Thank you so much for the fantastic insights in "What I Read Last Week." Each pearl deserves its own commentary, but I'll keep it brief by focusing on your favorite article of the week by Pan et al. on "Gastric cancer prevention through community eradication of Helicobacter pylori: a cluster-randomized controlled trial."[ 1]
The evolution of understanding "acid-peptic" disease—from its association with gastric hypersecretion, Type A personality, and hydrogen ion retrodiffusion, to identifying Helicobacter pylori (originally Campylobacter pylori) as a "causal" agent of gastric cancer—has sparked heated debates across specialties. Whether discussing with gastroenterologists, infectious disease specialists, oncologists, or surgeons, this topic often shifts from a neurovegetative to an infectious perspective, highlighted by the shared Nobel Prize awarded to its discoverers.
It comes as no surprise to me (and it confirms the thesis we've held for the last 20 years) that, as shown by Pan et al., gastric cancer incidence is lower among those uninfected, followed by those who received curative therapy, and finally, those with untreated H. pylori infections.
However, when comparing those who underwent H. pylori eradication therapy to those who received only a PPI, the relative risk reduction for developing gastric cancer is a mere 14% (95% CI from 1%-26%), with a number needed to treat (NNT) of 182. No differences in mortality between treated and untreated groups are observed, which, in my opinion, does not support antibiotic eradication treatment at all—especially considering the global rise in bacterial resistance that this approach contributes to.
Ten years ago, Ford et al. [2], conducted a meta-analysis of controlled clinical trials that demonstrated, though not significantly, that eradication is more effective if there are no pre-neoplastic lesions. Ultimately, all the protective benefits are attributed EXCLUSIVELY to the addition of antioxidants to the treatment (see graph 4). Antibiotic eradication alone is ineffective (OR 0.82, not significant), compared to the clinically significant protective effects (OR 0.52, CI 95% 0.31-0.87) of adding vitamins and antioxidants, highlighting inflammation as a causal pathogenic mechanism where Helicobacter might merely be an incidental factor. Warning: See graph 6 of Ford's paper, which indicates that eradication of Helicobacter may increase all-cause mortality by 9% (although not significantly).
The question, with all due respect, should not be whether we could adopt a "detection and treatment" approach for H. pylori in populations at high risk of gastric cancer. From my perspective, the hypothesis that warrants future study is that a healthy individual inherently has gastric health and vice versa, as confirmed by Pan et al., where individuals free of infection exhibit lower all-cause mortality. In infected patients, there might be a local immunodeficiency in their gastric environment, exacerbated by inflammation, possibly due to factors like a toxic diet, nitrosamines from food combustion, environmental influences, and a lack of harmony with the Universe—"multiple associated previous factors"—that induce immunodeficiency. This predisposes individuals to Helicobacter colonization and subsequent cancer development, making the infectious agent more of a marker of immunodeficiency rather than the primary cause. In this sense, H. pylori is an intermediate effect in a causal chain, and our focus should not be on its eradication, but rather on using it as an indicator of whether we are succeeding in improving the gastric microenvironment.
Conceptually, if an individual requires two or more escalating antibiotics to "cure" H. pylori, do they not exhibit signs of immunodeficiency?
Ensuring a healthy diet (free from added sugar, processed products, and transgenic polyunsaturated vegetable oils), along with avoiding cigarettes, limiting coffee and alcohol consumption, and incorporating chamomile or Calendula officinalis tea, might prove to be a more effective strategy than undergoing multiple cycles of antibiotics that often fail to achieve complete eradication and have a high likelihood of reinfection.
How do we engage in this discussion with specialists without challenging their core beliefs?
