM), and Operative Link on Gastric Intestinal Metaplasia assessment (OLGIM). Serum pepsinogen I and II levels were assessed using enzyme-linked immunosorbent assay. CGI subjected were followed up at least 1 year after H. pylori eradication. Results NUD subjects had higher prevalence rates of CGI (47.0% vs 29.9%, P

Summary Background Adequate bowel preparation is an important quality indicator of colonoscopy. This study validated whether the bowel cleansing quality and adenoma detection rate (ADR) could be different between two bowel preparation schedules in individuals receiving health examinations. Methods We enrolled individuals who had received a colonoscopy as part of the regimen for their health checkup program with split-dose phosphosoda for bowel preparation. Prior to December 31, 2012, the second dose of phosphosoda was administered at 10:00 pm before the day of the colonoscopy and the individuals were defined as the 10- pm group. After January 1, 2013, the schedule was changed to 4:00 am the same day as the colonoscopy and was defined as the 4- am group. The bowel cleansing quality was assessed using the Aronchick scale. Results A total of 431 individuals were included, 259 in the 10- pm group and 172 in the 4- am group. The 4- am group individuals had a higher rate of excellent or good bowel cleansing quality as compared with the 10-PM group (77.3% vs. 22%, respectively; p am group than in the 10- pm group (36% vs. 25.5%, respectively; p = 0.019). Conclusion Modifying the time schedule of bowel preparation could improve bowel cleansing quality and increase the colonic ADR in a health management center.

Antibiotic resistance among Helicobacter pylori strains has been increasing worldwide and has affected the efficacy of current treatments. The aim of this study was to evaluate whether treatment failure was due to the presence of antibiotic-susceptible and -resistant H. pylori simultaneously within the same host before eradication. In order to discover H. pylori with antibiotic heteroresistance in the same patient, we examined the antibiotic susceptibility of H. pylori isolated from 412 patients without H. pylori eradication. The E-test was used to determine the minimal inhibitory concentration of these strains. The results showed 19 (4.6%) of patients harbored antibiotic heteroresistant H. pylori , resistant to levofloxacin (5/19), clarithromycin (1/19) and metronidazole (16/19). Among them, three patients’ isolates showed heteroresistance to two antibiotics. The genetic diversity of each isolate was evaluated by random amplified polymorphic DNA PCR and the results showed that only 1 patient’ isolate (5.3%) had a different pattern while the others showed identical or similar fingerprinting patterns. Mutations in the genes responsible for antibiotic resistance were investigated by direct sequencing and compared between strains within each pair. All 5 levofloxacin-resistant isolates had mutations in GyrA at the QRDR region (N87 or D91). Strain 1571R with clarithromycin resistance had a A2042G substitution in its 23S rRNA. There were 15 metronidazole-resistant strains (100%) with isogenic variation of RdxA, and 6 strains (40%) contained FrxA variation (excluded pair 1159). These results suggest that the treatment failure of heteroresistant H. pylori mostly develops from high genomic variation of pre-existing strains through long term evolution rather than mixed infection with different strains.

Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions.To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores.We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding.Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th-28th day in the oral double-dose group remained lower than that of the group with Rockall scores6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th-28th day: 10.8% vs 28.7%, p=0.002).Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6.NCT01591083.

The transcriptional network of the SRY (sex determining region Y)-box 17 (SOX17) and the prognostic impact of SOX17 protein expression in human cancers remain largely unclear. In this study, we evaluated the prognostic effect of low SOX17 protein expression and its dysregulation of transcriptional network in esophageal squamous cell carcinoma (ESCC). Low SOX17 protein expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor prognosis. Re-expression of SOX17 in ESCC cells caused reduced foci formation, cell motility, decreased ESCC xenograft growth and metastasis in animals. Knockdown of SOX17 increased foci formation in ESCC and normal esophageal cells. Notably, 489 significantly differential genes involved in cell growth and motility controls were identified by expression array upon SOX17 overexpression and 47 genes contained putative SRY element in their promoters. Using quantitative chromatin immunoprecipitation-PCR and promoter activity assays, we confirmed that MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17 via the SRY binding-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression. The inverse correlation between SOX17 and FN1 protein expression in ESCC clinical samples further strengthened our conclusion that FN1 is a transcriptional repression target gene of SOX17. This study provides compelling clinical evidence that low SOX17 protein expression is a prognostic biomarker and novel cell and animal data of SOX17-mediated suppression of ESCC metastasis. We establish the first transcriptional network and identify new suppressive downstream genes of SOX17 which can be potential therapeutic targets for ESCC.

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients. Methods: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients. Results: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17. Conclusions: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

Background and Aims. To compose upper gastrointestinal bleeding (UGIB) consensus from a nationwide scale to improve the control of UGIB, especially for the high-risk comorbidity group.Methods. The steering committee defined the consensus scope to cover preendoscopy, endoscopy, postendoscopy, and overview from Taiwan National Health Insurance Research Database (NHIRD) assessments for UGIB. The expert group comprised thirty-two Taiwan experts of UGIB to conduct the consensus conference by a modified Delphi process through two separate iterations to modify the draft statements and to vote anonymously to reach consensus with an agreement ≥80% for each statement and to set the recommendation grade.Results. The consensus included 17 statements to highlight that patients with comorbidities, including liver cirrhosis, end-stage renal disease, probable chronic obstructive pulmonary disease, and diabetes, are at high risk of peptic ulcer bleeding and rebleeding. Special considerations are recommended for such risky patients, including raising hematocrit to 30% in uremia or acute myocardial infarction, aggressive acid secretory control in high Rockall scores, monitoring delayed rebleeding in uremia or cirrhosis, considering cycloxygenase-2 inhibitors plus PPI for pain control, and early resumption of antiplatelets plus PPI in coronary artery disease or stroke.Conclusions. The consensus comprises recommendations to improve care of UGIB, especially for high-risk comorbidities.

BACKGROUND AND AIMS Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. METHODS We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication. RESULTS GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P