A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma.

BACKGROUND: The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy. METHODS: We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D). RESULTS: In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years. CONCLUSIONS: 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies. CLINICAL TRIAL REGISTRATION: EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.

A quick flow cytometry protocol to assess Helicobacter pylori viability.

Here we present an easy flow cytometry protocol to study the viability of Helicobacter pylori which also enables the detection of even low live bacteria densities. This protocol has potential utility for a fast and accurate assessment of experimental eradication methods against H. pylori.

Heterogeneity of clinical management of low-grade gastric lymphoma of mucosa-associated lymphoid tissue. An audit of 198 patients in Spain.

INTRODUCTION: Cure of Helicobacter pylori infection in patients with gastric lymphoma of mucosa-associated lymphoid tissue (MALT) leads to long-term clinical remission in the initial stages. As it is a rare disease, its management in clinical practice remains largely unknown and heterogeneity of care remains a concern. The aim was to audit the management and evolution of a large series of low-grade gastric MALT lymphomas from thirteen Spanish hospitals. MATERIALS AND METHODS: Multicentre retrospective study including data on the diagnosis and follow-up of patients with gastric low-grade MALT lymphoma from January 1998 to December 2013. Clinical, biological and pathological data were analyzed and survival curves were drawn. RESULTS: One-hundred and ninety-eight patients were included. Helicobacter pylori was present in 132 (69%) patients and 103 (82%) in tumors confined to the stomach (stage EI) and was eradicated in 92% of patients. Chemotherapy was given in 90 (45%) patients and 43 (33%) with stage EI. Marked heterogeneity in the use of diagnostic methods and chemotherapy was observed. Five-year overall survival was 86% (89% in EI). Survival was similar in EI patients receiving aggressive treatment and in those receiving only antibiotics (p=0.577). DISCUSSION: Gastric MALT lymphoma has an excellent prognosis. We observed, however, a marked heterogeneity in the use of diagnostic methods or chemotherapy in early-stage patients.

Prospective, study comparing the accuracy of two different stool antigen tests (Premier Platinum HpSA and novel ImmunoCard STAT! rapid test) for the diagnosis of Helicobacter pylori infection.

BACKGROUND: At present only monoclonal EIA (enzyme-immunoassay) stool antigen-tests have obtained optimal accuracy in the diagnosis of Helicobacter pylori. Our aim was to evaluate the accuracy of two stool antigen-tests, the validated Premier Platinum HpSA PLUS (EIA test) and the newly available ImmunoCard STAT! HpSA HD (rapid test) for the initial diagnosis and the confirmation of eradication of H. pylori infection. PATIENTS AND METHODS: Patients with indication of H. pylori diagnosis, or confirmation after treatment were included. Data were coded to protect personal data and ensure blindness between tests. Accuracy was considered as coincident diagnosis with the gold standard (13C-urea breath test, UBT). The EIA was used as a bench standard. All stool tests were performed in duplicate. RESULTS: 264 patients completed the protocol (100 naïve, 164 post-eradication). Average age was 52 years, 61% women, 11% ulcer. Positive diagnoses by UBT were 41% for naïve and 17% for post-eradication. Overall ImmunoCard and EIA accuracies were respectively 91% (95%C.I.=88-94%) and 89% (86-93%), sensitivities 72% (67-78%) and 72% (67-78%), and specificities 98% (96-100%), and 95% (92-97%). Concordance between ImmunoCard and EIA was 95% (93-98%). DISCUSSION: Our results indicate that the newly available ImmunoCard rapid stool antigen-test achieves 90% accuracy, with high specificity but suboptimal sensitivity. The ImmunoCard attained equivalent accuracies as the EIA bench standard, with 95% concordance.

Combination of Bismuth and Standard Triple Therapy Eradicates Helicobacter pylori Infection in More than 90% of Patients.

BACKGROUND & AIMS: Due to the poor eradication rates of standard triple therapy, the addition of bismuth salts has been proposed for first-line eradication of Helicobacter pylori. We assessed the effectiveness and safety of the combination of bismuth and the standard, clarithromycin-containing triple therapy in eradication of H pylori infection, using data from a large multi-center registry. METHODS: We performed an interim analysis of data from the European Registry on H pylori Management, a prospective trial registering clinical data and outcomes from infected patients from 27 countries in Europe since 2013. We extracted data on 1141 treatment-naïve patients who received first-line treatment with bismuth salts (240 mg) and a proton pump inhibitor (57% received esomeprazole, 18% received omeprazole, 11% received pantoprazole, and 14% received rabeprazole), amoxicillin (1 g), and clarithromycin (500 mg), all taken twice daily. RESULTS: Intention to treat and per-protocol rates of eradication were 88% and 94%, respectively. Intention to treat eradication increased to 93% in patients who received 14-day treatments. Adverse events occurred in 36% of patients; 76% of these events were mild, with a mean duration of 6 days. In multivariate analysis, eradication was associated with treatment compliance (odds ratio [OR], 13.0), a double dose (equivalent to 40 mg omeprazole) of proton pump inhibitor (OR, 4.7), and 14-day duration of treatment (OR, 2.0). CONCLUSIONS: In an analysis of data from a large multi-center registry, we found the addition of bismuth to 14-day standard triple therapy with clarithromycin and amoxicillin to eradicate H pylori infection in more than 90% of patients, based on intention to treat analysis, with an acceptable safety profile and level of adherence. ClinicalTrials.gov no: NCT02328131.