Best regards,
Jairo
References cited:
(1)Pan, KF., Li, WQ., Zhang, L. et al. Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03153-w
(2) Ford, A. C., Forman, D., Hunt, R. H., Yuan, Y., & Moayyedi, P. (2014). Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ (Clinical research ed.), 348, g3174. https://doi.org/10.1136/bmj.g3174
I had a perforated ulcer in my stomach and almost died years ago. The cause--H. pylori. The over diagnosis factor scares me. There are autopsies that have been done on ppl and they discover they had an advanced form of cancer but didn't know. Some of these ppl are in their eighties and nineties. Interesting because I think once you get that diagnosis it's all downhill. Not saying you shouldn't--just saying. Your posts make me think about more about modern medicine. Very informative! sabrinalabow.substack.com
Thank you for acknowledging Richard Lehman and his weekly BMJ blog, which is sorely missed indeed. One of the most British blogs I've ever known. Of corse such a blog would include gardening. You may want to consider subscribing to TOCs of journals outside the US, Adam ;-)
This was great! Is this a new thing, cuz I don’t recall seeing this before. I read TWIC by Dr. Mandrola religiously, but no longer have the time/energy/inclination to keep up with GIM literature, so a series like this would be a welcome update. This could become “TWIGIM”.
The longitudinal cancer study is interesting. The y axes is log scale, so those 6 types of cancers in the included graph here have actually exploded in incidence. But before we infer “increased (unnecessary) diagnosis” vs “improved treatment” to account for those generally flat mortality curves, we need to know if effective treatments have in fact been developed over the timeframe, for each of those cancer types (by organ system, let alone cell type). And I don’t know the answer to that.
Hey Adam. First one of these EBM wekly reflections I had a chance to read. Enjoyed a lot … my only question, you may be approaching the batting average but do you really fancy you have Ichiro’s arm from right field? ⚾️
I have questions about the H. Pylori study. First, if H. Pylori is really the causative factor in gastric cancer, why is there still such a big gap between those who tested negative for it and those who received treatment for it, beginning several years after treatment was administered? Second, PPIs are not a neutral intervention. They're not designed for long-term use and have consequences of their own for the digestive system. This could be sufficient to explain the gap between the PPI and the treated groups. A truly neutral intervention in the third arm might show no effect of H. Pylori treatment on gastric cancer at all. Is there something else I'm missing? Thanks for the post!
"First, if H. Pylori is really the causative factor in gastric cancer, why is there still such a big gap between those who tested negative for it and those who received treatment for it, beginning several years after treatment was administered? "
Because H.Pylori has already caused damage to stomach epithelial DNA that isn't undone by eradicating the bacteria?
Your second study "The authors propose many different causes for the increasing incidence of many different cancers. I prefer the simpler explanation of over diagnosis." While that may be true if would be an interesting study to see the quality of GUT bacteria (which some relate to healthy immune system) and the incidence of cancer. We know that "gut issues" of all sorts have been dramatically higher of late.
Also noted that this study went to 2019. If what some are saying is true about the vaccine I can't wait to see what the numbers after 2019 look like!
I’m not a doctor or researcher. That may be why I don’t understand the question at the end of the H pylori study. Why would we eventually have a screen and treat approach if there’s no difference in mortality when H Pylori is treated? Why screen for something you can’t treat? Why treat something when treatment doesn’t decrease mortality?
“The absolute risk reduction comparing (successfully) treated patients and untreated patients (per protocol here) was 0.55%. H. pylori negative patients had lower overall and gastric cancer related mortality. Mortality did not differ between the treated and untreated groups.
Might we eventually have a “screen and treat” approach to H. pylori in populations at high risk for gastric cancer?”
My comment exactly! Utterly stupid to contemplate an intervention on this scale that doesn't decrease mortality.... Unless you have convincing evidence it improves quality of life, and only if your intervention is a decision tool given to patients telling them the treatment isn't going to make them live any longer and inviting them to make an informed choice around whether to do it or not
About the article in Lancet Public health: An increased incidence may reflect increased early detection (and, therefore, overdiagnosis), but also an actual increase. The absence of an increase in mortality when the incidence increases could be due to overdiagnosis, but also to improved treatment. It is possible to distinguish these possibilities because overdiagnosis is linked to early detection, i.e., to an increasing incidence of cancer in younger people (at the time of screening, for example). An analysis by age group can provide information both on overdiagnosis and on improving treatment.
Pls do continue. Richard’s space is unfilled and you are best person to do so
Dear Dr. Cifu,
Thank you so much for the fantastic insights in "What I Read Last Week." Each pearl deserves its own commentary, but I'll keep it brief by focusing on your favorite article of the week by Pan et al. on "Gastric cancer prevention through community eradication of Helicobacter pylori: a cluster-randomized controlled trial."[ 1]
The evolution of understanding "acid-peptic" disease—from its association with gastric hypersecretion, Type A personality, and hydrogen ion retrodiffusion, to identifying Helicobacter pylori (originally Campylobacter pylori) as a "causal" agent of gastric cancer—has sparked heated debates across specialties. Whether discussing with gastroenterologists, infectious disease specialists, oncologists, or surgeons, this topic often shifts from a neurovegetative to an infectious perspective, highlighted by the shared Nobel Prize awarded to its discoverers.
It comes as no surprise to me (and it confirms the thesis we've held for the last 20 years) that, as shown by Pan et al., gastric cancer incidence is lower among those uninfected, followed by those who received curative therapy, and finally, those with untreated H. pylori infections.
However, when comparing those who underwent H. pylori eradication therapy to those who received only a PPI, the relative risk reduction for developing gastric cancer is a mere 14% (95% CI from 1%-26%), with a number needed to treat (NNT) of 182. No differences in mortality between treated and untreated groups are observed, which, in my opinion, does not support antibiotic eradication treatment at all—especially considering the global rise in bacterial resistance that this approach contributes to.
Ten years ago, Ford et al. [2], conducted a meta-analysis of controlled clinical trials that demonstrated, though not significantly, that eradication is more effective if there are no pre-neoplastic lesions. Ultimately, all the protective benefits are attributed EXCLUSIVELY to the addition of antioxidants to the treatment (see graph 4). Antibiotic eradication alone is ineffective (OR 0.82, not significant), compared to the clinically significant protective effects (OR 0.52, CI 95% 0.31-0.87) of adding vitamins and antioxidants, highlighting inflammation as a causal pathogenic mechanism where Helicobacter might merely be an incidental factor. Warning: See graph 6 of Ford's paper, which indicates that eradication of Helicobacter may increase all-cause mortality by 9% (although not significantly).
The question, with all due respect, should not be whether we could adopt a "detection and treatment" approach for H. pylori in populations at high risk of gastric cancer. From my perspective, the hypothesis that warrants future study is that a healthy individual inherently has gastric health and vice versa, as confirmed by Pan et al., where individuals free of infection exhibit lower all-cause mortality. In infected patients, there might be a local immunodeficiency in their gastric environment, exacerbated by inflammation, possibly due to factors like a toxic diet, nitrosamines from food combustion, environmental influences, and a lack of harmony with the Universe—"multiple associated previous factors"—that induce immunodeficiency. This predisposes individuals to Helicobacter colonization and subsequent cancer development, making the infectious agent more of a marker of immunodeficiency rather than the primary cause. In this sense, H. pylori is an intermediate effect in a causal chain, and our focus should not be on its eradication, but rather on using it as an indicator of whether we are succeeding in improving the gastric microenvironment.
Conceptually, if an individual requires two or more escalating antibiotics to "cure" H. pylori, do they not exhibit signs of immunodeficiency?
Ensuring a healthy diet (free from added sugar, processed products, and transgenic polyunsaturated vegetable oils), along with avoiding cigarettes, limiting coffee and alcohol consumption, and incorporating chamomile or Calendula officinalis tea, might prove to be a more effective strategy than undergoing multiple cycles of antibiotics that often fail to achieve complete eradication and have a high likelihood of reinfection.
How do we engage in this discussion with specialists without challenging their core beliefs?
Best regards,
Jairo
References cited:
(1)Pan, KF., Li, WQ., Zhang, L. et al. Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03153-w
(2) Ford, A. C., Forman, D., Hunt, R. H., Yuan, Y., & Moayyedi, P. (2014). Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ (Clinical research ed.), 348, g3174. https://doi.org/10.1136/bmj.g3174
I had a perforated ulcer in my stomach and almost died years ago. The cause--H. pylori. The over diagnosis factor scares me. There are autopsies that have been done on ppl and they discover they had an advanced form of cancer but didn't know. Some of these ppl are in their eighties and nineties. Interesting because I think once you get that diagnosis it's all downhill. Not saying you shouldn't--just saying. Your posts make me think about more about modern medicine. Very informative! sabrinalabow.substack.com
Thank you for acknowledging Richard Lehman and his weekly BMJ blog, which is sorely missed indeed. One of the most British blogs I've ever known. Of corse such a blog would include gardening. You may want to consider subscribing to TOCs of journals outside the US, Adam ;-)
I can barely keep up with the 3 I do subscribe to!
This was great! Is this a new thing, cuz I don’t recall seeing this before. I read TWIC by Dr. Mandrola religiously, but no longer have the time/energy/inclination to keep up with GIM literature, so a series like this would be a welcome update. This could become “TWIGIM”.
The longitudinal cancer study is interesting. The y axes is log scale, so those 6 types of cancers in the included graph here have actually exploded in incidence. But before we infer “increased (unnecessary) diagnosis” vs “improved treatment” to account for those generally flat mortality curves, we need to know if effective treatments have in fact been developed over the timeframe, for each of those cancer types (by organ system, let alone cell type). And I don’t know the answer to that.
Thanks for the feedback!
Hey Adam. First one of these EBM wekly reflections I had a chance to read. Enjoyed a lot … my only question, you may be approaching the batting average but do you really fancy you have Ichiro’s arm from right field? ⚾️
I have questions about the H. Pylori study. First, if H. Pylori is really the causative factor in gastric cancer, why is there still such a big gap between those who tested negative for it and those who received treatment for it, beginning several years after treatment was administered? Second, PPIs are not a neutral intervention. They're not designed for long-term use and have consequences of their own for the digestive system. This could be sufficient to explain the gap between the PPI and the treated groups. A truly neutral intervention in the third arm might show no effect of H. Pylori treatment on gastric cancer at all. Is there something else I'm missing? Thanks for the post!
"First, if H. Pylori is really the causative factor in gastric cancer, why is there still such a big gap between those who tested negative for it and those who received treatment for it, beginning several years after treatment was administered? "
Because H.Pylori has already caused damage to stomach epithelial DNA that isn't undone by eradicating the bacteria?
Perhaps! Has that been proposed as a mechanism?
You are ignoring data that has long suggested a causal link...albeit not foolproof
Thank you, Dr. Cifu, I enjoyed the post.
Your second study "The authors propose many different causes for the increasing incidence of many different cancers. I prefer the simpler explanation of over diagnosis." While that may be true if would be an interesting study to see the quality of GUT bacteria (which some relate to healthy immune system) and the incidence of cancer. We know that "gut issues" of all sorts have been dramatically higher of late.
Also noted that this study went to 2019. If what some are saying is true about the vaccine I can't wait to see what the numbers after 2019 look like!
I’m not a doctor or researcher. That may be why I don’t understand the question at the end of the H pylori study. Why would we eventually have a screen and treat approach if there’s no difference in mortality when H Pylori is treated? Why screen for something you can’t treat? Why treat something when treatment doesn’t decrease mortality?
“The absolute risk reduction comparing (successfully) treated patients and untreated patients (per protocol here) was 0.55%. H. pylori negative patients had lower overall and gastric cancer related mortality. Mortality did not differ between the treated and untreated groups.
Might we eventually have a “screen and treat” approach to H. pylori in populations at high risk for gastric cancer?”
My comment exactly! Utterly stupid to contemplate an intervention on this scale that doesn't decrease mortality.... Unless you have convincing evidence it improves quality of life, and only if your intervention is a decision tool given to patients telling them the treatment isn't going to make them live any longer and inviting them to make an informed choice around whether to do it or not
Can you say MONEY?? LOL
About the article in Lancet Public health: An increased incidence may reflect increased early detection (and, therefore, overdiagnosis), but also an actual increase. The absence of an increase in mortality when the incidence increases could be due to overdiagnosis, but also to improved treatment. It is possible to distinguish these possibilities because overdiagnosis is linked to early detection, i.e., to an increasing incidence of cancer in younger people (at the time of screening, for example). An analysis by age group can provide information both on overdiagnosis and on improving treatment.
https://www.researchgate.net/publication/349924779_Cause_of_the_Decades_of_Increase_in_Cutaneous_Melanoma_Overdiagnosis_Ultraviolet_Rays_Non-Ultraviolet_Radiation
https://pubmed.ncbi.nlm.nih.gov/26562826/
https://www.biorxiv.org/content/10.1101/238527v1.full
https://pubmed.ncbi.nlm.nih.gov/31875513/