American Journal of Gastroenterology
C ?2005 by Am. Coll. of Gastroenterology
Published by Blackwell Publishing
Helicobacter pylori Eradication Has the Potential to
Prevent Gastric Cancer: A State-of-the-Art Critique
Peter Malfertheiner, M.D.,1Pentti Sipponen, M.D.,2Michael Naumann, Ph.D.,3Paul Moayyedi, M.B., Ch.B.,
Ph.D., M.P.H., F.R.C.P.,4Francis M´ egraud, M.D.,5Shu-Dong Xiao, M.D.,6Kentaro Sugano, M.D., Ph.D.,7and
Olof Nyr´ en, M.D., Ph.D.,8and the Lejondal H. pylori–Gastric Cancer Task Force
1Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University,
Magdeburg, Germany;2Department of Pathology, Helsinki University District Central Hospital, Jorvi Hospital,
Espoo, Finland;3Institute of Experimental Internal Medicine, Otto-von-Guericke University, Magdeburg,
Germany;4Department of Medicine, Division of Gastroenterology, Health Sciences Centre, McMaster
University, Hamilton, Ontario, Canada;5Laboratoire de Bacteriologie, Universit´ e Victor Segalen Bordeaux 2,
Bordeaux, France;6Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University,
Shanghai, China;7Department of Internal Medicine, Division of Gastroenterology, Jichi Medical School,
Saitama-shi, Saitama-ken, Japan; and8Department of Medical Epidemiology & Biostatistics, Karolinska
Institute, Stockholm, Sweden
Helicobacter pylori infection continues to play a key role in gastric diseases. Colonization of the gastric mucosa
with the bacterium invariably results in the development of chronic gastritis and subsets of patients have a
progression of the chronic gastritis to either ulcer or cancer. Epidemiological evidence indicates that the proportion
of all gastric cancers attributable to H. pylori infection, and hence potentially preventable upon elimination of this
risk factor, is somewhere in the range of 60% to 90%. This portends significant benefit in terms of morbidity and
mortality, not least in populations with high prevalence of H. pylori infection coupled with high incidence of gastric
cancer. The effect of prophylactic H. pylori eradication on gastric cancer incidence in humans remains unknown,
however. Results from randomized trials are eagerly awaited, but availability of strong conclusive results may take
many years. A growing number of studies show considerable variation in risk for gastric cancer development,
depending on H. pylori strain type and the genetic predisposition of the host. There is also a remote possibility that
elimination of the infection may have adverse health implications (e.g., antibiotic resistance), and therefore
“simple” risk stratification and targeted chemoprevention is required. Based on “in depth” evidence presented at
this workshop, the majority of the scientific task force favored a search-and-treat strategy in first-degree relatives
of gastric cancer patients and an overwhelming majority felt that a more general screen-and-treat strategy should
be focused in the first instance on a population with a high incidence of H. pylori-associated diseases.
(Am J Gastroenterol 2005;100:2100–2115)
It is now more than 10 yr since Helicobacter pylori was cited
as a gastric carcinogen (1). In the latest available epidemio-
logical studies, based on the most accurate methodology, the
status increases the risk of gastric cancer 20-fold, compared
with controls. One estimate attributed 70% of distal gastric
cancers to H. pylori (2), while the highest estimate claimed
that H. pylori is a condition sine qua non for gastric cancer
There is, however, no conclusive evidence that H. pylori
eradication prevents gastric cancer. Supportive data could,
theoretically, be obtained from prospective trials of eradica-
For a list of the Contributors to the Lejondal H. pylori–Gastric Cancer Tast Force,
tion, but, in practice, such trials do not exist and may be im-
and on indirect evidence which shows a beneficial effect of
eradication on conditions and lesions of the stomach mucosa
that precede overt gastric cancer. There is no doubt that the
pathogenesis of gastric cancer is associated with a variety of
be the most prominent and with genetic predisposition, a va-
riety of gene errors and abnormal gene expression. Changes
in biology, growth, and death of the cancer cells have been
observed in conjunction with H. pylori infection. It is also a
known fact that these same genomic and cellular lesions also
occur in the benign gastric epithelium long before the ap-
to the development of cancer. It is conceivable, therefore,
therapy on these precancerous conditions, lesions, or cellu-
lar and genomic changes (i.e., reversal) should also prevent
This review represents a state-of-the-art critique of evi-
dence obtained from many experimental investigations con-
discussed at a workshop with experts in the field of H. pylori
in that particular field and a vote was taken concerning the
tary evidence. In view of the depth of information required
for each statement, two parallel workshops took place, one
dealing with experimental and microbiological evidence and
the other with clinical evidence. These were followed by a
joint plenary session with all experts present, at which they
were invited to vote on all statements under discussion and
to agree/disagree with the suggested level of the evidence.
The methods used for voting and for assessing documentary
evidence are summarized in Table 1.
The document is based largely on information available
at the time of the workshop, but has also been updated with
more recent relevant literature. In view of the magnitude of
also made for additional comments from the perspective of
specialists practicing in these geographical areas (Professors
Xiao and Sugano).
GASTRIC CANCER PREVENTION: THE EVIDENCE
Experimental and Microbiological Evidence
The statements voted upon for this section are presented in
EVIDENCE FOR THE ROLE OF BACTERIAL VIRU-
LENCE. There is some evidence that bacterial strain vari-
ation may affect disease outcome in H. pylori-infected indi-
viduals, as only a subset of colonized individuals develops
serious H. pylori-related disease (4). Microbial and host fac-
tors that are thought to contribute to pathogenesis have been
described and these factors, together with the environment,
seem to determine which groups of individuals are predis-
such as the pathogenicity island (PAI) are found in bacteria
infecting all types of patients, and thus cannot be used to ex-
plain these differences. H. pylori strains are highly diverse
and over a period of years, the populations colonizing an in-
well defined. However, H. pylori have a plastic genome that
presumably allows the organism to adapt and persist in the
human stomach throughout the life of the colonized individ-
ual (7). Unrelated individuals are rarely, if ever, colonized
by strains with the same genetic fingerprint. Individuals are
normally colonized with one single strain of H. pylori, but
multiple strain infections occur (8, 9). Genetic variation is
accomplished by recombination, point mutations, and hori-
zontal transfer of genetic elements as mentioned above (10).
recombination is so frequent that alleles at independent loci
are rarely co-inherited for long time periods (linkage equi-
librium) (11). In addition, the median mutation frequency
in H. pylori is very high (12, 13). This feature might influ-
ence diversity and adaptation, with a correlation to biolog-
ical fitness, compared with other competing strains. It may
of nonessential genes through, e.g., phase variation (14). The
to create subpopulations of clones or subspecies with differ-
ing genotypic and phenotypic features. In these microniches,
affect the macroniche of the entire stomach. The subclones
can vary their virulence potential, for example, by excising
the PAI or switching the Lewis epitopes expressed on the
At any given time, there may be a varying ratio of PAI-
positive (virulent) to PAI-negative (less virulent) subclones.
