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Life Sciences => Physiology & Medicine => Topic started by: iko on 22/03/2007 21:47:08

Title: The Helicobacter connection
Post by: iko on 22/03/2007 21:47:08
Some friend enjoyed this page from 'New Theories', so I thought to resuscitate it into 'Physiol.& Med.' for the fun of our Newbies and medical students.
The discussion is open:
are there other forms of cancer switched on by 'innocent' infectious agents?

All cancers are fungus related" is a blanket statement that is just incorrect. Perhaps some cancers are caused by certain fungal infections I just don't know. I do know however that all of them are not.


 Shortly, we should be careful not to generalize so much talking about cancer. We fortunately live in a new century and scientific research has done something about it. At least we should talk about different forms of tumors, leukemias and lymphomas. In some particular case scientists finally managed to find a cause and design effective and specific treatments (without toxicity, compared to chemotherapy).

A type of slow growing gastrointestinal lymphomas called MALTomas (Mucosa Associated Lymphoid Tissue) had been treated by standard chemotherapy (CHOP protocol...what a name for a chemo!) until the end of the last century.
There was no suggestion about the origin of this clonal expansion of lymphoid cells in the gut. So the following action had to be blind and toxic.

But in the middle of the '80s two smart researchers from Australia, Barry J. Marshall and J. Robin Warren (Nobel Prize 2005) started their battle: they tried to demonstrate that a common bacteria, Helicobacter pylori, was the major cause of gastroduodenal ulcers in humans.
A standard antibiotic treatment was able to eradicate the bacteria,  allowing the ulcers (wounds in the mucosa) to heal spontaneously.


They initially got veggies and bananas at medical meetings, nevertheless they went on collecting more and more evidence to prove the "infectious theory" of peptic ulcer.
It had to be tough. Medicine is highly conservative for various reasons, and for a long time infectious diseases had been strictly defined: one bacteria, one disease.  Helicobacter pylori is very common in humans...but just few of us develop ulcers.   That was just enough to keep stalling any bright theory for years.
Finally H.p. eradication became the standard treatment.
Now there is growing evidence that persistent Helicobacter infection and continuous release of toxic substances for years, could be one of the causes of stomach cancer.

"...tumors: wounds that never healed..."

"...leukemia&lymphoma: infections never resolved..."

Shortly after it was found that the majority of the patients with MALT lymphomas were carrying H.p. and that eradication therapy alone was able to induce a spontaneous regression of the tumors.
It was obviously too good to be true, so over the years some patients were found to be resistant to antibiotic treatment (2-3 weeks, no chemo!) and their lymphomas where identified as more advanced, with more chromosomal damage, unable to stop growing even when the bacterial stimuli were removed by eradication treatment.

Here we have a model for cancer treatment:

SPOT the cause (if there is any, but never stop searching), remove it as fast as you can. Some clone of cells will STOP proliferating and gradually disappear.
In advanced cases, most cells have been damaged so much and their DNA heavily deranged, that they cannot stop dividing (even in cell cultures).  Trying to block these resistant cells, scientists are now assemblying properly designed molecules, non-toxic "magic bullets" that should take advantage of the great differences at molecular level showed by some tumor cells (abnormal receptors, defective enzymes, etc.).  Time runs fast for everybody, patients and scientists.


H. pylori in a gastric pit


Robert M. Genta, M.D.
David Y. Graham, M.D.
Veterans Affairs Medical Center
Houston, TX 77030

N.Engl.J.Med. 1996;335:250 Jul 25, 1996.       Images in Clinical Medicine


Title: Re: The Helicobacter connection
Post by: Zoey on 23/03/2007 03:36:52
  You always post such interesting and useful information. The distinction you draw between the various disorders, "tumors, lymphomas, leukemias," is much needed to minimize confusion from grouping them into a single heading, as creates major confusion in figuring out how to deal with other disorders such as seizures.
  Of course, this discussion would not be well rounded without turning to how helicobacter pylori might be affected by cod liver oil. A search on the net returned me to one of your posts... not at all surprising.
Title: Re: The Helicobacter connection
Post by: neilep on 23/03/2007 03:48:23
  You always post such interesting and useful information.

Here here !!
Title: Re: The Helicobacter connection
Post by: iko on 23/03/2007 22:04:13
  You always post such interesting and useful information. The distinction you draw between the various disorders, "tumors, lymphomas, leukemias," is much needed to minimize confusion from grouping them into a single heading, as creates major confusion in figuring out how to deal with other disorders such as seizures.
  Of course, this discussion would not be well rounded without turning to how helicobacter pylori might be affected by cod liver oil. A search on the net returned me to one of your posts... not at all surprising.