Protocol of the European Registry on the management of Helicobacter pylori infection (Hp-EuReg).

INTRODUCTION: Helicobacter pylori selectively infects the human stomach, being the most prevalent chronic infection in the world. H pylori presence causes chronic gastritis in 100% of infected patients and is the major cause of relevant diseases such as atrophic gastritis, peptic ulcer disease, and gastric cancer; it is for this reason that from a public health standpoint, it is considered a high-impact pathogen, responsible of a significant morbidity and mortality. Nowadays, there are consensus and clinical guidelines regarding the infection management at a European level and in most of European countries, but no data have shown the level of implementation of these recommendations. The high costs that this infection carries both socially and to the health system require the continuous and systematic assessment of the diagnostic and treatment strategies, as well as the accessibility to diagnostic methods and most efficient drugs. AIM: To register the diagnosis, management strategies, and treatment of H pylori-infected adult patients in the Digestive Services outpatient clinics throughout Europe. METHODS: Noninterventionist prospective multicentre international Registry promoted by the European Helicobacter and Microbiota Study Group. National Coordinators will select recruiting gastroenterologists in their country that will register the H pylori-related routine clinical practice consultations they receive in an electronic case report form (e-CRF) provided by AEG-REDCap. Variables retrieved will include clinical, diagnostic, treatment, eradication confirmation, and outcome data. The database will allow researchers to perform specific subanalyses after approval by the Scientific Committee of the study.

Spanish primary care survey on the management of Helicobacter pylori infection and dyspepsia: Information, attitudes, and decisions.

INTRODUCTION: Dyspepsia and Helicobacter pylori are two of the most relevant digestive conditions in primary care. Several consensuses on the subject have been published, but the assimilation/implementation of these guidelines is uncertain. AIMS AND METHODS: To evaluate the attitudes, perceptions, limitations, and adherence to recommendations of Spanish primary care physicians using an open online survey. Responses were anonymously codified. Estimated margin of error was 3.4%. Responses were weighted by province, gender, age, and type of practice. Survey was performed using the AEG-REDCap platform. RESULTS: A total of 1445 responses, received between December 2017 and April 2018, were analyzed. Women represented 54%, and the average age was 48 years; 59% were from urban context, 20% from semi-urban, and 21% from rural; 93% provided public practice. Over 40% had read at least one Maastricht consensus (24% Maastricht V), and 34% had attended a course related to H. pylori. 16% reported no direct access to any validated diagnostic method, only 44% to urea breath test, and 33% did not systematically refer to eradication confirmation test. The first-line treatment of choice was standard triple therapy in 56%, followed by concomitant therapy (28%). Only 20% of physicians had optimal adherence to recommendations. CONCLUSION: Even though some improvements from guidelines have been partially incorporated, the level of penetration of recommendations is still poor and delayed. To provide optimal primary care, the barriers for implementation, access to diagnostic tests and to continuous medical education, should be removed. Rigorous dissemination, implementation, and evaluation programs are desired in future consensuses.

Meta-analysis of three-in-one single capsule bismuth-containing quadruple therapy for the eradication of Helicobacter pylori.

BACKGROUND: Bismuth-containing quadruple therapy has been suggested as first-line and rescue alternative for Helicobacter pylori eradication. Our objective was to perform a meta-analysis evaluating the efficacy and safety of single capsule Pylera® (bismuth, metronidazole, and tetracycline) plus a proton-pump inhibitor (PPI) in any line of treatment. METHODS: Studies were selected up to October 2018. Outcomes were eradication and adverse events (AEs) rates pooled using the generic inverse variance method. RESULTS: In total, 30 studies (6482 patients) were included in the systematic review. The intention-to-treat (ITT) efficacy was 90% (95% CI: 87%-92%, 21 studies, I2  = 88%) in first-line therapy, 89% (95% CI: 86%-93%, 12 studies, I2  = 78%) in second-line and 82% (95% CI: 78%-87%, nine studies, I2  = 60%) in third-line; with no differences by the type or dosage of PPI used. For metronidazole-resistant infection, the ITT efficacy as first-line therapy was 93% (95% CI: 90%-96%, six studies, I2  = 0%). In second-line therapies where patients had been previously treated with clarithromycin, the ITT efficacy was 90% (95% CI: 87%-93%, 11 studies, I2  = 78%). The overall incidence of AEs was 43% (95% CI: 35%-50%, 24 studies, I2  = 92%) and they were mostly mild. In nearly 3% of the cases, treatment was interrupted due to AEs. CONCLUSIONS: A 10-day treatment with Pylera® achieved an effective eradication rate of approximately 90% both in first- and second-line therapy. This applies regardless of the type and dose of the PPI, in patients with clarithromycin- or metronidazole-resistant strains, and in those previously treated with clarithromycin.

Probiotic supplementation with Lactobacillus plantarum and Pediococcus acidilactici for Helicobacter pylori therapy: A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety, tolerability and efficacy of a probiotic supplementation for Helicobacter pylori (H. pylori) eradication therapy. DESIGN: Consecutive adult naive patients with a diagnosis of H. pylori infection who were prescribed eradication therapy according to clinical practice (10-day triple or nonbismuth quadruple concomitant therapy) randomly received probiotics (1 × 109 colony-forming units each strain, Lactobacillus plantarum and Pediococcus acidilactici) or matching placebo. Side effects at the end of the treatment, measured through a modified De Boer Scale, were the primary outcome. Secondary outcomes were compliance with therapy and eradication rates. RESULTS: A total of 209 patients (33% triple therapy, 66% non-bismuth quadruple therapy) were included [placebo (n = 106) or probiotic (n = 103)]. No differences were observed regarding side effects at the end of the treatment between groups (ß -0.023, P 0.738). Female gender (P < 0.001) and quadruple therapy (P 0.007) were independent predictors of side effects. No differences in compliance were observed, regardless of the study group or eradication therapy. Eradication rates were similar between groups [placebo 95% (95% confidence interval (CI), 89% to 98%) vs probiotic 97% (95% CI, 92% to 99%), P 0.721]. There were no relevant differences in cure rates (>90% in all cases) between triple and quadruple concomitant therapy. CONCLUSION: Probiotic supplementation containing Lactobacillus Plantarum and Pediococcus acidilactici to H. pylori treatment neither decreased side effects nor improved compliance with therapy or eradication rates.

Helicobacter Pylori Treatment Results in Slovenia in the Period 2013-2015 as a Part of European Registry on Helicobacter Pylori Management.

BACKGROUND: Helicobacter pylori (H. pylori) is the most common chronic bacterial infection in the world affecting over 50% of the world's population. H. pylori is a grade I carcinogen, responsible for the development of 89 % of noncardia gastric cancers. In the present study we analyzed the data for H. pylori eradication treatments in Slovenia. PATIENTS AND METHODS: Slovenia is a part of the European Registry on Helicobacter pylori Management from the beginning. In seven medical institutions data for H. pylori eradication treatments was collected for 1774 patients from April 16th 2013 to May 15th 2016. For further modified intention to treat (mITT) analysis 1519 patients were eligible and for per protocol (PP) analysis 1346 patients. RESULTS: Patients' dropout was 11.4%. Eradication rate for 7 day triple therapy with proton pump inhibitor (PPI) + Clarithromycin (C) + Amoxicillin (A) was 88.7% PP and 72.0% mITT; for PPI + C + Metronidazole (M) 85.2% PP and 84.4% mITT. Second line 14 day therapy PPI + A + Levofloxacin had 92.3% eradication rate PP and 87.1% mITT. Ten to fourteen day Bismuth quadruple therapy was the therapy in difficult to treat patients. At the end all patients that adhered to prescribed regimens were cured of their H. pylori infection. CONCLUSIONS: High dropout rate deserves further analysis. Slovenia is still a country with < 15% H. pylori resistance to clarithromycin, triple therapy with PPI plus two antibiotics reaches PP eradication rate > 85%, but mITT eradication rates are suboptimal.

Corrigendum: Research to the N-Power: The Strengths of Networked Clinical Collaboration in Spain.

This corrects the article DOI: 10.1038/ajg.2017.416.

Efficacy and safety of rifaximin associated with standard triple therapy (omeprazole, clarithromycin and amoxicillin) for H. pylori eradication: A phase IV pilot clinical trial.