The net virulence of the total population as well as the vir-
ulence of a single clone might affect the outcome of infec-
tion. The evolution and divergence of these subclones can
affect the outcome of infection for both host and microbe
by skewing the balance of minimal inflammation (that pro-
is unfavorable for H. pylori (such as atrophy and intestinal
metaplasia). In addition, these divergent subclones can in-
tify genetic or functional markers in the micro-organism that
predict the development of gastric cancer, as well as con-
stitutional factors in the host or environmental factors that
affect/modify the H. pylori-gastric cancer relationship.
In Western populations, the carriage of cagA+ strains is
associated with an increased risk of development of pep-
tic ulcer disease and adenocarcinoma of the distal stomach,
as well as its precursor lesions. In Asian countries such as
cagA+ strains (95%) (15) and the associations with disease
difference of PAI between the H. pylori strains isolated from
patients with distal gastric cancer, peptic ulcer, and nonulcer
dyspepsia in these Asian countries (18)?
Several studies have shown that gastric cancer develop-
ment is influenced by certain virulence characteristics of the
ognized association of gastric cancer with the cagA+ geno-
have also been implicated as markers of a particularly strong
association (23, 24). In this context it is also important to
quote the new discovery of Lehours et al. (25) regarding the
role of other virulence patterns (e.g., HopZ) in the develop-
ment of gastric B-cell lymphoma.
2102Malfertheiner et al.
Table 1. Methods Used for Voting and for Assessing Documentary Evidence
Method of Voting
Each proposition considered by the workshop was evaluated for:
• Strength of recommendation
• Level (quality of evidence)
The strength of recommendation was voted on formally in the plenary sessions by all workshop participants, using electronic voting.
The level (quality of evidence) was considered in detail within the workshops and graded according to the criteria given below. The
consensus of workshops on level of evidence was reported to the plenary sessions, but was not voted on within these sessions.
Strength of recommendation
Participants chose one of the following options:
1 Strongly agree
2 Agree with reservation
3 Disagree with reservation
4 Strongly disagree
Grading level of evidence
The quality of the evidence was categorized into five levels A–E. These levels are summarized below, and involved judgement on study
design and execution, consistency of the findings, and the directness of the evidence.
Level of EvidenceStudy DesignStudy Execution ConsistencyDirectness of Evidence
A Meta-analysis of RCTs (for interventions)
RCTs (for interventions)
Nonrandomized studies (for diagnosis and prognosis)
Meta-analysis of RCTs or RCTs (for interventions)
Nonrandomized studies (for diagnosis or prognosis)
Nonrandomized controlled studies (for interventions)
Nonrandomized controlled studies (for interventions)
Meta-analyses or RCTs with a combination of important flaws AND inconsistency AND/OR indirect evidence
Other evidence (not expert opinion)
No important flaws ConsistentDirect or strong indirect
B Important flaw < OR > Inconsistent < OR > Weak indirect
Important flaw < OR > Inconsistent < OR > Weak indirect
No important flaws Consistent
Important flaw < OR > Inconsistent < OR > Weak indirect
Direct or strong indirect
Exceptions that can alter the quality of grading.
Sparse data (few events); use of data not in its initial randomization or apparent publication bias can lower the quality; a very strong association can raise the quality.
Important flaws occur when the highest standards of research that could be achieved by a study are not applied.
Consistency occurs at two levels—design: consistent methods, patients, outcomes; and, statistical: a test of homogeneity of a summary estimate when the level of design consistency
is acceptable and meta-analysis appropriate.
Directness. Direct evidence: relevant patient benefits and harms are measured in studies; strong indirect: the surrogate endpoint is strongly related to desirable endpoints, or that
direct evidence is available for a sufficiently related patient group; weak indirect: the relationship between the study outcomes and patient benefits or harms is insufficient.
Table 2. Preclinical Evidence, Clinical Evidence, and Risks
Experimental and microbiological evidence
1. Certain H. pylori characteristics are associated with an increased risk of gastric
cancer, but currently genotyping cannot predict individual risk of disease.
2. Host genetic factors contribute to an increased risk of gastric cancer
3. There is strong cell biological evidence to implicate H. pylori in gastric carcinogenesis
4. Experimental studies with animal models provide evidence that eradication of H. pylori
at an early time point can prevent gastric cancer development
5. There is correlation between effects of eradication and expression of molecular
markers linked to gastric carcinogenesis
6a. H. pylori eradication heals chronic activation of atrophic gastritis and halts the
progression to preneoplastic conditions (atrophic gastritis and intestinal metaplasia)
6b. In a subset of patients, regression of preneoplastic conditions (atrophic gastritis &
intestinal metaplasia) may occur.
7. H. pylori eradication can reduce the risk of developing gastric cancer
8. The use of antimicrobials for H. pylori is a moderate risk for antimicrobial resistance
in H. pylori and other bacteria
9. There is an inverse association between H. pylori infection and GERD
10. H. pylori eradication in the short term does not lead to GERD symptoms and/or erosive
11. There is an inverse association between H. pylori infection and esophageal
∗These studies are not related to clinical trials.
nr = not recorded.
Limitations of evidence: At present, no definite predictive
diagnosis can be made as to who will suffer from the infec-
tion and who will live unaffected by it. Genetic or functional
markers in the micro-organism and constitutional factors in
the host that predict or lead to development of gastric cancer
remain yet to be identified.
EVIDENCE FOR THE ROLE OF HOST GENETIC
FACTORS. Host genetic factors contribute significantly to
the clinical outcome of H. pylori infection. There is emerg-
ing evidence of important host genetic factors that control
both the host’s innate immune response and its inflammatory
response against H. pylori infection. There is an important
interaction between these host genetic factors and H. pylori
physiological abnormalities that increase the risk of cancer
and its precursors. In the host, there are functional polymor-
phisms in the interleukin-1 (IL-1) gene cluster (26, 27) and
tumor necrosis factor alpha genes (TNF-A-308) (28) that in-
GI malignancies) (29), and the risk seems to be significantly
increased in the presence of pro-inflammatory genotypes of
IL-1 and of H. pylori virulent strains (23) in some geographi-
cal areas. The risk applies to both intestinal and diffuse types
of gastric adenocarcinoma (30).
Limitations of evidence: Most of the evidence relating to
host genetic factors and their influence on disease outcome
has been obtained from studies in Caucasian populations. A
in regions with a high incidence (Shanxi) and low incidence
(Guangdong) of gastric cancer in China showed that IL-1B-
511T/T genotypes are also associated with gastric cancer.
(31). There is now some evidence emerging that there are
similar associations in Asians, but the studies so far have
been underpowered and have given mixed conclusions (32).
order to consolidate the data obtained thus far and to confirm
that they are universal in application. There is currently no
in peptic ulcer disease, but this may be because most of the
not been adequately characterized.
EVIDENCE FROM EXPERIMENTAL CELL BIOLOGY.
There is considerable evidence that H. pylori takes direct
command of gastric epithelial cell signaling and triggers hy-
perproliferative processes. H. pylori regulates the activity
of growth factor receptors, i.e., the EGF receptor (33), the
EGFR-related receptor (Her2/Neu), and the c-Met receptor
(34), thus promoting epithelial cell growth and cell survival,
as well as cell dissociation and cell motility. The translo-
cated H. pylori effector protein, CagA, targets the c-Met re-
ceptor (intracellularly) and enhances the cell motility (34).
between CagA and the adaptor protein Grb2 (35), the tyro-
sine phosphatase SHP-2 (36), or phospholipase C gamma
(34) has also been described. Thus, CagA directly interacts
with signal transducing proteins and may play a role as an
adaptor protein in H. pylori-induced growth factor receptor
signaling. For the evasion of apoptosis H. pylori activates
nuclear hormone receptor peroxisome proliferator activated
receptor δ (PPARδ) (37), which involves H. pylori-induced
cyclo-oxygenase-2 (COX-2) activity (38). Moreover, H. py-
lori induce VegfA (39) and drive putatively the angiogenesis
process. Decreased cell-cell contacts are common in gas-
tric cancers and may be related to the tendency to develop
metastasis. In polarized epithelial cells, H. pylori affects the
scaffolding protein ZO-1 and the tight junctional adhesion
protein (JAM), and disrupt the junction-mediated epithelial
more, the H. pylori effector protein VacA binds to the tyro-
sine phosphatase receptor PTP-ζ and the induced signaling
leads to the phosphorylation of the G protein-coupled re-
ceptor kinase-interactor 1 (Git1) and induces ulcerogenesis
in mice (41). In summary, H. pylori interfere with cell bio-
logical phenomena that are linked with gastric carcinogene-
sis. Consequently, H. pylori infection induces alterations in
cell physiology which could collectively contribute to malig-
(ii) evasion of apoptosis; (iii) unlimited replicative potential;
(iv) sustained angiogenesis; and (v) cell dissociation and tis-
Limitations of evidence: Although the data are very strong,
an understanding of which pathways are involved, in regula-
tion or dysregulation of these cellular processes, should en-
able us to examine whether H. pylori eradication reverses
EVIDENCE FROM EXPERIMENTAL ANIMAL MOD-
ELS. In early studies it was noticed that aged ferrets who
were infected with Helicobacter mustelae developed spon-
taneous gastric adenocarcinomas (42). A number of animal
genesis in animals, the most widely used being ferrets, mice,
and Mongolian gerbils. A few studies in the Mongolian ger-
bil have provided, for the first time, evidence that H. pylori is
indeed a complete carcinogen and can, by itself, induce well-
differentiated adenocarcinomas (43–45). More consistently
it has been shown that H. pylori is a weak carcinogen on its
own, but in the presence of nitrosamine it leads to a high rate
of cancer 1-yr postinfection (46–49). The standard model to
study Helicobacter infection is the mouse model and some
mouse strains develop a vigorous TH1response to H. py-
lori or Helicobacter felis, while others have a predominant
TH2immune response and are relatively resistant to mucosal
changes (50). Those with the vigorous TH1response (the
C57BL/6 strain) go on to develop atrophy, metaplasia, and
invasive gastric cancer in H. felis infection. The majority of
male mice infected with H. felis for more than 14 months
show the development of gastric cancer (51). These studies
2104Malfertheiner et al.
have suggested that progression to gastric cancer is deter-
mined by the host immune response, being influenced to a
lesser extent by dietary factors (e.g., high-salt diet), or bac-
terial virulence factors. Studies in gerbils (52–54), and more
recently in mice (55) have provided important evidence of
beneficial effects from H. pylori eradication, where atrophy
Overall, within a few months of inoculation, H. pylori in-
fection in animal models can lead to the disintegration of
the gastric mucus by the release of endotoxins and H. py-
is associated with the production of free radicals, including
reactive oxygen species, and inducible nitric oxide synthase
hypergastrinemia, who have increased parietal cell numbers
and acid secretion, show an increased expression of TGF-
family growth factors and a progression toward gastric can-
cer (59). Within the cascade to the initiation of precancerous
lesions, the attracted neutrophils enhance the generation of
idative DNA damage that leads to genotoxic effects on the
gastric mucosa (60).
Limitations of evidence: Whether we can use data from an-
imal models in humans is still questionable.
EVIDENCE FOR THE REVERSIBILITY OF MOLECU-
LAR CHANGES. Various molecular and genetic changes
have been identified in gastric cancer cells obtained from es-
mutations in E-cadherin (50% of diffuse cancers), α-catenin
(60%), and β-catenin (25%), the presence of microsatellite
instability (25–40%) and increased telomerase activity has
been described in nearly all gastric cancers (61). The most
common abnormalities are inactivation of tumor suppres-
sor genes such as p53 (occurs in 60–70%), which occur in
but the effect of eradication on p53 expression/mutation has
not been well studied. In an early study, eradication of H.
pylori infection resulted in a significant reduction in iNOS
and nitrotyrosine, and a marginally significant reduction in
that H. pylori eradication was associated with a reduction in
cyclooxygenase-2and ornithine decarboxylase expression in
atrophic in premalignant and malignant lesions (64, 65). H.
HB-EGF, amphiregulin, TGFα) along with their receptors
(EGFR, Her2/Neu) (61). H. pylori eradication led to a re-
duction in the levels of EGF and EGFR from gastric antral
biopsies (66). Furthermore, eradication of H. pylori from pa-
tients was associated with an improvement in metaplasia and
a disappearance of markers of genomic instability. Increased
expression of the oncogene c-Myc correlated with abnormal
DNA content and the presence of atrophy (67). Alterations
in cell cycle control, e.g., overexpression of cyclins D1/D2
and E were detected in H. pylori-associated chronic gastri-
tis and intestinal metaplasia. Cyclin D2 was reduced after
eradication of the organism (68). In addition, decreased p27
expression was seen in gastric cancer and intestinal meta-
plasia; in the latter, p27 expression was restored 1 yr after
eradication (68). Activation of oncogenes such as c-Met and
Her2/Neu is relatively frequent, while K-ras mutations ap-
pear to be less common (<10%) (69). It must be stressed
that none of these changes is specific for gastric cancer. The
most frequently reported changes in the gastric mucosa are
changes in proliferation and apoptosis.
Limitations of evidence:
As yet, the precise sequence of
molecular events leading to gastric cancer has not been elu-
cidated. None of the indicated changes is specific for gastric
EVIDENCE FOR REGRESSION OF ATROPHIC GAS-
TRITIS/INTESTINAL METAPLASIA AFTER H. PYLORI
ERADICATION. The overwhelming majority of subjects
with atrophic gastritis (defined as the presence of signifi-
cant areas of atrophy in the gastric mucosa) have metaplastic
atrophy, i.e., intestinal metaplasia is seen in the biopsy in as-
sociation with classic atrophy, where there is loss of normal
cells. Pure “nonmetaplastic” atrophy may exist focally, but
it is quite rare, thus these two inextricably related conditions
should not be calculated separately (70, 71). There is con-
sistent evidence that eradication of H. pylori cures gastritis,
but the question remains as to whether this intervention can
not only halt the progression to atrophic gastritis and meta-
plasia, but also reverse these lesions. Review of the literature
indicates that, in studies with a control group who remain H.
pylori positive, there is either no change or else progression
of atrophy and metaplasia in those patients. In contrast, atro-
phy and metaplasia do not progress in patients who have had
H. pylori eradicated (72–90). H. pylori eradication is associ-
ated with reduced cell turnover, elimination of DNA damage
by reactive oxygen species, increased gastric acid secretory
capacity, and an increase in ascorbic acid secretion into the
gastric juice (91–96). These data are most important with re-
spect to the issue of gastric cancer prevention. The majority
of data support the proposition that a regression of atrophic
gastritis can occur in a subset of patients, although many
of the available studies have significant limitations in their
design, including inability to blind pathologists to the pres-
ence of H. pylori. The recent randomized prospective study
by Wong et al. (97) does, however, suggest that H. pylori
eradication reduces the incidence of gastric cancer only in
patients without preexistent atrophy or intestinal metaplasia.
the proposition that regression of atrophic gastritis and, to a
lesser extent, intestinal metaplasia, can occur in a subset of
patients with long-term follow-up (98, 99). Even though re-
gression of lesions may occur in some patients at the present
stage we have no markers to tell us whether this may hap-
pen or not in the individual patient. Therefore eradication at
the earliest stage in the disease seems reasonable, when the
probability of progression to neoplasia is likely to be at its
Limitations of evidence: Baseline scores for atrophy and
metaplasia are very low and most studies had significant lim-
numbers of patients, short follow up periods).
EVIDENCE THAT ERADICATION OF H. PYLORI CAN
REDUCE THE RISK OF DEVELOPING GASTRIC
CANCER. The progression from normal gastric mucosa to
and an important analysis is provided by the Helicobacter
and Cancer Collaborative Group (101) as this analysis com-
bined data from all (and only) case-control studies nested
within prospective cohorts, to assess more reliably the rel-
ative risk of gastric cancer. H. pylori infection was associ-
ated with noncardia gastric cancer (OR 3.0; 95% CI 2.3–3.8)
and the association was stronger when blood samples for H.
pylori serology were obtained 10 yr or more before cancer
diagnosis (5.9; 3.4–10.3). Thus, although H. pylori infection
has been demonstrated to be a significant risk factor for the
development of gastric cancer in case–control epidemiolog-
ical studies, data to suggest that eradication of the infection
can prevent the progression from normal gastric mucosa to
gastric cancer are still few.
The only way to determine the effect of H pylori eradi-
cation is to perform a prospective randomized clinical trial.
Unfortunately, attempts to do this have met with problems.
pylori and the nature of the trial has been explained, few are
prepared to enter the placebo arm. Recruitment, therefore,
has been a major drawback for some studies (102, 103) and
some have been abandoned or are progressing only slowly.
If cancer is taken as the endpoint, large numbers have to be
recruited—at least 100,000—and follow-up should be over
one to two decades (104). Alternatively, smaller studies are
ongoing where patients are randomized to treatment or non-
treatment and are then followed up endoscopically. In these,
a primary endpoint such as atrophy or intestinal metaplasia
may be a surrogate marker for cancer.
Since the efficacy of eradication in cancer prevention is
unknown, Parsonnet et al. (105) assumed estimates of pre-
vention varying from 30% to 5%. Results of this decision
analytical model suggested that screening and treatment for
tric cancer, particularly in high-risk populations. The possi-
bility to look at atrophy and intestinal metaplasia as inter-
mediate markers of gastric cancer risk and to evaluate their
reversibility after eradication has been considered in many
studies. Existing data (e.g., Ito et al. 2002) (76) suggest that
precancerous gastric lesions (atrophy and intestinal metapla-
sia) do not progress as much, and may even regress, after
successful eradication of H. pylori. On the other hand, the
definition of a point (lesion) of “no return” remains diffi-
cult to determine and other changes in the gastric mucosa
that follow eradication may be more important to arrest the
progression to cancer than the regression of atrophy and in-
testinal metaplasia (106). From this viewpoint, there are few
interventional studies that have examined the effect of H.
pylori eradication on cancer incidence. Uemura et al. (107)
conducted a nonrandomized H. pylori eradication trial in pa-
tients whose gastric cancer was removed by endoscopic re-
section; after 3-yr follow-up, 6 of 67 metachronous cancers
developed in those not treated, compared with 0 of 65 in
those who received anti-H. pylori therapy. Furthermore, in
a prospective observational study, the same group were able
to show that gastric cancer develops in persons infected with
H. pylori, but not in uninfected persons (108). Although this
was not planned as an interventional study, no gastric can-
cer developed after eradication of H. pylori in 253 infected
patients. A 7-yr prospective-randomized, placebo-controlled
study to assess the long-term effect of H. pylori eradication
on the incidence of gastric cancer has recently been pub-
lished (97). Although no difference in gastric cancer inci-
dence was observed between treated and placebo groups,
H. pylori eradication was shown to reduce the incidence of
gastric cancer significantly in the subgroup of those with-
out atrophy/intestinal metaplasia at baseline, suggesting that
eradication may be beneficial in arresting the progression to
gastric cancer only if applied before the appearance of pre-
Limitations of evidence:
Data from randomized control
studies are few and long-term follow-up would be required
to confirm the benefit of treatment. Further, data on preven-
tion of gastric cancer recurrence are even more scant and it
is difficult to draw any conclusion at this moment. There are
still few data to confirm that eradication of the infection can
prevent the progression from normal gastric mucosa to gas-
tric cancer. Only a few interventional studies have examined
the effect of H. pylori eradication on cancer incidence. The
role of eradication in preventing cancer, though suggestive,
remains to be confirmed.
The statements voted upon for this section are presented in
THE POSSIBLE RISKS OF POPULATION H. PYLORI
TESTING AND TREATMENT. (a) The induction of an-
timicrobial resistance. An association has been found be-
terial resistance to antimicrobials. The association between
level of antibiotic consumption and resistance development
is strong only in closed environments such as special depart-
(112–115). In Europe, a trend toward a higher resistance of
H. pylori to macrolides can be noted in countries with the
highest consumption of these drugs (116–124). An associ-
ation is more likely to be causal if there is a temporal rela-
tionship, there is a dose–response effect, the association is
2106Malfertheiner et al.
biologically plausible, and intervention has an impact on the
A temporal relationship indeed exists, since resistance
is usually nonexistent when antibiotics are first employed.
A dose–response effect has also been observed with most
antibacterial-antibiotic combinations, but only in some hos-
pitals (125–127). There is a biological plausibility based on
the selective pressure of antibiotics, but it is important to dif-
ferentiate between the cases where resistance is due to muta-
tions leading to vertical transmission (the case of H. pylori)
and those where it is done by gene acquisition, i.e., plas-
mids, leading to horizontal transmission which may evolve
as outbreaks. The effect of an intervention is the strongest
argument for causality (128, 129). However, few data exist
in the community (130–135). The best example may be the
limitation of macrolide use in Finland, which was followed
by a decreased resistance of Streptococcus pyogenes to this
drug, but only after a lag time of 5 yr (131). No similar data
are available for H. pylori.
The risk of antimicrobial resistance for bacteria other than
tance to antibiotics after administration of PPI-amoxycillin-
metronidazole or PPI-clarithromycin-metronidazole (136).
Amoxycillin MICs against Streptococcus species and
Enterococcus species increased when this drug was admin-
istered, as did the ratio of resistance to susceptible strains.
The same occurred for clarithromycin in those receiving this
drug for Streptococcus species, Enterococcus species, En-
terobacteriaceae, and Bacteroides species. The total anaero-
bic microflora was suppressed in both treatment groups, but
the effect was more pronounced with PPI-clarithromycin-
metronidazole. However, these changes were not observed
for more than 35 days after the end of the treatment.
In another study focused on intestinal Enterococcus
species, specimens were obtained 1 and 3 yr after treat-
ment. High-level clarithromycin resistant Enterococci were
selected in stools of five patients receiving clarithromycin-
based eradication treatment, and these persisted for 1–3 yr
in three cases (137). It can also be inferred from the study
in Finland by Seppala (131) that macrolide resistance would
increase in Streptococcus pyogenes, Streptococcus preumo-
niae, and other gram-positive bacteria if clarithromycin was
widely used, as would be the case for systematic H. pylori
In conclusion, the use of antimicrobials constitutes a risk
for antimicrobial resistance. However, for H. pylori: (1) the
resistance mechanism is mutation, (2) the spread of the bac-
teria is limited in our Western societies, and (3) the type of
prescription is essentially with more than one antibiotic, the-
oretically avoiding the possibility of resistance development.
Consequently, this risk is likely to be moderate. We can also
foresee that resistance will increase for other bacteria but the
magnitude of resistance is difficult to estimate because of a
lack of data.
(b) The development of gastroesophageal disease. A sys-
tematic review of case–control studies suggested that H. py-
lori infection was less common in patients with GERD com-
pared to controls (138), particularly in studies conducted
in Eastern countries. Evidence supporting the proposition
that H. pylori eradication leads to GERD symptoms and/or
erosive esophagitis is conflicting, however. While one study
(139) showed an increase in the prevalence of GERD after
H. pylori eradication, during the first year following eradi-
cation another study (140) showed an increase in new reflux
esophagitis only in patients who carried the predisposition
of hiatus hernia and in whom atrophic gastritis was reversed
following H. pylori eradication. A post hoc meta analysis
of eight double blind studies of H. pylori eradication (141)
and a large post hoc analysis of the peptic ulcer trials, GU
MACH, and DU MACH (142, 143) revealed no indication
that H. pylori eradication for ulcer disease led to develop-
ment of erosive esophagitis or new symptomatic GERD or
isting GERD. The results were similar for studies conducted
in patients with preexisting GERD (144–146), or in the gen-
eral population (147, 148). Overall, therefore, there is little
eradication leads to de novo GERD development (149).
(c) Risk of Barrett’s esophagus and esophageal adenocar-
cinoma. There appears to be an inverse association between
agus (150–152). Epidemiological studies have also demon-
strated that H. pylori CagA seropositivity is inversely and
strongly associated with risk of esophageal adenocarcinoma
(153, 154), although this has not been a universal observa-
tion (155). The uncertainty in the data is reflected in the vot-
ing of the panel, but overall it was felt that there was mod-
erate evidence of an inverse association between H. pylori
and esophageal adenocarcinoma. Whether this association is
causal is not clear and as long as the incidence of gastric can-
cer is much higher than that of esophageal adenocarcinoma
(which seems to be the case in all populations, although the
latter cancer is coming close to the former in some parts of
nocarcinoma associated with H. pylori infection outweighs
adenocarcinoma (70–80% reduction according to available
AND PREVENTION STRATEGIES
The statements voted upon for this section are presented in
(a) Test and Treat (i.e., patients with dyspeptic symptoms
tested for H. pylori and treated accordingly). A number of
studies have indicated that the test and treat approach for H.
pylori is as effective and safe as endoscopy in uncomplicated
Table 3. Treatment Recommendations and Prevention Strategies
1a. H. pylori eradication resolves symptoms in a small proportion of NUD patients, but the efficacy is similar to
the alternative treatments.
1b. H. pylori eradication is the treatment of choice in uninvestigated dyspepsia.
1c. H. pylori test and treat is more appropriate than endoscopy in uncomplicated dyspepsia.
2. Search for H. pylori and a treatment strategy should be offered to first-degree relatives of gastric cancer
3a. Screen and treat will reduce H. pylori-associated death by about 15%.
3b. A screen and treat strategy should be evaluated in a population with a high incidence of H. pylori-associated
also be some benefit in non ulcer dyspepsia (162).
Although patients who seek health care for dyspeptic
symptoms do not constitute a high-risk group that should
be targeted specifically in an attempt to reduce the incidence
of gastric cancer, this opens a window of opportunity not
only for curing H. pylori infection with the aim of resolving
dyspeptic symptoms (i.e., patients with peptic ulcer disease
and subsets of patients with functional dyspepsia) but also
for minimizing the risk of gastric cancer development.
(b) Search and Treat (i.e., screening of asymptomatic in-
dividuals who carry a risk for gastric cancer and treatment
of H. pylori-infected individuals). It is important to identify
groups that may benefit from prophylactic H. pylori eradi-
cation, for example, those with a family history of gastric
cancer and those who live in high-risk geographical areas,
if they have gastritis. First-degree relatives of patients with
gastric cancer are at greater risk, although there are few true
“gastric families” with defined genetic mutations (163, 164).
It appears that the risk among offspring is only moderate
(about 50% excess), but higher among siblings (about three-
fold), most of the concordance being attributed to shared en-
vironment, where H. pylori no doubt plays a most important
role (165). The risk is enhanced by the presence of H. py-
lori infection, particularly virulent strains. The Maastricht II
guidelines strongly recommend screening of first-degree rel-
atives of gastric cancer patients. The increased risk of gastric
in favor of search and treat.
portant etiological cause of gastric cancer, but the real ques-
tion is whether infection with the organism is a necessary
prerequisite for the disease or whether other risk factors such
as diet and bile reflux could cause the disease in the absence
of H. pylori. In certain cases H. pylori infection is not a nec-
essary prerequisite. Cardia gastric cancer, for example, is not
associated with the infection. The etiology of this particular
cancer, which affects a small vulnerable area of the gastric
mucosa and accounts for up to 20% of gastric cancer in some
countries (166), is probably different from other gastric can-
cers. Similarly, certain hereditary gastric cancers appear to
arise irrespective of H. pylori infection. In others, the disease
results from autoimmune gastritis where infection with H.
pylori is uncommon. Nevertheless, the major burden of gas-
tric cancer is that associated with H. pylori infection together
with other risk factors, which on their own would probably
not lead to the development of this disease.
There is uncertainty as to how long H. pylori has to be
present before eradication will no longer prevent the devel-
opment of gastric cancer.
H. pylori infection occurs in early childhood (167, 168).
However, there is little benefit in treating individuals who
are at high risk of re-infection. It seems reasonable to as-
sume, however, that if the progression to a corpus predom-
inant gastritis with atrophy and intestinal metaplasia could
be prevented, this would provide the greatest opportunity of
to “intestinal” type. Diffuse cancer may be the product of di-
rect inflammation, while intestinal type cancer probably fol-
lows mutation in intestinal metaplasia (169). If that were the
case, H. pylori eradication would have a greater, immediate
effect upon diffuse cancer because of the rapid elimination
of the inflammatory reaction, while cancers arising from in-
testinal metaplasia would be less amenable to H. pylori erad-
In spite of these limitations, one would expect H. pylori
treatment to have some benefit, even if given at a late stage.
The reason for this is that once the infection is eradicated, the
In a proportion of individuals, gastric acid secretion recovers
to some extent and may reduce colonization by other micro-
the mucosa. Intestinal metaplasia does not seem to progress
once treatment has been given compared with placebo. In
those stomachs that are less severely damaged, not only will
acid secretion improve, but the level of ascorbic acid in the
gastric lumen will increase, cell turnover will decline and the
production of reactive oxygen metabolites by inflammatory
cells will fall.
2108Malfertheiner et al.
(d) Health economics of a screening program. One of the
resources. H. pylori screening and treatment is likely to be
although it must be borne in mind that cost-effectiveness di-
favorably with other screening programs, where the expen-
sive tests need to be repeated at regular intervals. There is,
however, no direct evidence that population H. pylori screen-
ing and treatment is cost-effective, as there are currently no
trial data showing that it reduces mortality. Thus, data have
to be extrapolated using health economic models in order
to infer whether the strategy is cost-effective. A MEDLINE
search revealed six papers modeling H. pylori screening and
treatment to prevent gastric cancer and all concluded that the
strategy is cost-effective (172–177). Four U.S. models (173,
174, 176, 177) suggested that H. pylori screening and treat-
ment would cost between €6,300 to €25,000 per life year
saved, whereas two U.K. models suggested that the strategy
would at the most cost €8,500 per life year saved and under
vice money (172, 175). The model suggesting that H. pylori
test and treat was cost saving also assessed the possibility
that the strategy would reduce the dyspepsia burden in the
A Global Policy for Prevention of Gastric Cancer
quarters of a million per year. As the disease is not often cur-
able at discovery, the eradication of H. pylori should lead to
considerable health benefit, without significant danger to the
population. The benefit is likely to be greater in those coun-
tries with a high incidence of gastric cancer, but often these
are the ones where, at present, economic conditions are not
Nevertheless, the economy in Asia generally and Southeast
Asia in particular is likely to grow within the foreseeable fu-
measures. In China, the government is now paying more at-
tention to health care as a consequence of its rapid economic
growth. Gastric cancer is one of the most common malig-
nant diseases in the northern part of China, as well as in the
provinces and cities along the seacoast. Ideally, the incidence
of gastric cancer should decrease if the prevalence of H. py-
lori infection becomes lower. Other areas of high incidence
such as Central and Southern America will represent more
of a problem in the near future, while the incidence of gastric
cancer in Africa and India are relatively low compared with
other developing countries, despite the high prevalence of H.
pylori infection—the “African Enigma” (178). It has been
suggested that this is because the populations do not have
the same life expectancy as western populations and there-
fore are less likely to reach their sixth or seventh decade,
when gastric cancer more commonly develops. Additionally,
it has been shown that co-infection with parasites changes
the immune response of the gastric mucosa from TH1 to
TH2 (179), which would be more protective against gastric
cancer. Furthermore, in the countries of Africa, the ravages
of the malaria and HIV infection will justifiably consume the
oped world there is every reason to believe that a screen and
treat policy would not only be effective in health terms, but
cost effective as well. However, the greatest opportunity lies
in the emerging countries of Eastern Europe, where the inci-
annual death rate from gastric cancer has been almost 50,000
and more than 100,000 cases of gastric cancer are newly
diagnosed annually. Up until now, secondary preventative
measures such as mass screening programs (including radio-
graphic and endoscopic examination) for those above 40 yr
ity (180). Almost half of the gastric cancer patients in Japan
are now diagnosed as early gastric cancer and many of them
can be treated with minimally invasive measures such as en-
doscopic mucosal resection (EMR). Even when they require
operation and/or chemotherapy their survival rates are much
fective disease prevention, primary prevention by interfering
with the mechanisms of gastric carcinogenesis is necessary.
Eradication of H. pylori as a primary preventative measure
may be feasible in a country like Japan with a high incidence
of gastric cancer and a strong economy. Japan would also
achieve a reduction in gastric cancer incidence. At present,
the Japanese national health insurance system has not yet ap-
proved the use of eradication therapy for H. pylori-infected
chronic gastritis, although it is recognized as a predisposing
will serve to implement a primary intervention program to
prevent gastric cancer in Japan as well as in the rest of the
Whom to Target?
country or district with a high level of gastric cancer so as
to demonstrate potential benefits. This could be done at the
same time as increasing pressure on the developed countries
themselves to introduce a screen and treat policy. What is
needed is the introduction of public health measures aimed
toward eradication of H. pylori in specific areas in order to
demonstrate that a screen and treat policy is possible, that
it is reasonably constrained in financial terms, that it does
not produce significant disadvantage to the community and,
that after some 5 to 10 yr, there is a fall in the incidence of
death from H. pylori-related disease compared with contigu-
term is proof of concept. If that can be done, it will stimu-
late health-care groups and governments to introduce similar
time enabling the screen and treat protocol to be improved,
generate more research in identifying more effective and less
expensive measures for identifying infection and curing the
disease. The introduction of community “screen and treat”
will also stimulate further research aimed toward identifying
the best age for intervention and possibly even the discovery
of how the organism is transmitted.
In conclusion, for countries with a high risk of cancer, the
Helicobacter infection in early adulthood.
Benefit of Broadening the Indication
for Anti-H. Pylori Therapy
bacterium invariably results in the outcome of chronic gas-
tritis. Subsets of patients have a progression of the chronic
gastritis to either ulcer or cancer. Several indications have
proved beneficial over the years but are not as yet imple-
mented on a large scale. Apart from the classical indications
such as peptic ulcer (181), there are several other beneficial
indications for H. pylori eradication and therapy strategies.
45–50 yr of age with no alarm symptoms, the key variable
in determining the appropriateness and cost-effectiveness of
screening for H. pylori infection versus initiation of empiric
proton pump inhibitor therapy is the prevalence of the infec-
tion and peptic ulcer disease in the local population. The test
and treat approach is considered cost-effective if the preva-
lence of H. pylori in the population is 20% or greater, while
lence is less than 20%.
Epidemiological evidence indicates that the proportion of
potentially preventable upon elimination of this risk factor is
somewhere in the range of 60–90%. This portends signif-
icant benefit in terms of morbidity and mortality, not least
in populations with high prevalence of H. pylori infection
coupled with high incidence of gastric cancer. While there
is some discordance regarding who should undergo a search
and treat strategy with the current available therapy, there is
broad agreement that cure of the infection reduces the risk
for gastric cancer development.
Whether the association between H. pylori infection and
gastric cancer is causal or not is no longer an issue. Largely
consistent results from epidemiological studies and animal
experiments all support a carcinogenic role of the microor-
ganism, and a web of plausible mechanisms is slowly emerg-
ing. Although the true strength of the association, and the
proportion of all gastric cancers that can be attributed to
H. pylori, is still under debate, it is becoming increasingly
evident that the early studies may have underestimated the
importance of the infection. The effect of prophylactic erad-
ication on gastric cancer incidence in humans remains un-
known, though. Results from ongoing randomized trials are
eagerly awaited, but it will probably take many years before
able, if at all. Given the growing number of studies showing
considerable variation in H. pylori strain type and genetic
predisposition of the host, and the admittedly remote possi-
bility that elimination of the infection might increase the risk
for other adverse health outcomes, including an increase in
the prevalence of antibiotic-resistant micro-organisms, there
is a need for “simple” risk stratification and a targeted ap-
proach to chemoprevention. There is little scientific support
symptoms constitute a high-risk group that should be partic-
ularly targeted. This population will, in any case, have the
opportunity for therapy with the dual aim of relieving their
symptoms and preventing H. pylori-related complications.
Presently, the critical question is whether it is justifiable to
wait with chemoprevention for another decade or two, until
the desired solid scientific data are at hand, or whether pro-
phylactic eradication should be offered already now to some
In conclusion, a majority of this scientific panel favored
a test-and-treat strategy in first-degree relatives of gastric
cancer patients. The overwhelming majority also felt that a
more general screen-and-treat strategy should be focused in
the first instance on a population with a high incidence of
H. pylori-associated diseases.
List of Contributors to the Lejondal H. pylori–Gastric
Cancer Task Force
Anthony T.R. Axon, Gastroenterology Unit, Room 190,
Clarendon Wing, Leeds General Infirmary, Great George
Street, Leeds, LS1 3EX, United Kingdom.
timento di Medicina Interna e Gastroenterologia, Universit` a
di Bologna, Policlinico S. Orsola, Via Massarenti 9, 40138
Emad El-Omar, Department of Medicine & Therapeutics,
University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD.
Lars Engstrand, Swedish Institute for Infectious Disease
Control, 171 82 Solna, Sweden.
sity of Leeds, Arthington House, Cookridge Hospital, Leeds
LS16 6QB, United Kingdom.
Antonio Gasbarrini, Internal Medicine Department,
Catholic University, Gemelli Hospital, 00168 Rome, Italy.
2110Malfertheiner et al.
Universitaire de Gen` eve, 24, rue Micheli-du-Crest, 1211
Gen` eve, Switzerland.
Ernst J. Kuipers, Department of Gastroenterology and
Hepatology, Erasmus MC, P.O. Box 2040, Dr. Molewater-
plein 40, 3000 CA Rotterdam, The Netherlands.
Angel Lanas, Unidad Mixta de Investigaci´ on, Hospital
Cl´ ınico & Universidad de Zaragoza, Domingo Miral s/n,
50009 Zaragoza, Spain.
Kenneth E.L. McColl, Section of Medicine, Western Infir-
mary, 44, Church Street, Glasgow G11 6NT, Scotland, UK.
Colm O’Morain, The Adelaide and Meath Hospital, Peter
Street, Dublin, Ireland.
sity of Kansas School of Medicine, Kansas City, KS 66209,
Nimish Vakil, University of Wisconsin Medical School,
Aurora-Sinai Medical Center, Milwaukee, WI 53233, USA.
Timothy Cragin Wang, Chief, Division of Digestive and
Liver Diseases, Dorothy L. and Daniel H. Silberberg Pro-
fessor of Medicine, Division of Digestive and Liver Dis-
eases, Department of Medicine, College of Physicians and
Surgeons, Columbia University, 630 West 168th Street, Box
83, New York, NY 10032, USA.
AstraZeneca M¨ olndal provided the grant for the Lejondal
workshop, on which this article is based. We would like
to thank the following AstraZeneca personnel: Dr. Michael
Wrangstadh for coordinating the workshop with the assis-
tance of Irene Linnerhag, and Dr. Madeline Frame for com-
piling the workshop material for the manuscript with the as-
sistance of Linda Hug.
Professor of Medicine, Otto-von-Guericke University, Department
Str. 44, 39120 Magdeburg, Germany.
Received October 19, 2004; accepted March 23, 2005.
1. IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans. Schistosomes, liver flukes and Heli-
graphs on the evaluation of carcinogenic risks to humans.
Int Agency Res Cancer 1994;61:177–240.
2. Ekstr¨ omAM,HeldM,HanssonL-E,etal.Helicobacterpy-
lori infection a necessary condition for non-cardia gastric
cancer? Am J Epidemiol 2004;159(3):252–8.
4. Nilsson C, Sill´ en A, Enroth H, et al. Correlation be-
tween Cag pathogenecity island status and Helicobacter
pylori associated gastroduodenal disease. Infect Immun
5. Blaser MJ, Kirschner D. Dynamics of Helicobacter py-
lori colonization in relation to the host response. Proc Natl
Acad Sci U S A 1999;96:8359–64.
6. Blaser MJ, Berg DE. Helicobacter pylori genetic diversity
and risk of human disease. J Clin Invest 2001;107:767–73.
7. Israel DA, Salama N, Krishna U, et al. Helicobacter pylori
host. Proc Natl Acad Sci U S A 2001;98:14625–30.
8. Alm RA, Ling LS, Moir DT, et al. Genomic-sequence
comparison of two unrelated isolates of the human gastric
pathogen Helicobacter pylori. Nature 1999;397:176–80.
lori observed in paired isolates obtained years apart in the
same host. J Infect Dis 2000;181:273–82.
10. Aras RA, Takata T, Ando T, et al. Regulation of the HpyII
restriction-modification system of Helicobacter pylori by
tation during long-term gastric colonization by Helicobac-
12. Salama N, Guillemin K, McDaniel TK, et al. A whole-
genome microarray reveals genetic diversity among he-
licobacter pylori strains. Proc Natl Acad Sci U S A
strain specific differences in genetic content, identified by
microarray, influence host inflammatory responses. J Clin
14. Bj¨ orkholm B, Lundin A, Sill´ en A, et al. Comparison of
genetic divergence and fitness between two subclones of
Helicobacter pylori. Infect Immun 2001;69:2832–8.
15. Pan ZJ, vander Hulst RWM, Feller M, et al. Equally high
prevalence of infection with CagA-positive Helicobacter
pylori in Chinese patients with peptic ulcer disease and
those with chronic gastritis-associated dyspepsia. J Clin
to specific Helicobacter pylori antigens: Antibody against
CagA antigen is not predictive of gastric cancer in a devel-
oping country. Am J Gastroenterol 1996;91:1785–8.
17. Maeda S, Kanai F, Ogura K, et al. High seropositivity of
Dis Sci 1997;42:1841–7.
18. Datta S, Chattopadhyay S, Balakrish Nair G, et al. Vir-
ulence genes and neutral DNA markers of Helicobacter
pylori isolates from different ethnic communities of West
Bengal, India. J Clin Microbiol 2003;41:3737–43.
19. Konturek SJ, Starzynska T, Konturek PC, et al. Helicobac-
gastric acid secretion in gastric cancer. Scand J Gastroen-
20. Parsonnet J, Friedman GD, Orentreich N, et al. Risk for
tive in Helicobacter pylori infection. Gut 1997;40(3):297–
21. Queiroz DM, Mendes EN, Rocha GA, et al. Cag-A pos-
itive Helicobacter pylori and risk for developing gastric
carcinoma in Brazil. Int J Cancer 1998;78:135–9.
22. Ekstr¨ om AM, Held M, Hansson LE, et al. Helicobac-
ter pylori in gastric cancer established by CagA im-
munoblot as a marker of past infection. Gastroenterology
23. Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter
pylori and interleukin 1 genotypoing: An opportunity to
identify high-risk individuals for gastric carcinoma. J Natl
Cancer Inst 2002;94(22):1680–7.
24. Nardone G, Morgner A. Helicobacter pylori and gastric
malignancies. Helicobacter 2003;8(suppl 1):44–52.
25. Lehours P. Evaluation of the association of nine Heli-
cobacter pylori virulence factors with strains involved in
phoma. Infect Immun 2004;72:880–8.
26. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-
1 polymorphisms associated with increased risk of gastric
cancer. Nature 2000;404:398–402.
27. Machado JC, Pharoah P, Sousa S, et al. Interleukin
1B and interleukin 1RN polymorphisms are associated
with increased risk of gastric carcinoma. Gastroenterology
28. El-Omar EM, Rabkin CS, Gammon MD, et al. Increased
risk of noncardia gastric cancer associated with proinflam-
matory cytokine gene polymorphisms. Gastroenterology
29. Rad R, Prinz C, Neu B, et al. Synergistic effect of Heli-
cobacter pylori virulence factors and interleukin-1 poly-
morphisms for the development of severe histological
changes in the gastric mucosa. J Infect Dis 2003;188:272–
30. Machado JC, Figueiredo C, Canedo P, et al. A proinflam-
matory genetic profile increases the risk for chronic at-
rophic gastritis and gastric carcinoma. Gastroenterology
31. Zeng ZR, Hu PJ, Hu S, et al. Association of inter-
leukin 1B gene polymorphism and gastric cancers in high
and low prevalence regions in China. Gut 2003;52:1684–
morphisms increase risk of hypochlorhydria and atrophic
gastritis and reduce risk of duodenal ulcer recurrence in
Japan. Gastroenterology 2002;123:92–105.
33. Wallasch C, Crabtree JE, Bevec D, et al. Helicobacter
pylori-stimulated EGF receptor transactivation requires
metalloprotease cleavage of HB-EGF. Biochem Biophys
Res Commun 2002;295:695–701.
34. Churin Y, Al-Ghoul L, Kepp O, et al. Helicobacter py-
lori CagA protein targets the c-Met receptor and en-
of Helicobacter pylori CagA protein activities. Mol Cell
phatase as an intracellular target of Helicobacter pylori
CagA protein. Science 2002;295:683–86.
37. Gupta RA, Polk DB, Krishna U, et al. Activation of per-
oxisome proliferator-activated receptor gamma suppresses
licobacter pylori in gastric epithelial cells. J Biol Chem
38. J¨ uttner S, Cramer T, Wessler S, et al. Helicobacter py-
lori stimulates host cyclooxygenase-2 gene transcription:
Critical importance of MEK/ERK-dependent activation of
USF1/-2 and CREB transcription factors. Cell Microbiol
39. Strowski MZ, Cramer T, Schafer G, et al. Helicobacter
pylori stimulates host vascular endothelial growth factor-a
(vegf-A) gene expression via MEK/ERK-dependent acti-
vation of Sp1 and Sp3. FASEB J 2004;18(1):218–20. Full
express article 10.1096/fj.03-0055fje.
40. Amieva MR, Vogelmann R, Covacci A, et al. Disruption
pylori CagA. Science 2003;300:1430–4.
to gastric ulecer induction by VacA of Helicobacter pylori.
Nat Genet 2003;33:375–81.
42. Fox JG, Dangler CA, Sager W, et al. Helicobacter
mustelae-associated gastric adenocarcinoma in ferrets
(Mustela putorius furo). Vet Pathol 1997;34:225–9.
43. Watanabe T, Tada M, Nagai H, et al. Helicobacter pylori
licobacter pylori-induced gastric carcinoma in Mongolian
gerbils. Cancer Res 1998;58:4255–9.
differentiated adenocarcinoma and carcinoid due to long-
term Helicobacter pylori colonization in Mongolian ger-
bils. J Gastroenterol 1999;34:450–4.
46. Sugiyama A, Maruta F, Ikeno T, et al. Helicobacter py-
lori infection enhances N-methyl-N-nitrosourea-induced
stomach carcinogenesis in the Mongolian gerbil. Cancer
47. Shimizu N, Inada K, Nakanishi H, et al. Helicobacter py-
lori infection enhances glandular stomach carcinogenesis
in Mongolian gerbils treated with chemical carcinogens.
48. Tokieda M, Honda S, Fujioka T, et al. Effect of He-
licobacter pylori infection on the N-methyl-N?-nitro-N-
nitrosoguanidine-induced gastric carcinogenesis in Mon-
golian gerbils. Carcinogenesis 1999;20:1261–6.
in Mongolian gerbils infected with Helicobacter pylori.
Cancer Lett 2000;160:99–105.
50. Fox JG, Sheppard BJ, Dangler CA, et al. Germ-line p53-
nant lesions and invasive gastric carcinoma through down-
51. Fox JG, Rogers AB, Ihrig M, et al. Helicobacter pylori-
associated gastric cancer in INS-GAS mice is gender spe-
cific. Cancer Res 2003;63:942–50.
52. Shimizu N, Inada K, Tsukamoto T, et al. Eradication di-
Cancer Res 2000;60:1512–4.
53. Keto Y, Ebata M, