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"Graham, David"
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Why the Vonoprazan Helicobacter pylori Therapies in the US-European Trial Produced Unacceptable Cure Rates
IntroductionHelicobacter pylori infects a large percentage of the world’s population and is etiologically related to gastric cancer. The U.S. Food and Drug Administration recently approved two 14-day vonoprazan-containing regimens (vonoprazan–amoxicillin with or without clarithromycin) for H. pylori infections in the United States/Europe.MethodsWe critically reviewed the trial methods to discover why the results were unacceptable low [i.e., no regimen achieved clinically acceptable (≥ 90%) or even conditionally acceptable cure rates (≥ 85%)]. Cure rates with antibiotic susceptible strains were 84.7 for vonoprazan triple therapy, 78.5 for vonoprazan–amoxicillin, and 78.7 for lansoprazole triple therapy, respectively. As was previously shown in Japan, the benefit from adding clarithromycin to vonoprazan–amoxicillin was minimal and the majority of the clarithromycin administered was unnecessary.ResultsThe possible reasons for failure to achieve high cure rates discussed include (a) reduced intragastric antibiotic concentrations, (b) an increase in heteroresistance, and (c) failure to achieve an intragastric pH conducive for amoxicillin to eradicate the infection. In addition, there was no pilot study or other attempt to optimize any regimen.ConclusionThe most likely reason for failure was failure to achieve high intragastric concentrations of antibiotics or to achieve an intragastric pH conducive for amoxicillin to be active. Importantly, vonoprazan triple therapy resulted in > 10 tons of unneeded clarithromycin/million courses of vonoprazan triple therapy. Antibiotic misuse combined with low cure rates suggest that vonoprazan–clarithromycin triple therapies should not be prescribed for H. pylori infection. Dual vonoprazan–amoxicillin therapy has proven effective elsewhere and after optimization may eventually prove useful in the U.S./Europe.
Journal Article
Mechanotransduction: from the cell surface to the nucleus via RhoA
Cells respond and adapt to their physical environments and to the mechanical forces that they experience. The translation of physical forces into biochemical signalling pathways is known as mechanotransduction. In this review, we focus on two aspects of mechanotransduction. First, we consider how forces exerted on cell adhesion molecules at the cell surface regulate the RhoA signalling pathway by controlling the activities of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In the second part of the review, we discuss how the nucleus contributes to mechanotransduction as a physical structure connected to the cytoskeleton. We focus on recent studies that have either severed the connections between the nucleus and the cytoskeleton, or that have entirely removed the nucleus from cells. These actions reduce the levels of active RhoA, thereby altering the mechanical properties of cells and decreasing their ability to generate tension and respond to external mechanical forces.
This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.
Journal Article
Antimicrobial Susceptibility Testing for Helicobacter pylori Is Now Widely Available: When, How, Why
Theoretically, proton pump inhibitor or vonoprazan plus amoxicillin dual therapy are candidates for an empiric first-line choice, especially in Asia, but the regimen has not yet been optimized for use in Western countries. AML offers a reflex option for stool antigen or polymerase chain reaction testing using NGS to reflexively test stool for the 6 commonly prescribed antibiotics. [...]the US Food and Drug Administration warning about serious long-term side effects of quinolone therapy dictate that fluoroquinolones be used only in susceptibility-based therapies. D.Y.G. is supported in part by the Office of Research and Development Medical Research Services Department of Veterans Affairs, Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center.
Journal Article
Cross-roads for meta-analysis and network meta-analysis of H. pylori therapy
Helicobacter pylori infections are responsible for tremendous morbidity and mortality worldwide, leading to efforts to eradicate the organism. However, the effectiveness of antimicrobial therapy has been undermined by the progressive development of antimicrobial resistance. Treatments and treatment guidelines have been based on traditional pairwise meta-analyses of randomised controlled trials. More recently, network meta-analyses have also been used in an attempt to provide useful information to the clinician regarding which therapies appear best and which to avoid as the least efficacious. However, both forms of meta-analysis have been undermined by the same problems including the poor quality of the clinical trials using unoptimised regimens and incomparable comparisons related to marked geographic and ethnic genotypic and phenotypic heterogeneity. In addition, the comparator regimens often consist of invalid strawman comparisons. New approaches concerning H. pylori treatment and analysis of therapies are needed. H. pylori therapies should be based on antimicrobial stewardship, as in other infectious diseases. This approach requires the use of only optimised therapies proven to be reliably highly effective in the local population (eg, a cure rate of >90%) for both the study and the comparator regimens. Meta-analyses should be restricted to regimens that meet these criteria and must take into account the presence of marked geographical and host genetic and phenotypic heterogeneity. In addition, to provide clinically relevant results, treatment outcomes should focus on, and present, actual cure rates in addition to odd ratios.
Journal Article