Thank you for appreciating my efforts to tell (in English!) the H.pylori story.
It is a crucial example of a slow medical research achievement due to...multiple factors! Bacteria were found much before, but the Koch's criteria for infectious disease were not satisfied, so it couldn't be an infectious problem.
As I wrote above, it HAD to be tough.

Now again for leukemia: sometimes you find active infections or a recent common pathogen's 'visit' before diagnosis, but patients are immune suppressed by the leukemia itself, then by the treatment, so those are 'opportunistic' infections.
It could be the opposite at least in a few cases, an infection switching an overidden immune response and boosting an overgrowth of white cells (clones).  In some case it might be possible to stop the process by eradicating the offending germ (bacteria, viruses, protozoa?) and reverse the cell proliferation.
It really is a PERSONAL opinion only.
Very few spontaneous remissions of acute leuk had been reported after heavy antibiotic treatment at diagnosis for fever and septic presentation, even quite recently, but this is obviously not enough.  If I get leuk tomorrow, please put me a drip of at least 3 types of intravenous antibiotics for 2-3 weeks, after that I'll consider chemo (I feel too old for that!).
If anything of the previous hypothesis were real, most of the investigation work still should have to be started from the very beginning. And all this could take ages.
I'd feel quite better knowing that I'm perfectly and totally wrong.

Cod liver oil.  In all this mess of hypotheses and mechanisms to be proven, CLO stands with its serendipitously-found-epidemiological-2decades-old-evidence ready to be used, but still far away from demonstrating anything or shedding any light on this mystery.

This is not the H.pylori case. There you have a very well known germ, you see it and kill it 99% by 2-3 weeks of specific non-toxic treatment. And that's it.
Even some naughty MALTomas regress and disappear: how beautiful!
It wouldn't make sense to look for an alternative treatment there; actually this has been done before.  Garlic had been reported to 'prevent' stomach cancer, and now it has been tested against H.p., but it eradicates it in less than 30%...and so does Vitamin C.  Nobody would choose this type of performance now that we know the whole story and fortunately have a 99% efficacy.
I am so glad that those two nice guys got their well deserved Nobel Prize in 2005!

I hope I explained my point in an proper way..

Title: Re: The Helicobacter connection
Post by: Zoey on 23/03/2007 22:30:57
 Does a teaspoon of COL per day help to smother helicobacters and decrease their population?
Title: Re: The Helicobacter connection
Post by: iko on 23/03/2007 23:01:52
Yes, maybe...who knows!
I should check this out. I wouldn't recommend it for this specifically.
It could 'help' like garlic or ascorbate, I don't know.  But for patients with H.p. gastroduodenal ulcers there is a very effective standard treatment and should be used,  it took so many decades to be 'discovered'!
Cod liver oil is probably good for the more 'mysterious' ailments...

Take care


Title: Re: The Helicobacter connection
Post by: iko on 30/03/2007 22:47:08
Now that Helicobacter pylori from the pathetic role of 'fastidious germ', opportunistic bacterium or 'innocent bystander' has ascended to the throne as a real PATHOGEN, this bad beast is being investigated and found responsible for a long list of crimes:

Childhood Helicobacter pylori infection
 and growth impairment in developing countries: a vicious cycle?

Windle HJ, Kelleher D, Crabtree JE.
School of Medicine, Trinity College Dublin and Dublin Molecular Medicine Centre, Dublin, Ireland.

We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in developing countries is the initiator of a vicious cycle of events that result ultimately in malnutrition and growth impairment.
Acute infection with H. pylori is accompanied by hypochlorhydria, which facilitates the acquisition of other enteropathogens because of removal of the gastric acid barrier, which then results in diarrheal disease and iron-deficiency anemia. This is likely to occur most frequently in developing regions where the prevalence of H. pylori infection is disproportionately high and multiple enteric coinfections are common. The consequent synergistic impact of diarrheal disease and micronutrient deficiency on growth and cognitive function in children has significant public health implications for socioeconomic development in these countries.

Pediatrics. 2007 Mar;119(3):e754-9. Epub 2007 Feb 26.
Title: Re: The Helicobacter connection
Post by: iko on 30/03/2007 23:04:47
H.pylori has finally been added to the list of oncogenic suspects:

Infectious agents and cancer: criteria for a causal relation.

