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We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori ( H. pylori ). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori -infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori -infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori -infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori , but TNFα decreased the cell viability in H. pylori -infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori -infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori . Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori -infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori -infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Background: Culture of Helicobacter pylori with previous eradication failure has been emphasized in clinical guidelines. The current unmet need to manage previously treated H pylori is one tool with diagnostic accuracy and ability for antibiotics susceptibility. Gastric juice PCR can provide diagnosis and antibiotics susceptibility; however, whether treatment failure affects its accuracy remains uninvestigated. Our study aimed to investigate diagnostic accuracy and antibiotics susceptibility of juice PCR in previously treated H pylori and to compare with the current standard of culture., Methods: We categorized all 547 patients into treatment-naïve, post-1st treatment, post-2nd treatment, and post-3rd treatment. Helicobacter pylori infection was confirmed using gold standards. Sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and area under ROC curve (AUC) of juice PCR and culture were calculated. Intra-gastric H pylori density was evaluated. Lastly, the antibiotics susceptibility results of gastric juice and culture were compared., Results: Our findings demonstrated AUC was higher in juice PCR than culture in all patients (96.7% vs 91.3%, P < 0.0001). The superiority of juice PCR was statistically significant in previously treated patients (P < 0.0001) but not in treatment-naïve patients (P = 0.13). Antral H pylori density was less marked in previously treated patients (P = 0.014). The comparisons of PCR-RFLP and E-test for Clarithromycin resistance showed reliable AUC = 89.8%., Conclusion: Compared with the current standard of culture, the gastric juice PCR contains the strengths of performing the antibiotics susceptibility and overcomes the shortcomings of low accuracy. Consequently, gastric juice PCR suits the unmet need to manage previously treated H pylori., (© 2019 John Wiley & Sons Ltd.)

Objectives: Proton pump inhibitor (PPI)-amoxicillin-fluoroquinolone triple therapy is recommended as a second-line treatment of Helicobacter pylori infection in the Maastricht V/Florence Consensus Report. However, the eradication rate of this standard salvage treatment is suboptimal. The objective of this study is to compare the efficacy of esomeprazole-bismuth-tetracycline-levofloxacin therapy (TL quadruple therapy) and esomeprazole-amoxicillin-levofloxacin triple therapy (AL triple therapy) in rescue treatment for H. pylori infection., Methods: Consecutive H. pylori-infected subjects after failure of first-line therapies were randomly allocated to receive either TL quadruple therapy (esomeprazole 40 mg b.d., bismuth 120 mg q.d.s., tetracycline 500 mg q.d.s., and levofloxacin 500 mg o.d.) or AL triple therapy (esomeprazole 40 mg b.d., amoxicillin 500 mg q.d.s., and levofloxacin 500 mg o.d.) for 10 days. H. pylori status was assessed 6 weeks after the end of treatment., Results: The study was stopped after an interim analysis. Of 50 patients in the TL quadruple therapy, 49 (98.0%) had successful eradication of H. pylori infection. Cure of H. pylori infection was achieved in 36 of 52 patients (69.2%) receiving AL triple therapy. Intention-to-treat analysis demonstrated that TL quadruple therapy achieved a markedly higher eradication rate than AL triple therapy (difference: 28.8%; 95% confidence interval: 15.7% to 41.9%; P<0.001). Per-protocol analysis yielded a similar result (97.8% vs. 68.6%; P<0.001). The two treatment groups exhibited comparable frequencies of overall adverse events (22.0% vs. 11.5%) and drug compliance (90.0% vs. 98.1%). The subgroup analysis showed that TL quadruple therapy was superior to AL triple therapy in patients with failure of either standard triple therapy (100% vs. 75.0%; P=0.010) or non-bismuth quadruple therapy (95.0% vs. 52.6%; P=0.003)., Conclusions: Ten-day PPI-bismuth-tetracycline-levofloxacin quadruple therapy is a good option for rescue treatment of H. pylori infection following failure of standard triple or non-bismuth quadruple therapy.

Objective: This was a prospective study aiming to investigate whether levofloxacin plus bismuth-based quadruple therapy was more effective than levofloxacin-based triple therapy after failed first-line eradication therapies for Helicobacter pylori (H. pylori) infection., Methods: Sixty-seven patients infected with H. pylori were randomly assigned to two groups; the levofloxacin plus bismuth-based quadruple therapy group (RBAL [n = 33]; rabeprazole 20 mg twice daily, bismuth subcitrate 120 mg four times daily, amoxicillin 1 g twice daily and levofloxacin 500 mg once daily, for 10 days) and the levofloxacin-based triple therapy group (RAL [n = 34]; rabeprazole 20 mg twice daily, amoxicillin 1 g twice daily and levofloxacin 500 mg once daily, for 10 days). Endoscopy was performed 4-8 weeks after H. pylori eradication to assess treatment response. We followed up patient response and compliance and checked their resistance to antibiotics., Results: Intention-to-treat analysis revealed that both groups had similar eradication rates (RBAL vs RAL: 84.8% [95% confidence interval {CI} 72.6-97.1%] vs 67.6% [95% CI 51.9-83.4%], P = 0.0987). No significant differences in compliance or adverse events were found (P = 0.9829 and 0.0720). Epsilometer test showed that most eradication failure cases were levofloxacin-resistant., Conclusions: Adding bismuth subcitrate to levofloxacin-based triple therapy was not more effective than not doing so, but no further side effects were noted. Both eradication therapies were equally safe and patients had the same tolerance to both regimens. Resistance rate to levofloxacin may be important when choosing second-line therapy., (© 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Because Helicobacter pylori (H pylori) would cause carcinogenesis of the stomach, we need sufficient information for deciding on an appropriate strategy of eradication. Many factors affect the efficacy of eradication including antimicrobial resistance (especially clarithromycin resistance) and CYP2C19 polymorphism. This study was to survey the efficiency of gastric juice for detecting H pylori infection, clarithromycin resistance, and CYP2C19 polymorphism.The specimens of gastric juice were collected from all patients while receiving gastroscopy. DNA was extracted from gastric juice and then urease A and cag A were amplified by polymerase chain reaction (PCR) for detecting the existence of H pylori. By PCR-restriction fragment length polymorphism (PCR-RFLP), the 23S rRNA of H pylori and CYP2C19 genotypes of host were examined respectively. During endoscopy examination, biopsy-based specimens were also collected for rapid urease test, culture, and histology. The blood samples were also collected for analysis of CYP2C19 genotypes. We compared the results of gastric juice tests with the results of traditional clinical tests.When compared with the results from traditional clinical tests, our results from gastric juice showed that the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy to detect H pylori infection were 92.1% (105/114), 92.9% (143/154), 90.5% (105/116), 94.1% (143/152), and 92.5% (248/268), respectively. The SEN, SPE, PPV, and NPV to detect clarithromycin resistance were 97.3% (36/37), 91.5% (43/47), 90.0% (36/40), and 97.7% (43/44), respectively. By using PCR-RFLP, the consistency of human CYP2C19 gene polymorphism from blood samples and gastric juice was as high as 94.9% (149/157).The manipulated gastric juice is actually an effective diagnostic sample for evaluation of H pylori existence, clarithromycin resistance, and host CYP2C19 polymorphism.

The bismuth-based quadruple regimen has been applied in Helicobacter pylori rescue therapy worldwide. The non-bismuth-based quadruple therapy or "concomitant therapy" is an alternative option in first-line eradication but has not been used in second-line therapy. Discovering a valid regimen for rescue therapy in bismuth-unavailable countries is important. We conducted a randomized controlled trial to compare the efficacies of the standard quadruple therapy and a modified concomitant regimen. One hundred and twenty-four patients were randomly assigned into two groups: RBTM (rabeprozole 20 mg bid., bismuth subcitrate 120 mg qid, tetracycline 500 mg qid, and metronidazole 250 mg qid) and RATM (rabeprozole 20 mg bid., amoxicillin 1 g bid., tetracycline 500 mg qid, and metronidazole 250 mg qid) for 10 days. The eradication rate of the RBTM and RATM regimen was 92.1% and 90.2%, respectively, in intention-to-treat analysis. Patients in both groups had good compliance (~96%). The overall incidence of adverse events was higher in the RATM group (42.6% versus 22.2%, P = 0.02), but only seven patients (11.5%) experienced grades 2-3 events. In conclusion, both regimens had good efficacy, compliance, and acceptable side effects. The 10-day RATM treatment could be an alternative rescue therapy in bismuth-unavailable countries.

The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.

Eradication of Helicobacter pylori infection has become an important issue recently, because this bacterial species cluster can cause many gastrointestinal diseases. Elevated antibiotic resistance is related to an increasing failure rate of H. pylori eradication. Standard triple therapy is still the first-line therapy; however, according to the Maastricht IV Consensus Report, it should be abandoned in areas of high clarithromycin resistance. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential, concomitant, and hybrid therapies. Quinolone-based triple therapy may be considered as first-line therapy in areas of clarithromycin resistance >15-20% and quinolone resistance <10%. Unique second-line therapy is still unclear, and bismuth-containing quadruple therapy or levofloxacin-based triple therapy can be used as rescue treatment. Third-line therapy should be under culture guidance to select the most effective regimens (such as levofloxacin-based, rifabutin-based, or furazolidone-based therapies). Antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports., (Copyright © 2013. Published by Elsevier B.V.)

Background: Helicobacter pylori (H. pylori) was linked with several extragastrointestinal diseases, including preeclampsia and intrauterine growth restriction of fetus. One of the signals which can be transferred from mother to fetus is the H. pylori IgG antibody. Aims. We utilized a commercial immunochromatographic kit to detect the antibody in maternal and cord serum., Methods: Three hundred and forty-six females were enrolled and the blood samples were collected on antenatal examination and on delivery. The maternal H. pylori infection was determined by stool H. pylori antigen test., Results: One hundred and five females (30.3%) were H. pylori-infected, and the prevalence was higher in immigrants (43.5%) than in Taiwanese (28.7%, P = 0.058). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the kit were 77.1%, 88.0%, 73.6%, 89.8%, and 84.7%, respectively. This kit also had similar performance in cord serum. Comparing to the maternal result on delivery, this kit offered a consistent performance in antenatal maternal serum (kappa coefficient 0.92) and in cord serum (kappa coefficient 0.88)., Conclusions: H. pylori IgG antibody can be transferred through the placenta into the fetal circulation. However, accuracy of the test kit needs to be evaluated before utilization in screening.

Objectives: This prospective study was designed to compare the efficacies of levofloxacin-containing and high-dose metronidazole-containing quadruple therapies after failure of standard triple therapies., Methods: A total of 150 Helicobacter pylori-infected patients were enrolled in our study and randomly assigned to levofloxacin-containing quadruple therapy (EBTL group) (40 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of tetracycline four times daily and 500 mg of levofloxacin once daily for 10 days) (n = 76) or high-dose metronidazole-based quadruple therapy (EBTM group) (40 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of tetracycline four times daily and 500 mg of metronidazole four times daily for 10 days) (n = 74). Follow-up endoscopy or urea breath test was done 16 weeks later to assess the treatment response. Patients' responses, CYP2C19 genotypes and antibiotic resistances were also examined. All participants, caregivers and those assessing the outcomes were blinded to group assignment., Results: Intention-to-treat analysis revealed that both groups showed similar eradication rates: EBTL, 78.9% (60/76) (95% CI 69.7%-88.1%) and EBTM, 79.7% (59/74) (95% CI 70.5%-88.7%) [risk ratio (RR) 0.97, 95% CI 0.44-2.14]. Per-protocol results were EBTL = 87.0% (60/69) (95% CI 79.4%-94.9%) and EBTM = 90.8% (59/65) (95% CI 83.8%-97.8%) (RR 0.68, 95% CI 0.23-2.0). We did not find significant differences in compliance (RR 0.5, 95% CI 0.54-2.3) and adverse events (RR 1.11, 95% CI 0.54-2.3) between the two groups. Logistic regression analysis showed that only compliance was an important predictor for eradication failure. CYP2C19 polymorphism did not influence the eradicating effect., Conclusions: The 10 day bismuth quadruple therapies with high-dose metronidazole or levofloxacin were effective even in areas with high resistance. These two therapies were equally safe and tolerated. Besides this, the metronidazole-containing therapy was cheaper. So it is persuasive that high-dose metronidazole-containing quadruple therapy could be a good choice for second-line H. pylori eradication in areas with high resistance.

Aim: To evaluate the influence of multiple samplings during esophagogastroduodenoscopy (EGD) on the accuracy of the rapid urease test, and the validity of newly developed rapid urease tests, HelicotecUT plus test and HelicotecUT test, CLO test and ProntoDry test., Methods: A total of 355 patients undergoing EGD for dyspepsia were included. Their Helicobacter pylori (H. pylori) treatment status was either naïve or eradicated. Six biopsy specimens from antrum and gastric body, respectively, were obtained during EGD. Single antral specimens and dual (antrum + body) specimens were compared. Infection status of H. pylori was evaluated by three different tests: culture, histology, and four different commercially available rapid urease tests (RUTs)-including the newly developed HelicotecUT plus test and HelicotecUT test, and established CLO test and ProntoDry test. H. pylori status was defined as positive when the culture was positive or if there were concordant positive results among histology, CLO test and ProntoDry test., Results: When dual specimens were applied, sensitivity was enhanced and RUT reaction time was significantly reduced, regardless of their treatment status. Thirty minutes were enough to achieve an agreeable positive rate in all the RUTs. Both newly developed RUTs showed comparable sensitivity, specificity and accuracy to the established RUTs, regardless of patient treatment status, RUT reaction duration, and EGD biopsy sites., Conclusion: Combination of antrum and body biopsy specimens greatly enhances the sensitivity of rapid urease test and reduces the reaction duration to 30 min.

Background: Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC., Methods: One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression., Results: In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 - 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 - 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 - 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 - 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 - 0.47, p for multiplicative interaction 0.008), Conclusion: H. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus.

Objectives: This prospective study was designed to determine the efficacy of a levofloxacin-based rescue therapy for Helicobacter pylori infection after failure of standard triple therapies. We also surveyed the predictors of this rescue therapy., Patients and Methods: From June 2005 to March 2007, 1036 patients infected with H. pylori received standard triple regimens (proton pump inhibitor, clarithromycin and amoxicillin). H. pylori eradication was achieved in 855 (82.5%) subjects. One hundred and sixty-six eradication-failure patients were enrolled and randomly assigned to receive a 7 day eradication therapy with esomeprazole, bismuth subcitrate, tetracycline and metronidazole (EBTM) or esomeprazole, amoxicillin and levofloxacin (EAL). Follow-up endoscopy was done 16 weeks later to assess the treatment response. Patients' response, CYP2C19 genotypes and antibiotic resistances were also examined., Results: Intention-to-treat analysis revealed that both groups showed similar eradication rates [EBTM 63.9%; 95% confidence interval (CI): 53.6-74.2 and EAL 69.9%; 95% CI: 60.1-79.7] (P = 0.89). Per-protocol results were EBTM = 84.1% (95% CI: 75.1-93.1) and EAL = 75.3% (95% CI: 65.8-84.8) (P = 0.82). Both regimens had similar compliance (P = 0.32), but the EBTM group had more adverse events (P = 0.27). Logistic regression analysis showed that poor compliance, CYP2C19 homozygous extensive metabolizer genotype and levofloxacin resistance were important predictors for eradication failure., Conclusions: The EAL regimen can achieve an efficacy similar to that of the standard EBTM therapy. It may be very useful in countries where bismuth salts are not available. Compliance, CYP2C19 genotype and resistances to antibiotics may influence the outcome of levofloxacin-based rescue therapy. It seems advisable to reserve levofloxacin for rescue treatment to avoid an increase in the resistance phenomenon.

Background: Our aim was to evaluate the accuracy of the stool antigen test and the optimal time point for detecting Helicobacter pylori infection in a Mongolian gerbil model., Methods: We inoculated 8-week-old Mongolian gerbils with H. pylori (Vac A (+)/CagA(+)). The gerbil-infected model was developed as follows: H. pylori was put into broth (about 10(9) CFU/ml), and 50 gerbils were then fed with 1 ml intragastrically twice within a 3-day interval. Another ten gerbils were fed broth only. Twenty-six weeks after the inoculation, the gerbils were killed. The gastric mucosa was sampled for a series of examinations including culture, histology, rapid urease test, and polymerase chain reaction. Stool samples for a stool antigen test, H. pylori-specific stool antigen assay (HpSA), were collected during weeks 4, 6, 8, 12, and 26 after inoculation. Of the 50 gerbils inoculated with H. pylori, the inoculation was successful in 88%. Severe active gastritis, ulceration, and intestinal metaplasia were obvious., Results: The HpSA test results were sensitivity, 88.6%; specificity, 100%; positive predictive value (PPV), 100%; negative predictive value (NPV), 54.5%, and accuracy, 90%. The HpSA test began to be more sensitive and accurate (P < 0.05) beginning during week 6 after inoculation. We also found that H. pylori could be detected earlier and more easily in the group with high H. pylori density., Conclusions: HpSA seems to be suitable for confirming colonization of gerbils with H. pylori. The optimal testing time point is around 6 weeks after inoculation. This test is a good choice for long-term observation of H. pylori infection in Mongolian gerbils.

Background/aims: To evaluate the accuracy and clinical utility of two immunochromatographic methods, the STAT-PAK and RAPIRUN tests, in detecting H. pylori antibodies in serum and in urine separately., Methodology: 130 patients undergoing gastroendoscopy (70 men and 60 women; mean age, 50.6 years) were enrolled in this study. Their H. pylori status was determined based on 4 tests: CLO test, culture, histology and UBT test. The H. pylori positive status was confirmed when the culture was positive, or 2 of the other 3 tests were positive. Serum samples and urine samples were collected. We used the STAT-PAK test for detecting H. pylori antibodies in serum, and read the results 24 hours later. Antibodies were also detected in urine by the RAPIRUN test, with a reading time of 25 minutes. 3 doctors read the results of both tests separately, and a positive result was determined when at least 2 of the doctors read a positive result., Results: In the STAT-PAK pretest using serum samples from 21 randomly selected patients (16 patients with H. pylori infection and 5 patients without infection), the sensitivity at 1-hour and 24-hour reading time was 18.7% and 37.5%. Specificity in both reading times was the same at 100%. Of 129 patients, 82 (64%) were H. pylori infected and 47 (36%) were uninfected. The sensitivity, specificity, and positive and negative predictive values were 31.7%, 93.6%, 89.6% and 44.0% in the STAT-PAK test with a 24-hour reading time, and 93.9%, 85.1%, 91.6%, 88.8% in the RAPIRUN test. One female was excluded because of an invalid urine test., Conclusions: The urine RAPIRUN test is a faster and more accurate office-based test than the serum STAT-PAK test for detecting the H. pylori infection in untreated patients in Taiwan. The non-invasive urine RAPIRUN test can be used as a large scale screening test for H. pylori status, particularly in children, uncooperative patients, those who have a family history of gastric cancer, or patients who can not tolerate the suffering of endoscopic examination.