Publications by authors named "Jeng-Yih Wu"

53 Publications

Gastroduodenal intussusception caused by gastric gastrointestinal stromal tumor: A case report and review of the literature.

World J Clin Cases 2021 Feb;9(4):838-846

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.

Background: Gastric gastrointestinal stromal tumor (GIST) is the most common etiology of gastroduodenal intussusception. Although gastroduodenal intussusception caused by gastric GIST is mostly treated by surgical resection, the first case of gastroduodenal intussusception caused by gastric GIST was treated by endoscopic submucosal dissection (ESD) in Japan in 2017.

Case Summary: An 84-year-old woman presented with symptoms of postprandial fullness with nausea and occasional vomiting for a month. Initially, she visited a local clinic for help, where abdominal sonography revealed a space-occupying lesion around the liver, so she was referred to our hospital for further confirmation. Abdominal sonography was repeated, which revealed a mass with an alternating concentric echogenic lesion. Esophagogastroduodenoscopy (EGD) was performed under the initial impression of gastric cancer with central necrosis and showed a tortuous distortion of gastric folds down from the lesser curvature side to the duodenal bulb with stenosis of the gastric outlet. EGD was barely passed through to the 2nd portion of the duodenum and a friable ulcerated mass was found. Several differential diagnoses were suspected, including gastroduodenal intussusception, gastric cancer invasion to the duodenum, or pancreatic cancer with adherence to the gastric antrum and duodenum. Abdominal computed tomography for further evaluation was arranged and showed gastroduodenal intussusception with a long stalk polypoid mass 5.9 cm in the duodenal bulb. Under the impression of gastroduodenal intussusception, ESD was performed at the base of the gastroduodenal intussusception; unfortunately, a gastric perforation was found after complete resection was accomplished, so gastrorrhaphy was performed for the perforation and retrieval of the huge polypoid lesion. The gastric tumor was pathologically proved to be a GIST. After the operation, there was no digestive disturbance and the patient was discharged uneventfully on the 10th day following the operation.

Conclusion: We present the second case of gastroduodenal intussusception caused by GIST treated by ESD. It is also the first case report of gastroduodenal intussusception by GIST in Taiwan, and endoscopic reduction or resection is an alternative treatment for elderly patients who are not candidates for surgery.
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http://dx.doi.org/10.12998/wjcc.v9.i4.838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852652PMC
February 2021

Comparison of Endoscopic Submucosal Dissection Application on Mucosal Tumor and Subepithelial Tumor in stomach.

J Cancer 2021 1;12(3):765-770. Epub 2021 Jan 1.

Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Endoscopic submucosal dissection is minimal invasive endoscopic procedure to deal with gastric tumor. Initially, it was developed to resect mucosal neoplasm since 2000 and extended its application to submucosal tumor in the following years. Although the basic ESD skills are similar in gastric mucosal tumor and subepithelial tumor, the success rate, complication may be different between the two types of gastric tumor resection. This retrospective study is conducted to analyze the ESD procedure in gastric mucosal tumor and subepithelial tumor. From 2007 to 2016, we reviewed all patients who underwent endoscopic submucosal dissection for gastric mucosal tumor and subepithelial tumor in Kaohsiung Medical University Hospital. Totally, 35 patients with gastric subepithelial tumor and 41 patients with gastric mucosal tumor received endoscopic submucosal dissection are enrolled. Among 35 patients with subepithelial tumor, 32 (91.4%) patients achieved curative treatment. 1 patient received emergent operation and 2 patients received salvage operation to complete tumor resection. 8 patients (22.9%) occurred perforation and no delay bleeding was found. Among 41 patients with mucosal neoplasm, 30 (71.4%) patients achieved curative treatment. 2 patients received emergent operation and 9 patients received salvage operation to complete tumor resection. 9 patients (21.9%) occurred complication, 6 patients occurred delay bleeding and 3 patients had perforation. Comparing ESD between gastric mucosal tumor and subepithelial tumor, ESD had similar efficiency in curative treatment. However, ESD in subepethelial tumor encountered higher perforation and lesser delay bleeding.
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http://dx.doi.org/10.7150/jca.47653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778549PMC
January 2021

Screening and eradication of for gastric cancer prevention: the Taipei global consensus.

Gut 2020 12 1;69(12):2093-2112. Epub 2020 Oct 1.

Department of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Objective: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of for prevention of gastric cancer (GC).

Methods: 28 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.

Results: Consensus was reached in 26 statements. At an individual level, eradication of 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. 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 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 .

Conclusion: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with . Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of should be considered in populations at higher risk of GC.
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http://dx.doi.org/10.1136/gutjnl-2020-322368DOI Listing
December 2020

Proactive measures for the pandemic COVID-19 infection in outpatient clinics of Otolaryngology Department.

Kaohsiung J Med Sci 2020 06 3;36(6):473-474. Epub 2020 Jun 3.

Department of Otorhinolaryngology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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http://dx.doi.org/10.1002/kjm2.12235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300878PMC
June 2020

Long-term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial.

Lancet Infect Dis 2019 10;19(10):1109-1120

Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background: In first-line treatment of Helicobacter pylori, we have previously shown that the eradication frequency was 83·7% (95% CI 80·4-86·6) for triple therapy for 14 days (T14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily), 85·9% (82·7-88·6) for concomitant therapy for 10 days (C10; lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily), and 90·4% (87·6-92·6) for bismuth quadruple therapy for 10 days (BQ10; bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). In this follow-up study, we assess short-term and long-term effects of these therapies on the gut microbiota, antibiotic resistance, and metabolic parameters.

Methods: This was a multicentre, open-label, randomised trial done at nine medical centres in Taiwan. Adult patients (>20 years) with documented H pylori infection were randomly assigned (1:1:1, with block sizes of six) to receive T14, C10, or BQ10. We assessed long-term outcomes (reinfection frequency, changes in the gut microbiota, antibiotic resistance, and metabolic parameters) in patients with available data, excluding all protocol violators and those with unknown post-treatment H pylori status. Faecal samples were collected before treatment and 2 weeks, 2 months, and at least 1 year after eradication therapy. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was done followed by high-throughput sequencing. Susceptibility testing for faecal Escherichia coli and Klebsiella pneumoniae was done. This trial is complete and registered with ClinicalTrials.gov, NCT01906879.

Findings: Between July 17, 2013, and April 20, 2016, 1620 participants were randomly assigned to the three treatment groups (540 [33%] per group). 1214 (75%) attended 1-year follow-up and are included in this analysis. Compared with baseline, alpha diversity was significantly reduced 2 weeks after T14 (p=0·0002), C10 (p<0·0001), and BQ10 (p<0·0001) treatment. Beta diversity was also significantly altered 2 weeks after T14 (p=0·0010), C10 (p=0·0001), and BQ10 (p=0·0001). Alpha diversity and beta diversity were restored at week 8 (p=0·14 and p=0·918, respectively) and 1 year (p=0·14 and p=0·918) after T14, but were not fully recovered at week 8 and after 1 year in patients treated with C10 (p=0·0001 and p=0·013 at week 8; p=0·019 and p=0·064 at 1 year) and BQ10 (p<0·0001 and p=0·0002; p=0·001 and p=0·029). A transient increase at week 2 after T14 and C10 of the resistance rates of E coli to ampicillin-sulbactam (12% [15/127] to 66% [38/58] for T14, 7% [10/135] to 64% [28/44] for C10), cefazolin (13% [16/127] to 43% [25/58] for T14, 10% [13/135] to 41% [18/44] for C10), cefmetazole (8% [10/127] to 26% [15/58] for T14, 4% [5/135] to 18% [8/44] for C10), levofloxacin (8% [10/127] to 35% [20/58] for T14, 7% [10/135] to 32% [14/44] for C10), gentamicin (13% [19/146] to 47% [27/58] for T14, 15% [22/149] to 45% [20/44] for C10), and trimethoprim-sulfamethoxazole (33% [48/146] to 86% [50/58] for T14, 28% [42/148] to 86% [38/44] for C10; p<0·05 in paired samples in the above analyses) returned to basal state at week 8 and after 1 year. Although bodyweight and body-mass index slightly increased, there were significant improvements in metabolic parameters, with a decrease in insulin resistance, triglycerides, and LDL and an increase in HDL. Overall, there was no significant change in the prevalence of metabolic syndrome at week 8 and 1 year after T14, C10, and BQ10.

Interpretation: Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. Collectively, these results lend support to the long-term safety of H pylori eradication therapy.

Funding: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
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http://dx.doi.org/10.1016/S1473-3099(19)30272-5DOI Listing
October 2019

The eradication of Helicobacter pylori to prevent gastric cancer: a critical appraisal.

Expert Rev Gastroenterol Hepatol 2019 Jan 13;13(1):17-24. Epub 2018 Nov 13.

f Department of Medicine , Michael E. DeBakey VA Medical Center, and Baylor College of Medicine , Houston , TX , USA.

Introduction: Gastric cancer is one of the top causes of cancer-related death worldwide. How to eliminate gastric cancer is an urgent public-health issue. Areas covered: In this review, we present up-to-date results of studies on gastric cancer prevention through the eradication of Helicobacter pylori and discuss strategies and obstacles for the implementation of population-wide screening and treatment of this pathogen to prevent gastric cancer. Expert commentary: Gastric cancer is an inflammation-associated cancer with multistep carcinogenesis. The process consists of H. pylori infection, ongoing inflammation, development of metaplastic epithelia and genetic instability eventuating in gastric cancer. H. pylori infection is critical for development of the disease and studies have consistently shown that H. pylori eradication results in a reduction in (a) gastric mucosal inflammation, (b) progression of histologic damage, (c) risk of peptic ulcers and ulcer recurrence, and (d) risk of gastric cancer. Compared with a large number of clinical trials evaluating chemopreventive approaches, studies of population-wide screening, and eradication of H. pylori have only recently begun and only in high-risk populations. To eliminate gastric cancer requires information on how to implement an effective program for screening and treatment of H. pylori taking into consideration the other health priorities in any specific population.
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http://dx.doi.org/10.1080/17474124.2019.1542299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391731PMC
January 2019

Predictor of slower gastric emptying in gastroesophageal reflux disease: Survey of an Asian-Pacific cohort.

J Gastroenterol Hepatol 2019 May 15;34(5):837-842. Epub 2019 Jan 15.

Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background And Aim: Asian populations have relatively lower prevalence of gastroesophageal reflux disease and tend to exhibit symptoms of prolonged gastric retention. However, it remains unknown if slower gastric emptying influences its features in Asian countries. We prospectively assessed the potential implications of slower gastric emptying in an Asian-Pacific cohort of gastroesophageal reflux disease by a hospital-based survey.

Methods: One hundred fifty-two patients of gastroesophageal reflux disease complete the scintigraphic measurement of solid phase of gastric emptying. Clinical symptoms and psychological stress are recorded by self-report questionnaire. The status of Helicobacter pylori infection, blood level of pepsinogen I, and I/II ratio are assessed.

Results: Forty-seven percent and 28% of the patients have slower gastric emptying rate, depending on the incremental defined cut-off values of slower gastric emptying, respectively. Multiple logistic regression analysis indicates that older age and depression score are independently related to slower gastric emptying. Subgroup analysis discloses that patients with slower gastric emptying and higher depression score tend to present with non-erosive esophagitis whereas higher body mass index level and male gender in patients with normal gastric emptying predict the presence of erosive reflux disease.

Conclusions: Our study cohort of Asian patients indicates distinctive clinical implications of slower gastric emptying in patients with gastroesophageal reflux disease.
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http://dx.doi.org/10.1111/jgh.14572DOI Listing
May 2019

The role of integrating conjugative elements in Helicobacter pylori: a review.

J Biomed Sci 2018 Nov 29;25(1):86. Epub 2018 Nov 29.

Department of Environmental and Preventive Medicine, Oita University, Faculty of Medicine, Yufu City, Oita, Japan.

The genome of Helicobacter pylori contains many putative genes, including a genetic region known as the Integrating Conjugative Elements of H. pylori type four secretion system (ICEHptfs). This genetic regions were originally termed as "plasticity zones/regions" due to the great genetic diversity between the original two H. pylori whole genome sequences. Upon analysis of additional genome sequences, the regions were reported to be extremely common within the genome of H. pylori. Moreover, these regions were also considered conserved rather than genetically plastic and were believed to act as mobile genetic elements transferred via conjugation. Although ICEHptfs(s) are highly conserved, these regions display great allele diversity, especially on ICEHptfs4, with three different subtypes: ICEHptfs4a, 4b, and 4c. ICEHptfs were also reported to contain a novel type 4 secretion system (T4SS) with both epidemiological and in vitro infection model studies highlighting that this novel T4SS functions primarily as a virulence factor. However, there is currently no information regarding the structure, the genes responsible for forming the T4SS, and the interaction between this T4SS and other virulence genes. Unlike the cag pathogenicity island (PAI), which contains CagA, a gene found to be essential for H. pylori virulence, these novel T4SSs have not yet been reported to contain genes that contribute significant effects to the entire system. This notion prompted the hypothesis that these novel T4SSs may have different mechanisms involving cag PAI.
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http://dx.doi.org/10.1186/s12929-018-0489-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264033PMC
November 2018

Polyethylene glycol-conjugated HER2-targeted peptides as a nuclear imaging probe for HER2-overexpressed gastric cancer detection in vivo.

J Transl Med 2018 06 19;16(1):168. Epub 2018 Jun 19.

Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan.

Background: The human epidermal growth factor receptor 2 (HER2) involved proliferation, angiogenesis, and reduced apoptosis in gastric cancer (GC), which is a common target for tumor therapy. HER2 is usually overexpressed in more than 15% GC patients, developing a reliable diagnostic tool for tumor HER2 detection is important. In this study, we attend to use polyethylene glycol (PEG) linked anti-HER2/neu peptide (AHNP-PEG) as a nuclear imaging agent probe for HER2 detection in GC xenograft animal model.

Methods: The HER2 expression of human sera and tissues were detected in GC patients and normal subjects. GC cell lines NCI-N87 (high HER2 levels) and MKN45 (low HER2 levels) were treated with AHNP-PEG to assess the cell viability and HER2 binding ability. The NCI-N87 was treated with AHNP-PEG to observe the level and phosphorylation of HER2. The MKN45 and NCI-N87-induced xenograft mice were intravenous injection with fluorescence labeled AHNP-PEG for detecting in vivo fluorescence imaging properties and biodistribution. The AHNP-PEG was conjugated with diethylenetriaminopentaacetic acid (DTPA) for indium-111 labeling (In-DTPA-AHNP-PEG). The stability of was assessed in vitro. The imaging properties and biodistribution of In-DTPA-AHNP-PEG were observed in NCI-N87-induced xenograft mice.

Results: The serum HER2 (sHER2) levels in GC patients were significantly higher than the normal subjects. The sHER2 levels were correlated with the tumor HER2 levels in different stages of GC patients. The AHNP-PEG inhibited the cell growth and down-regulated HER2 phosphorylation in HER2-overexpressed human GC cells (NCI-N87) via specific HER2 interaction of cell surface. In addition, the GC tumor tissues from HER2-postive xenograft mice presented higher HER2 fluorescence imaging as compared to HER2-negative group. The HER2 levels in the tumor tissues were also higher than other organs in NCI-N87-induced xenograft mice. Finally, we further observed that the In-DTPA-AHNP-PEG was significantly enhanced in tumor tissues of NCI-N87-induced xenograft mice compared to control.

Conclusions: These findings suggest that the sHER2 measurement may be as a potential tool for detecting HER2 expressions in GC patients. The radioisotope-labeled AHNP-PEG may be useful to apply in GC patients for HER2 nuclear medicine imaging.
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http://dx.doi.org/10.1186/s12967-018-1550-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009821PMC
June 2018

Comparison of adjuvant FOLFOX4 chemotherapy and oral UFUR/LV following adjuvant FOLFOX4 chemotherapy in patients with stage III colon cancer subsequent to radical resection.

Oncol Lett 2017 Dec 26;14(6):6754-6762. Epub 2017 Sep 26.

Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

The present study aimed to demonstrate the potential advantage of oral uracil-tegafur (UFUR)/leucovorin (LV) as the subsequent therapy in patients with stage III colon cancer following adjuvant LV, 5-fluorouracil and oxaliplatin (FOLFOX4) chemotherapy. Of a total 143 patients, 62 patients received only FOLFOX adjuvant chemotherapy (FOLFOX4 biweekly × 12 cycles for 6 months), and 81 patients received FOLFOXU adjuvant treatment (which consisted of FOLFOX4 biweekly × 12 cycles for 6 months followed by oral UFUR/LV for an additional 6 months). The 3-year disease-free survival (DFS) rate of the FOLFOXU group was 74.3%; which was superior to that of the FOLFOX4 group (59.9%). The average DFS time of the FOLFOXU group was superior to that of the FOLFOX4 group (P=0.003). The 5-year overall survival (OS) rate of the FOLFOXU group was 76.9%, which was also superior to that of the FOLFOX4 group (63.8%). The average OS time of patients in the FOLFOXU group was longer than that of the patients in the FOLFOX4 group (hazard ratio, 0.155; 95% confidence interval, 0.054-0.450; P=0.001). In comparison to the FOLFOX regimen, the FOLFOXU regimen achieved a more favorable response and survival time without a significant increase of toxicities in patients with stage III colon cancer as the adjuvant chemotherapy.
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http://dx.doi.org/10.3892/ol.2017.7073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686528PMC
December 2017

Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis.

Lancet Gastroenterol Hepatol 2017 10 7;2(10):707-715. Epub 2017 Aug 7.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background: So far, a comprehensive systematic review and meta-analysis has not been done of the prevalence of primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region. We aimed to assess the trends and regional differences in primary antibiotic resistance to H pylori in the Asia-Pacific region and to examine the relation between resistance and first-line eradication.

Methods: We did a systematic review and meta-analysis of primary antibiotic resistance to H pylori and the efficacy of first-line regimens in the Asia-Pacific region. We searched PubMed, Embase, and the Cochrane Library for articles published between Jan 1, 1990, and Sept 30, 2016; we also searched abstracts from international conferences. Both observational studies and randomised controlled trials were eligible for inclusion in the analysis of primary antibiotic resistance, but only randomised controlled trials were eligible for inclusion in the analysis of efficacy of first-line therapies. Meta-analysis was by the random-effects model to account for the substantial variations in resistance across the region. We did subgroup analyses by country and study period (ie, before 2000, 2001-05, 2006-10, and 2011-15) to establish country-specific prevalences of primary antibiotic resistance and first-line eradication rates. This study is registered with PROSPERO, number CRD42017057905.

Findings: 176 articles from 24 countries were included in our analysis of antibiotic resistance. The overall mean prevalences of primary H pylori resistance were 17% (95% CI 15-18) for clarithromycin, 44% (95% CI 39-48) for metronidazole, 18% (95% CI 15-22) for levofloxacin, 3% (95% CI 2-5) for amoxicillin, and 4% (95% CI 2-5) for tetracycline. Prevalence of resistance to clarithromycin and levofloxacin rose significantly over time during the period investigated, whereas resistance to other antibiotics remained stable. 170 articles from 16 countries were included in analysis of efficacy of first-line therapies. We noted unsatisfactory efficacy (ie, <80%) with clarithromycin-containing regimens in countries where the clarithromycin resistance rates were higher than 20%.

Interpretation: The prevalence of primary antibiotic resistance varied greatly among countries in the Asia-Pacific region, and thus treatment strategy should be adapted relative to country-specific resistance patterns. Clarithromycin-containing regimens should be avoided in countries where the prevalence of clarithromycin resistance is higher than 20%.

Funding: Ministry of Health and Welfare of Taiwan, Ministry of Science and Technology of Taiwan, and Amity University.
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http://dx.doi.org/10.1016/S2468-1253(17)30219-4DOI Listing
October 2017

Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial.

Lancet 2016 11 18;388(10058):2355-2365. Epub 2016 Oct 18.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background: Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori.

Methods: In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01906879.

Findings: Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 [95% CI 87·6-92·6]) for 10-day bismuth quadruple therapy, 85·9% (464/540 [82·7-88·6]) for 10-day concomitant therapy, and 83·7% (452/540 [80·4-86·6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% [95% CI 2·7-10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy.

Interpretation: Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered.

Funding: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
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http://dx.doi.org/10.1016/S0140-6736(16)31409-XDOI Listing
November 2016

Patients with Metastatic Colorectal Cancer and Hyperbilirubinemia Treated with FOLFIRI plus Bevacizumab as First-Line Treatment.

Chemotherapy 2017 22;62(1):80-84. Epub 2016 Sep 22.

Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.

Metastatic colorectal cancer (mCRC) combined with hyperbilirubinemia is typically considered a contraindication to irinotecan-based therapy, a proven first-line treatment of mCRC. Herein, we present 6 consecutive patients with mCRC combined with hyperbilirubinemia who underwent UGT1A1 genotyping before receiving FOLFIRI plus bevacizumab. Dose escalation of irinotecan was performed according to the results of UGT1A1 genotyping in all patients. Improvement in the serum total bilirubin level to a normal range was noted in all 6 patients. Disease control was 100%. The median progression-free survival was 7.5 months and the median overall survival was 8.5 months. FOLFIRI plus bevacizumab as a first-line chemotherapy may achieve effective disease control and be safe in patients with mCRC and hyperbilirubinemia based on UGT1A1 genotyping. More prospective clinical studies are necessary to evaluate the clinical benefits and safety of this treatment approach.
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http://dx.doi.org/10.1159/000447118DOI Listing
February 2017

Development of a deregulating microRNA panel for the detection of early relapse in postoperative colorectal cancer patients.

J Transl Med 2016 04 29;14(1):108. Epub 2016 Apr 29.

Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and is associated with high recurrence and mortality, despite recent advancements in therapeutic strategies. MicroRNA (miR) deregulation is associated with CRC development and recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse postoperatively.

Methods: In this study ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141, miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in their expression levels between early relapsed (recurrences within 12 months after surgery) and non-early relapsed CRC patients. The validation study, including 50 early relapsed and 54 non-early relapsed patients, confirmed miR expression alterations in cancer tissue samples.

Results: Using a miR real-time quantitative polymerase chain reaction (RT-qPCR), we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased, whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC tissue samples from the early relapsed patients than in those from the non-early relapsed patients. Disease-free survival and overall survival were significantly worse in the high miR-7, miR-141, and miR-494 expression subgroups and the low miR-93 and miR-195 expression subgroups (all P < 0.05). A panel of 6 miRs (miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6 % and a specificity of 71.4 %. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4 % and a specificity of 88.9 %.

Conclusions: This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients.
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http://dx.doi.org/10.1186/s12967-016-0856-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850676PMC
April 2016

Levofloxacin Sequential Therapy vs Levofloxacin Triple Therapy in the Second-Line Treatment of Helicobacter pylori: A Randomized Trial.

Am J Gastroenterol 2016 Mar 2;111(3):381-7. Epub 2016 Feb 2.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Objectives: The efficacy of levofloxacin triple therapy has fallen below 80% in the second-line treatment of Helicobacter pylori (H. pylori). We aimed to assess whether the levofloxacin sequential therapy is more effective than levofloxacin triple therapy in the second-line treatment.

Methods: This open-label, randomized, multicenter trial was conducted between 2012 and 2015. H. pylori-infected subjects who failed from clarithromycin-based regimens (N=600) were randomized (1:1) to receive levofloxacin sequential therapy (LS: lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, levofloxacin, and metronidazole for another 5 days) or levofloxacin triple therapy (LT: lansoprazole, amoxicillin, and levofloxacin for 10 days). Successful eradication was defined as negative (13)C-urea breath test at least 6 weeks after treatment. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Antibiotic resistance was determined by agar dilution test.

Results: The prevalence of clarithromycin, levofloxacin, and metronidazole resistance was 60, 17.6, and 36.9%, respectively. The eradication rates of LS and LT were 84.3% (253/300) and 75.3% (226/300), respectively, in the ITT analysis (P=0.006) and 86.3% (253/293) and 78.8% (223/283), respectively, in the PP analysis (P=0.021). The efficacies of both LS and LT were affected by levofloxacin resistance. The secondary resistance of levofloxacin was 66.7 and 73.9% after LS and LT, respectively. The efficacies of LS and LT were not affected by the CYP2C19 polymorphism.

Conclusions: Levofloxacin sequential therapy was more effective than levofloxacin triple therapy, and it is recommended in the second-line treatment for H. pylori (

Trial Registration Number: NCT01537055).
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http://dx.doi.org/10.1038/ajg.2015.439DOI Listing
March 2016

Propofol target-controlled infusion for sedated gastrointestinal endoscopy: A comparison of propofol alone versus propofol-fentanyl-midazolam.

Kaohsiung J Med Sci 2015 Nov 31;31(11):580-4. Epub 2015 Oct 31.

Department of Anesthesiology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. Electronic address:

Gastrointestinal (GI) endoscopy is the major technique for diagnosis of GI disease and treatment. Various sedation and analgesia regimens such as midazolam, fentanyl, and propofol can be used during GI endoscopy. The purpose of the study was to compare propofol alone and propofol combination with midazolam and fentanyl in moderate sedation for GI endoscopy. One hundred patients undergoing GI endoscopy were enrolled in this study. All patients received a propofol target-controlled infusion (TCI) to maintain sedation during the procedure. Patients were randomly allocated into either Group P (propofol TCI alone) or Group C (combination of propofol TCI plus midazolam and fentanyl). Dermographic data, anesthetic parameters (sedation regimen, blood pressure, heart rate, and oxygen saturation), procedure parameters (procedure time, colonoscopy, or panendoscopy), propofol consumption, and adverse events (hypoxia, hypotension, and bradycardia) were all recorded. Postprocedural records included recovery time, postoperative adverse events (nausea, vomiting, dizziness, recall, and pain) and satisfaction. The average propofol consumption was 251 ± 83 mg in Group P and 159 ± 73 mg in Group C (p < 0.001). The incidence of transient hypotension was higher in Group P (p = 0.009). The recovery time and discharge time were both shorter in Group C (p < 0.001 and p = 0.006 respectively). Overall, postprocedural adverse events were similar in both groups. The postanesthetic satisfaction was comparable in both groups. TCI of propofol combined with midazolam and fentanyl achieved sedation with fewer hypotension episodes and shorter recovery and discharge time than propofol TCI alone in patients undergoing GI endoscopy.
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http://dx.doi.org/10.1016/j.kjms.2015.09.004DOI Listing
November 2015

Diagnosis of Helicobacter pylori infection: Current options and developments.

World J Gastroenterol 2015 Oct;21(40):11221-35

Yao-Kuang Wang, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan.

Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.
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http://dx.doi.org/10.3748/wjg.v21.i40.11221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616200PMC
October 2015

Sequential therapy for 10 days versus triple therapy for 14 days in the eradication of in the community and hospital populations: a randomised trial.

Gut 2016 11 3;65(11):1784-1792. Epub 2015 Sep 3.

Departments of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Objective: Significant heterogeneity was observed in previous trials that assessed the efficacies of sequential therapy for 10 days (S10) versus triple therapy for 14 days (T14) in the first-line treatment of We aimed to compare the efficacy of S10 and T14 and assess the factors affecting their efficacies.

Design: We conducted this open-label randomised multicentre trial in eight hospitals and one community in Taiwan. 1300 adult subjects with infection naïve to treatment were randomised (1:1) to receive S10 (lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, clarithromycin and metronidazole for another 5 days) or T14 (lansoprazole, amoxicillin and clarithromycin for 14 days). All drugs were given twice daily. Successful eradication was defined as negative C-urea breath test at least 6 weeks after treatment. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Antibiotic resistance was determined by agar dilution test.

Results: The eradication rates of S10 and T14 were 87.2% (567/650, 95% CI 84.4% to 89.6%) and 85.7% (557/650, 95% CI 82.8% to 88.2%) in the ITT analysis, respectively, and were 91.6% (556/607, 95% CI 89.1% to 93.4%) and 91.0% (548/602, 95% CI 88.5% to 93.1%) in the PP analysis, respectively. There were no differences in compliance or adverse effects. The eradication rates in strains susceptible and resistant to clarithromycin were 90.7% and 62.2%, respectively, for S10, and were 91.5% and 44.4%, respectively, for T14. The efficacy of T14, but not S10, was affected by CYP2C19 polymorphism.

Conclusions: S10 was not superior to T14 in areas with low clarithromycin resistance.

Trial Registration Number: NCT01607918.
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http://dx.doi.org/10.1136/gutjnl-2015-310142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099199PMC
November 2016

Decreased peritherapeutic VEGF expression could be a predictor of responsiveness to first-line FOLFIRI plus bevacizumab in mCRC patients.

Int J Clin Exp Pathol 2015 1;8(2):1900-10. Epub 2015 Feb 1.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan ; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University Kaohsiung, Taiwan ; Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University Kaohsiung, Taiwan ; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University Kaohsiung, Taiwan ; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan ; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.

Objective: Bevacizumab is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer (mCRC). Although chemotherapy plus bevacizumab has led to improve outcomes for mCRC patients and is a common choice for first-line treatment of mCRC, previous research has established no prominent biomarker that can help to select patients who may benefit from bevacizumab in order to improve cost-effectiveness and therapeutic outcomes. The aim of this study was to compare pre- and post-therapeutic VEGF immunohistochemical (IHC) expression in mCRC patients treated with FOLFIRI plus bevacizumab to identify its potential role as a predictive biomarker.

Methods: A total of 57 mCRC patients who underwent FOLFIRI combined with bevacizumab chemotherapy as a first-line neoadjuvant regimen were enrolled and clinical outcome data analyzed.

Results: Low post-therapeutic VEGF expression (P < 0.001) and decreased peri-therapeutic VEGF expression (P < 0.001) were significantly predictive factors of responders. Furthermore, the 6-month progression-free survival (PFS) rate in mCRC patients with decreased peri-therapeutic VEGF expression was significantly better than the rate for those patients with no peri-therapeutic VEGF expression alterations (P = 0.033).

Conclusions: Decreased peri-therapeutic VEGF expression in mCRC patients could probably be used to predict responsiveness to bevacizumab and subsequent PFS in clinical practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396259PMC
February 2016

The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors-A Nationwide Study.

PLoS One 2015 5;10(5):e0124199. Epub 2015 May 5.

Departments of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Objective: The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance.

Methods: The defined daily dose (DDD) of antibiotics was analyzed using the Taiwan National Health Insurance (NHI) research database. H. pylori strains isolated from treatment naïve (N=1395) and failure from prior eradication therapies (N=360) from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method.

Results: The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000-2007 to 8.3% in 2008-2010 and 13.4% in 2011-2012 (p=0.001). The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001), which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance.

Conclusions: The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124199PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420283PMC
April 2016

Detection of genotypic clarithromycin-resistant Helicobacter pylori by string tests.

World J Gastroenterol 2014 Mar;20(12):3343-9

Jeng-Yih Wu, Wen-Ming Wang, Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan.

Aim: To evaluate the utility of the string test to detect genotypic clarithromycin-resistant Helicobacter pylori (H. pylori) by polymerase chain reaction (PCR)-restriction fragment length polymorphism.

Methods: Patients undergoing endoscopic examinations were enrolled in the present study. String tests were done on the next day of endoscopy. Segments of 23S rRNA were amplified from DNA obtained from string tests. PCR-restriction fragment length polymorphism was accomplished by restriction enzymes BbsI and BsaI recognizing the mutation site A to G at 2143 or at 2142 of 23S rRNA domain V, respectively.

Results: One hundred and thirty-four patients with H. pylori infection underwent string tests. To compare phenotypic resistance, 43 isolates were successfully cultured in 79 patients in whom 23S rRNA was successfully amplified. Of five patients with clarithromycin-resistant H. pylori, 23S rRNA of H. pylori isolates from four patients could be digested by BsaI. In 38 susceptible isolates, 23S rRNA of H. pylori isolates from 36 patients could not be digested by either BsaI or BbsI. The sensitivity and specificity of the string test to detect genotypic clarithromycin resistance were 66.7% and 97.3%, respectively. Positive and negative predictive values were 80% and 94.7%, respectively.

Conclusion: String test with molecular analysis is a less invasive method to detect genotypic resistance before treatment. Further large-scale investigations are necessary to confirm our results.
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http://dx.doi.org/10.3748/wjg.v20.i12.3343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964405PMC
March 2014

Feasibility of shortening 14-day hybrid therapy while maintaining an excellent Helicobacter pylori eradication rate.

Helicobacter 2014 Jun 11;19(3):207-13. Epub 2014 Mar 11.

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.

Background: The need for new effective Helicobacter pylori eradication therapy has focused efforts on the development and optimization of regimens with excellent eradication rates such as 14-day hybrid therapy. This study evaluated whether the duration of hybrid therapy could be reduced while maintaining a high eradication rate and to examine the effect of antibiotic resistance on outcome.

Materials And Methods: Three separate multicenter pilot studies were carried out concurrently. To reduce selection bias, eligible subjects were randomized to 10-day, 12-day, or 14-day hybrid therapy consisting of esomeprazole 40 mg and amoxicillin 1 gm twice daily for 10, 12, or 14 days plus clarithromycin 500 mg, and metronidazole 500 mg twice daily for the final 7 days. The primary outcome was H. pylori eradication per-protocol assessed at least 8 weeks after therapy.

Results: A total of 220 subjects were entered. The per-protocol analyses contained 60, 61, 61 subjects in the 10-, 12- and 14-day therapy studies, respectively. The eradication rates, per-protocol, were similar: 95% (95% confidence interval (CI); 89.5-100%) for 10-day, 95.1% (95% CI; 89.7-100%) for 12-day, and 93.4% (95% CI; 87.2-99.7%) for 14-day hybrid therapies. Antibiotic resistance was infrequent; however, all metronidazole or clarithromycin resistances were cured with 12- and 14-day therapies.

Conclusion: These results suggest that in regions of moderate to low clarithromycin and/or metronidazole resistance it may be feasible to shorten hybrid therapy to 10 or 12 days. Further study is needed to compare hybrid and concomitant therapy in regions with moderate-to-high clarithromycin and/or metronidazole resistance.
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http://dx.doi.org/10.1111/hel.12113DOI Listing
June 2014

Evidence-based recommendations for successful Helicobacter pylori treatment.

Expert Rev Gastroenterol Hepatol 2014 Jan 2;8(1):21-8. Epub 2013 Dec 2.

Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

An effective Helicobacter pylori therapy reliably provides high cure rates in infections with susceptible strains. It is possible to predict the efficacy of any regimen if one knows the prevalence of antibiotic resistance for a regimen or for a specific patient. We show how to predict the outcome for current regimens and discuss the factors that undermine different regimens (i.e., their Achilles heel). In general, in Western countries, clarithromycin-containing triple and sequential therapy should be considered obsolete as empiric therapies. Preferred regimens are 14-day concomitant or bismuth-containing quadruple therapy. We provide details of how to identify a regimen for a patient or region that will reliably cure 90% or more as well as those that will reliably fail.
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http://dx.doi.org/10.1586/17474124.2014.859522DOI Listing
January 2014

Discovery of tumor markers for gastric cancer by proteomics.

PLoS One 2014 3;9(1):e84158. Epub 2014 Jan 3.

Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan ; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan ; Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Gastric cancer (GC) has a high rate of morbidity and mortality among various cancers worldwide. The development of noninvasive diagnostic methods or technologies for tracking the occurrence of GC is urgent, and searching reliable biomarkers is considered.This study intended to directly discover differential biomarkers from GC tissues by two-dimension-differential gel electrophoresis (2D-DIGE), and further validate protein expression by western blotting (WB) and immunohistochemistry (IHC).Pairs of GC tissues (gastric cancer tissues and the adjacent normal tissues) obtained from surgery was investigated for 2D-DIEG.Five proteins wereconfirmed by WB and IHC, including glucose-regulated protein 78 (GRP78), glutathione s-transferase pi (GSTpi), apolipoprotein AI (ApoAI), alpha-1 antitrypsin (A1AT) and gastrokine-1 (GKN-1). Among the results, GRP78, GSTpi and A1ATwere significantlyup-regulated and down-regulated respectively in gastric cancer patients. Moreover, GRP78 and ApoAI were correlated with A1AT for protein expressions.This study presumes these proteins could be candidates of reliable biomarkers for gastric cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084158PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880290PMC
September 2014

Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment.

PLoS One 2013 24;8(1):e53798. Epub 2013 Jan 24.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, Texas, United States of America.

Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4(+) T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF) are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4(+) T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-β, and IL-21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053798PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554710PMC
July 2013

Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial.

J Antimicrob Chemother 2013 Feb 25;68(2):450-6. Epub 2012 Oct 25.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Objectives: The efficacy of sequential therapy and the applicability of genotypic resistance to guide the selection of antibiotics in the third-line treatment of Helicobacter pylori have not been reported. We aimed to assess the efficacy of genotypic resistance-guided sequential therapy in third-line treatment.

Methods: Genotypic and phenotypic resistances were determined in patients who failed at least two eradication therapies by PCR with direct sequencing and agar dilution test, respectively. The patients were retreated with sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole plus clarithromycin, levofloxacin or tetracycline for another 7 days (all twice daily), according to genotypic resistance determined using gastric biopsy specimens. Eradication status was determined by the (13)C-urea breath test. Trial registered at clinicaltrials.gov (identifier: NCT01032655).

Results: The overall eradication rate was 80.7% (109/135, 95% CI 73.3%-86.5%) in the intention-to-treat analysis. The presence of amoxicillin resistance (OR 6.83, 95% CI 1.62-28.86, P = 0.009) and prior sequential therapy (OR 4.77, 95% CI 1.315-17.3, P = 0.017), but not tetracycline resistance (tetracycline group), were associated with treatment failure. The eradication rates in patients who received clarithromycin-, levofloxacin- and tetracycline-based sequential therapies were 78.9% (15/19), 92.2% (47/51) and 71.4% (25/35) in strains susceptible to clarithromycin, levofloxacin and tetracycline, respectively.

Conclusions: A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection.
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http://dx.doi.org/10.1093/jac/dks407DOI Listing
February 2013

Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days?

Helicobacter 2011 Apr;16(2):146-52

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

Background And Aims:  Ten-day sequential therapy with a proton-pump inhibitor (PPI) and amoxicillin followed by a PPI, clarithromycin, and an imidazole typically achieves Helicobacter pylori (H. pylori) eradication rates between 90 and 94% (i.e., Grade B success). It has been suggested that prolonging the duration of therapy might improve the treatment success. We tested whether prolonging treatment duration to 14-days would improve the results to 95% or greater eradication.

Methods:  This was a multi-center, single site, pilot study in which H. pylori-infected patients received a 14-day sequential therapy (esomeprazole and amoxicillin for 7 days followed by esomeprazole, clarithromycin, and metronidazole for 7 days). H. pylori status was assessed 8 weeks after therapy. Success was defined as achieving 95% or greater eradication by per-protocol (PP) analysis.

Results:   One hundred and twenty-three subjects received the 14-day sequential therapy. The eradication rate was 93.9% (95% confidence interval [CI], 89.5-98.3%) by PP and 91.9% (95% CI, 87.1-96.7%) by intention-to-treat analysis. Adverse events were experienced by 21.1%; compliance of 90% or greater was 95.9%.

Conclusions:  Extending sequential therapy to 14 days did not result in improving the treatment outcome to 95% or greater.
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http://dx.doi.org/10.1111/j.1523-5378.2011.00829.xDOI Listing
April 2011

Modified sequential Helicobacter pylori therapy: proton pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days.

Helicobacter 2011 Apr;16(2):139-45

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

Background: Ten-day sequential therapy with a proton pump inhibitor (PPI) and amoxicillin followed by a PPI, clarithromycin, and an imidazole typically achieves Helicobacter pylori eradication rates of 90-94% (Grade B success).

Aims: We tested whether prolonging treatment and continuing amoxicillin throughout the 14-day treatment period would produce a ≥ 95% result.

Methods: This was a multicenter pilot study in which H. pylori-infected patients received a 14-day sequential-concomitant hybrid therapy (esomeprazole and amoxicillin for 7 days followed by esomeprazole, amoxicillin clarithromycin, and metronidazole for 7 days). H. pylori status was examined 8 weeks after therapy. Success was defined as achieving ≥ 95% eradication by per-protocol analysis.

Results: One hundred and seventeen subjects received hybrid therapy. The eradication rate was 99.1% (95% confidence interval (CI), 97.3-100.0%) by per-protocol analysis and 97.4% by intention-to-treat analysis (95% CI, 94.5-100.0%). Adverse events were seen in 14.5%; drug compliance was 94.9%.

Conclusions: Fourteen-day hybrid sequential-concomitant therapy achieved > 95%H. pylori eradication (Grade A result). Further studies are needed 1, in regions with different patterns and frequencies of resistance to confirm these findings, and 2, to examine whether Grade A success is maintained with hybrid therapy shorter than 14 days.
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http://dx.doi.org/10.1111/j.1523-5378.2011.00828.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191844PMC
April 2011

Functional glutathione peroxidase 3 polymorphisms associated with increased risk of Taiwanese patients with gastric cancer.

Clin Chim Acta 2010 Oct 27;411(19-20):1432-6. Epub 2010 May 27.

Cancer Center, and Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Glutathione peroxidase 3 (GPX3) can enhance an antioxidant's capacity and reduce genomic damage caused by oxidants and thus influence tumorigenesis. We investigated the role of GPX3 as a risk of gastric cancer.

Methods: We first conducted a case-control study to test for the association between 5 tagging single nucleotide polymorphisms (SNPs) of GPX3 and the risk of gastric cancer in Chinese. Multivariate logistic regression analysis was performed to estimate the genetic effect with adjustments for age and sex. Functional studies were performed by using the luciferase reporter assay to assess functional consequences of the significant SNPs.

Results: Among five SNPs (rs3763013, rs8177412, rs3805435, rs3828599, and rs2070593) genotyped in 227 cases and 844 controls, 3 SNPs were significant: intronic SNP rs3805435 (OR=0.70, P=0.037), intronic SNP 3828599 (OR=0.68, P=0.025), and 3' UTR SNP rs2070593 (OR=0.48, P=0.001). The two intronic SNPs rs3805435 and SNP rs3828599 were in linkage disequilibrium (D'=0.91).

Conclusions: The reporter assays showed significant difference in the luciferase expression between protective and risk alleles of 2o intronic SNPs (P=0.004), whereas the 3'UTR SNP did not influence the luciferase expression. The intronic SNPs at GPX3 can influence gene expression leading to an alteration of gastric cancer risk.
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http://dx.doi.org/10.1016/j.cca.2010.05.026DOI Listing
October 2010

P-selectin-dependent platelet aggregation and apoptosis may explain the decrease in platelet count during Helicobacter pylori infection.

Blood 2010 May 22;115(21):4247-53. Epub 2010 Jan 22.

Institute of Biomedical Sciences, Sun Yat-Sen University, Kaohsiung, Taiwan.

P-selectin expression has been shown in Helicobacter pylori-infected persons, an infection that has been clinically associated with platelet-related diseases, such as idiopathic thrombocytopenic purpura. However, the role of P-selectin expression during H pylori infection remains unclear. In this study, we hypothesized that P-selectin expression was associated with platelet aggregation during H pylori infection. Using flow cytometry, we examined the levels of adhesion between H pylori and platelets as well as the levels of P-selectin expression and platelet phosphatidylserine (PS) expression during H pylori infection. Significantly high levels of adhesion between pro-aggregatory bacteria and platelets were observed. We identified that H pylori IgG is required for bacteria to induce P-selectin expression and that a significant release of P-selectin is essential for H pylori to induce aggregation. In addition, cellular apoptotic signs, such as membrane blebbing, were observed in platelet aggregates. PS expression was also detected in platelets during infection with both pro-aggrogatory and nonaggregatory strains of H pylori. These results suggest that the decrease in platelet counts seen during H pylori infection is the result of P-selection-dependent platelet aggregation and PS expression induced by the bacteria.
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http://dx.doi.org/10.1182/blood-2009-09-241166DOI Listing
May 2010