BACKGROUND: A progressive decrease in Helicobacter pylori eradication rates has been described over the years, driving the need for new antibiotic treatments. AIM: To evaluate the efficacy and safety of the addition of rifaximin (Spiraxin®) to standard triple therapy (omeprazole, amoxicillin and clarithromycin) for the eradication of H. pylori. METHODS: Independent prospective clinical trial (EUDRACT no.: 2013-001080-23). Forty consecutive adult patients were included with H. pylori infection, dyspeptic symptoms and naive to eradication treatment. A full blood test was performed in the first five patients enrolled to evaluate the safety of the treatment. H. pylori eradication was confirmed with the 13C-urea breath test at least four weeks after the end of treatment with rifaximin 400mg/8h, clarithromycin 500mg/12h, amoxicillin 1g/12h and omeprazole 20mg/12h for 10 days. RESULTS: Forty patients were consecutively enrolled, 53% woman, mean age 44 years. Indication for eradication: 60% non-investigated dyspepsia, 38% functional dyspepsia and 2% gastric ulcer. Four patients did not attend the eradication confirmatory breath test. The eradication rate was 61% (95% CI: 45-77%) for the protocol and 55% (40-70%) for intention-to-treat. About 76% of the patients experienced adverse events (35% diarrhea, 14% nausea and 24% metallic taste), none of which was serious. The blood tests did not show significant alterations. CONCLUSION: Acceptable H. pylori eradication rates are not achieved with rifaximin associated with standard triple therapy for 10 days.

Optimization strategies aimed to increase the efficacy of H. pylori eradication therapies.

BACKGROUND: As with any other infectious disease, we should aim for treatments offering ≥90% Helicobacter pylori eradication rates in clinical practice. AIM: To summarize optimization strategies aimed to increase the efficacy of H. pylori eradication therapies. METHODS: A systematic bibliographic search (in PubMed up to August 2016) was designed to identify studies investigating optimization strategies aimed to increase the efficacy of H. pylori eradication therapies. RESULTS: The most direct way to optimize a treatment is using higher doses of drugs unless it has been shown that lower doses are equally effective. Similarly, prescriptions should use 14-day duration unless a shorter scheme has been shown locally to be equally effective. Double-dose proton-pump inhibitor therapy is recommended for triple therapy and may probably increase the efficacy of nonbismuth concomitant regimen as well. The efficacy of triple therapies in the presence of resistance can be significantly improved by the addition of bismuth salts, which offer an additive effect in combination with antibiotics. Overall, probiotics seem to reduce antibiotic side effects, but the increase in eradication rates is not so evident; therefore, they cannot be generally recommended for clinical practice yet. CONCLUSIONS: Using potent acid inhibition and/or higher antibiotic doses-especially by increasing the number of daily intakes-and lengthening treatments up to 14 days improves efficacy in most regimens and should be generally recommended. Triple therapies can be efficiently improved by the addition of bismuth salts, turning them into quadruple therapies. Finally, some treatments will require a combination of optimization strategies to significantly improve results.

Efficacy and Safety of Quinolone-Containing Rescue Therapies After the Failure of Non-Bismuth Quadruple Treatments for Helicobacter pylori Eradication: Systematic Review and Meta-Analysis.

BACKGROUND: Anti-Helicobacter pylori eradication treatment fails in a significant percentage of cases. Although this percentage has been reduced to 5-15% with the use of non-bismuth quadruple therapies, limited data exist regarding rescue after failure of these treatments. AIM: The aim of this study was to systematically review the efficacy and safety of quinolone-containing therapies after the failure of non-bismuth quadruple regimens. METHODS: Studies evaluating the efficacy of second-line quinolone-containing therapies after the failure of non-bismuth sequential or concomitant regimens were selected. Efficacy (by intention to treat) was analyzed using the inverse variance method; safety data were recorded as the occurrence of any adverse event. The risk of bias of each primary study was evaluated using the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool. The quality of the evidence was summarized using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Sixteen studies were included. The 10-day levofloxacin/amoxicillin/proton pump inhibitor (PPI) triple therapy (LT) achieved eradication rates of 80% (95% CI 71-88). Regarding the moxifloxacin/amoxicillin/PPI triple therapy (MT), its efficacy was higher when administered for 14 days instead of 7 days (80 vs 63%). Two studies investigated the levofloxacin/bismuth-containing quadruple therapies (LBQ) obtaining eradication rates over 90%. Safety was similar in all treatments. The sensitivity analyses showed that results for LT were robust, but MT had weak evidence. CONCLUSIONS: Quinolone-containing triple therapies reported eradication rates ≤80%, but LBQ therapies showed encouraging rates. However, the strength of the evidence was very low. The efficacy of LBQ should be corroborated in more studies, and the usefulness of quinolones needs to be evaluated in areas with moderate to high bacterial resistances.