Pagano JS, Blaser M, Buendia MA, Damania B, Khalili K, Raab-Traub N, Roizman B.
Lineberger Comprehensive Cancer Center and Departments of Medicine and Microbiology, University of North Carolina at Chapel Hill, Campus Box 7295, Mason Farm Road, Chapel Hill, NC 27599-7295, USA.

Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas); hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias); and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe.
The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor (Burkitt's lymphoma-EBV; mesothelioma - SV(40)). For others the association is inconsistent (Hodgkin's Disease, gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious agents will continue to illuminate molecular oncogenic processes.

Semin Cancer Biol. 2004 Dec;14(6):453-71


Title: Re: The Helicobacter connection
Post by: iko on 02/04/2007 22:25:25
Hi everybody interested in H.pylori!

I think I owe you a note or comment to this topic.
Here we are NOT suggesting that one specific bug is responsible for numbers of ailments...

The aim of this story is to show how some common germs, previously described as 'fastidious' or 'opportunistic', able to bother us only when immune defenses are low (e.g. AIDS) have recently been found responsible for dreadful diseases of previously unknown origin (idiopathic).

Their eradication by simple antibiotic treatment has been reported as curative in many cases. 
This is the positive new thing.  We should celebrate!
Other 'fastidious' bacteria might be recognized as real pathogen in the near future.
You bet.
Maybe. [;)]


Title: Re: The Helicobacter connection
Post by: iko on 06/06/2007 23:03:38

Helicobacter pylori polyclonally activates murine CD4(+) T cells in the absence of antigen-presenting cells.

Rosenplänter C, Sommer F, Kleemann P, Belkovets A, Schmidt A, Lohoff M.
Institut für Medizinische Mikrobiologie und Hygiene der Universität Marburg, Marburg, Germany.

Helicobacter pylori is a Gram-negative bacterium that causes a variety of gastrointestinal diseases, such as duodenal ulcer and gastric carcinoma. The T cell response against H. pylori is thought to contribute to the pathogenesis of these diseases. Here, we show that mouse-adapted H. pylori is able to polyclonally activate murine CD4(+) T lymphocytes, irrespective of their antigen specificity. Murine T helper cell clones as well as short-term cultured, polyclonal Th1 and Th2 cell lines and a human T cell clone, but not naive CD4(+) T cells, could be activated in this manner. The effect was independent of antigen-presenting cells and required direct contact between H. pylori and T cells. Only whole cells of H. pylori, but not lysates or sonicates were able to activate T cells. The activity was lost after long-term culture of H. pylori on agar-plates. Degradation of H. pylori proteins with specific peptidases dramatically reduced the stimulating ability, implicating that the responsible molecule is likely to be a protein. This unexpected polyclonal T cell stimulatory mechanism may contribute to the T cell-mediated pathogenicity characteristic for H. pylori-mediated diseases.

Eur J Immunol. 2007 Jun 5; [Epub ahead of print]

Title: Re: The Helicobacter connection
Post by: iko on 09/06/2007 14:48:24
Please allow me a cut&paste from 'Toxoplasmosis'
topic here in Physiology and Medicine.

This is NOT about childhood leukemia
specifically and not about cod liver oil either.
Helicobacter pylori is the chief suspect here.
We'll never be able to prove it because the
following story happened more than 20 years ago...

At least in one case leukemia pulled back gently,
all by itself: a Lecture from Mother Nature to
young, smart and open-minded scientists in this world.

So another factor is needed to justify the expansion of the mutated clone.
Toxoplasma could be one of a restricted group of germs capable of jamming some crucial point of the complex immune reaction (involving T-cells, macrophages, complex cytokine interactions) evoked by protozoa and other 'fastidious' germs.
Helicobacter pylori and mycoplasmas might be in the number.

Another 'coincidence' buried in a prestigious
journal like the New England J. of Medicine
ten years ago.  Everybody laugh when I say
that the real title should actually be:
   "A Mother Nature's Lecture on CML"

Spontaneous remission in a patient with chronic myelogenous leukemia.

Musashi M, Abe S, Yamada T, Tanaka J, Gotohda Y, Maeda S, Sato Y, Morioka M, Sakurada K, Minagawa T, Asaka M, Miyazaki T.
Third Department of Internal Medicine, Sapporo, Japan.

N Engl J Med. 1997 Jan 30;336(5):337-9.

Unfortunately there is no abstract and full-text is not free, but as a
NEJMed subscriber I think I am allowed to write a short summary for you:

Case Report
A 45-year-old man was referred to our hospital for evaluation of leukocytosis in January 1985. Three months previously, he had reported tarry stools.
A peptic ulcer was diagnosed and treated with intravenous cimetidine. At that time, leukocytosis, thrombocytosis, and anemia were detected. A bone marrow aspirate showed marked myeloid hyperplasia. Cytogenetic analysis revealed Ph-positive cells in the bone marrow, and a diagnosis of CML was made. During the next month the leukocyte count decreased to 14,400 per cubic millimeter, but it subsequently gradually increased to 31,800 per cubic millimeter before admission to our hospital.
Physical examination on admission revealed anemia and mild hepatosplenomegaly. A complete blood count again showed leukocytosis and thrombocytosis. The neutrophil alkaline phosphatase score was 94 (normal range, 170 to 335). Plasma histamine and prostaglandin E concentrations were within the normal range.
An endoscopic examination revealed an ulcer scar in the duodenal bulb.

Regular follow-up, without chemotherapy, was planned for the patient. In February 1985, the hepatosplenomegaly disappeared. The leukocyte count and platelet count returned to normal in April 1985. As of January 30, 1996, the patient had been well, without any signs of recurrence, for 11 years. Blood counts since June 30, 1994, have been normal.

In 1984 the 'infectious theory' of peptic ulcer was still a matter of debate (1).
Consequently the word helicobacter cannot be found through the whole text (but it's a 1997 paper!).
Intravenous cimetidine had been available for several years, and found quite useful for healing peptic ulcers, and probably making life difficult to H. pylori as well.
In the past, cimetidine had been reported to have also an immunomodulating activity.
Something surely happened in that patient during the following weeks and months, and chronic myeloid leukemia (confirmed by more sophisticated tests over the following years) pulled back gently.
Average survival rate for CML was about <5 years then, with 1/3chance to find a donor for BMT.
In 2000 STI571-Gleevec-Imatinib (2pills/day - no BMT) finally came and life became much easier for CML patients.  According to some distiguished scientists, this new drug actually represents, in oncology, the most important achievement in the last two decades.
Thanks to Dr. Brian Druker and his colleagues from Oregon.
In 2000 that japanese man just turned 60, hopefully healthy and CML free.

ikod   [^]

1)  click down here for "Helicobacter connection"

CML Treatment

Treatment options and outcome from treatment have improved significantly over the years.

Year          Treatment          Survival (months)
1920-1950     Splenic irradiation         28
1950-1960     Busulfan                   35-45
1960-1970     Hydroxyurea                48-67
1970-1980     1st Allogeneic Stem Cell Transplant for CML
                                    50-60% CURE
1980-1990     IFNa (Interferon alpha)    55-89
1990-2001     IFNa + Cytosine arabinoside (Ara-C)
                 Recent studies showing significant improvement over IFNa alone
1995-2001     STI-571                >90% 5yrs survival (2007)

Table 1. Treatment options and survival. (JAMA, August 22/29 p. 896)


Do NOT be afraid to discuss this matter.
I'm more ignorant than anybody in this field!

Title: Re: The Helicobacter connection
Post by: iko on 16/06/2007 14:14:36

Gastric cancer is related to early Helicobacter pylori infection in a high-prevalence country.

Ferreccio C, Rollán A, Harris PR, Serrano C, Gederlini A, Margozzini P, Gonzalez C, Aguilera X, Venegas A, Jara A.Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 434, Santiago, Chile.

BACKGROUND AND AIMS: Chile ranks fifth in the world among countries with the highest incidence of gastric cancer. The aim was to quantify the association between Helicobacter pylori infection and gastric cancer mortality at the county of residence. METHODS: A cross-sectional household survey, a probability sample of the Chilean adult population, provided 2,615 participants in whom serum H. pylori IgG antibodies were measured (ELISA). The spatial pattern of 48,367 deaths due to gastric cancer which occurred from 1985 to 2002 was analyzed using a hierarchical Poisson regression model; 333 counties were categorized as low, medium, and high gastric cancer mortality with median gastric cancer death rates of 11.4, 19.1, and 26.0 per 100,000 inhabitants, respectively. The association between H. pylori positivity and gastric cancer mortality in the county of residence was assessed by multivariate Poisson regression for complex samples.
RESULTS: H. pylori prevalence was 73.0% [95% confidence intervals (CI), 70.0-76.0], higher in men [prevalence rate ratio (PRR), 1.1 (95% CI, 1.01-1.20)], peaked at ages 45 to 64, and dropped after age 65. It was higher among residents in counties with high gastric cancer mortality (79.7%; 95% CI, 76.4-82.6) compared to counties with low gastric cancer mortality (62.3%; 95% CI, 53.8-70.2; corresponding PRR, 1.3; 95% CI, 1.1-1.5); under age 24, H. pylori infection was 79.7% (95% CI, 72.2-85.6) versus 39.8% (95% CI, 19.6-64.2) among residents in counties with high and low gastric cancer mortalities, respectively (PRR, 2.0; 95% CI, 1.1-3.7).
CONCLUSIONS: The high prevalence of H. pylori at younger ages was associated with high gastric cancer mortality in the base population.

Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):662-7.

Title: Re: The Helicobacter connection
Post by: iko on 23/06/2007 16:46:56
Helicobacter pylori is now suspected to cause
some particular types of human lymphomas, so
called MALT (Mucosa Associated Lymphoid Tissue)
lymphomas and similar 'marginal-zone lymphomas',
together with other well-known infectious agents
such as Hepatitis C virus, Campylobacter jejuni,
Chlamydia psittaci and Borrelia burgdorferi...

Marginal-zone lymphoma.

Ferreri AJ, Zucca E.
Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.

The term marginal-zone lymphoma (MZL) encompasses three closely related lymphoma subtypes, namely the "low-grade B-cell lymphoma of MALT type" currently named MALT lymphoma, the "nodal marginal-zone B-cell lymphoma" and a provisional entity in the REAL classification named "primary splenic MZL with or without villous lymphocytes". These entities display different characteristics, with evident clinical and biological variations according to the organ where the lymphoma arises. Marginal-zone B-cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. Sequence and mutation analysis of the rearranged Ig heavy chain variable genes and that somatic mutations pattern indicate that MZL may arise from different subsets of marginal-zone B-cells. Pathogenesis of these groups of lymphomas is correlated to chronic infections, like Helicobacter pylori, hepatitis C virus, Campylobacter jejuni, Chlamydia psittaci and Borrelia burgdorferi. Several therapeutic strategies against these malignancies exist. Surgical resection, radiotherapy and alkylating agent-based chemotherapy constitute standard approaches, while antimicrobial therapies, anti-CD20 therapy and new forms of immunotherapy constitute interesting experimental approaches. However, prospective trials on these malignancies are rare and universally accepted therapeutic guidelines do not exist. MZLs constitute an exciting investigational setting both from molecular and clinical points of view.

Crit Rev Oncol Hematol. 2007 Jun 19;

Title: Re: The Helicobacter connection
Post by: iko on 10/08/2007 18:00:29
More details on H.p. and gastric tumours:

Carcinogenesis of Helicobacter pylori.

Correa P, Houghton J.Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee.

Helicobacter infection is the leading cause of gastric cancer worldwide. Infection with this ubiquitous bacterium incites a chronic active immune response that persists for the life of the host, in the absence of antibiotic-induced eradication. It is the combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer.
Although it may seem intuitively obvious that removing the offending organism would negate the cancer risk, this approach is neither feasible (half of the world harbors this infection) nor is it straightforward. Most patients are infected in childhood, and present with various degrees of mucosal damage before any therapy. This review outlines the histologic progression of human Helicobacter infection from the early stages of inflammation through the development of metaplasia, dysplasia, and, finally, cancer. The effects of dietary and bacterial eradication therapy on disease progression and lesion reversibility are reviewed within the context of population studies and compared between study designs and populations tested. Eradication studies in the mouse model of infection prevents the formation of gastric cancer, and allows regression of established lesions, providing a useful model to study interaction between bacterium, environment, and host, without the difficulties inherent in human population studies. Recent advances in identifying the bone marrow-derived stem cell as the cell of origin of Helicobacter-induced gastric cancer in the murine model are discussed and interpreted in the context of human disease, and implications for future treatment are discussed.

Gastroenterology. 2007 Aug;133(2):659-72.

Title: Re: The Helicobacter connection
Post by: iko on 20/12/2007 18:11:53
From the end to the beginning...
Please find a beautiful summary
of the "Helicobacter connections"
full-text free in nobelprize website: