Title: Long-Term Assessment of Helicobacter pylori cagA EPIYA Motif Changes and
Pathology Outcomes in Gastric Biopsies of Dyspeptic Patients: 10-year Follow-up
Version: 3 Date: 14 Sep 2024
Reviewer's report:
This study from Iran aimed to identify changes in the cagA EPIYA motif patterns during a
10-year follow-up and to explore how lifestyle factors such as smoking, alcohol consumption,
gender, and age influence these changes. In about half of the 100 patients included in the study,
notable changes occurred in the motif pattern of H. pylori cagA during the 10-year period. The
study also found a significant association between changes in pathology outcomes with gender
(P= 0.01) and smoking (P= 0.00).
Major Comments
1. Although approved by a local ethics committee in Iran, I find quite unethical the fact that the
patients had not received specific H. pylori treatment upon its initial detection or during the 10-
year period. H. pylori is a class I carcinogen according to the World Health Organization, and not
offering an H. pylori eradication regimen to patients with dyspeptic health issues for 10 whole
years, for the sake of an observational basic research study without any obvious clinical benefit,
seems rather inappropriate and a malpractice, at least to the eyes of a clinician. Were participants
explicitly informed that they would not receive treatment for H. pylori for the entire 10-year
period? Were the risks of non-treatment, such as the progression to gastric ulcers or cancer, fully
explained to them? I am truly concerned about whether the study’s benefits justify the risks.
2.  Antibiotic use over the 10-year period could have inadvertently affected the H. pylori
bacteria (e.g., partial eradication or selection of resistant strains), thus impacting the results.
Not controlling for this variable could undermine the reliability of the study's findings. The
manuscript does not appear to address how these confounding effects were mitigated.
3. The authors should explain how consistent the biopsy procedures were between the initial and
follow-up samples, as this could affect the comparability of the results.
4. The reliance on PCR-based methods alone, without culturing or histopathological
confirmation of H. pylori, might miss cases of bacterial overgrowth, co-infections, or other
pathologies. Also, it is not clear how the changes that occurred in the motif pattern of H. pylori
cagA affected the mucosa histopathology, based on the Correa's cascade of gastric cancer.
Title: Long-Term Assessment of Helicobacter pylori cagA EPIYA Motif Changes and
Pathology Outcomes in Gastric Biopsies of Dyspeptic Patients: 10-year Follow-up
Version: 3 Date: 14 Sep 2024
Reviewer's report:
This study from Iran aimed to identify changes in the cagA EPIYA motif patterns during a
10-year follow-up and to explore how lifestyle factors such as smoking, alcohol consumption,
gender, and age influence these changes. In about half of the 100 patients included in the study,
notable changes occurred in the motif pattern of H. pylori cagA during the 10-year period. The
study also found a significant association between changes in pathology outcomes with gender
(P= 0.01) and smoking (P= 0.00).
Major Comments
1. Although approved by a local ethics committee in Iran, I find quite unethical the fact that the
patients had not received specific H. pylori treatment upon its initial detection or during the 10-
year period. H. pylori is a class I carcinogen according to the World Health Organization, and not
offering an H. pylori eradication regimen to patients with dyspeptic health issues for 10 whole
years, for the sake of an observational basic research study without any obvious clinical benefit,
seems rather inappropriate and a malpractice, at least to the eyes of a clinician. Were participants
explicitly informed that they would not receive treatment for H. pylori for the entire 10-year
period? Were the risks of non-treatment, such as the progression to gastric ulcers or cancer, fully
explained to them? I am truly concerned about whether the study’s benefits justify the risks.
2.  Antibiotic use over the 10-year period could have inadvertently affected the H. pylori
bacteria (e.g., partial eradication or selection of resistant strains), thus impacting the results.
Not controlling for this variable could undermine the reliability of the study's findings. The
manuscript does not appear to address how these confounding effects were mitigated.
3. The authors should explain how consistent the biopsy procedures were between the initial and
follow-up samples, as this could affect the comparability of the results.
4. The reliance on PCR-based methods alone, without culturing or histopathological
confirmation of H. pylori, might miss cases of bacterial overgrowth, co-infections, or other
pathologies. Also, it is not clear how the changes that occurred in the motif pattern of H. pylori
cagA affected the mucosa histopathology, based on the Correa's cascade of gastric cancer.
Please review this paper.
user
Title: Long-Term Assessment of Helicobacter pylori cagA EPIYA Motif Changes and
Pathology Outcomes in Gastric Biopsies of Dyspeptic Patients: 10-year Follow-up
Version: 3 Date: 14 Sep 2024
Reviewer's report:
This study from Iran aimed to identify changes in the cagA EPIYA motif patterns during a
10-year follow-up and to explore how lifestyle factors such as smoking, alcohol consumption,
gender, and age influence these changes. In about half of the 100 patients included in the study,
notable changes occurred in the motif pattern of H. pylori cagA during the 10-year period. The
study also found a significant association between changes in pathology outcomes with gender
(P= 0.01) and smoking (P= 0.00).
Major Comments
1. Although approved by a local ethics committee in Iran, I find quite unethical the fact that the
patients had not received specific H. pylori treatment upon its initial detection or during the 10-
year period. H. pylori is a class I carcinogen according to the World Health Organization, and not
offering an H. pylori eradication regimen to patients with dyspeptic health issues for 10 whole
years, for the sake of an observational basic research study without any obvious clinical benefit,
seems rather inappropriate and a malpractice, at least to the eyes of a clinician. Were participants
explicitly informed that they would not receive treatment for H. pylori for the entire 10-year
period? Were the risks of non-treatment, such as the progression to gastric ulcers or cancer, fully
explained to them? I am truly concerned about whether the study’s benefits justify the risks.
2.  Antibiotic use over the 10-year period could have inadvertently affected the H. pylori
bacteria (e.g., partial eradication or selection of resistant strains), thus impacting the results.
Not controlling for this variable could undermine the reliability of the study's findings. The
manuscript does not appear to address how these confounding effects were mitigated.
3. The authors should explain how consistent the biopsy procedures were between the initial and
follow-up samples, as this could affect the comparability of the results.
4. The reliance on PCR-based methods alone, without culturing or histopathological
confirmation of H. pylori, might miss cases of bacterial overgrowth, co-infections, or other
pathologies. Also, it is not clear how the changes that occurred in the motif pattern of H. pylori
cagA affected the mucosa histopathology, based on the Correa's cascade of gastric cancer.
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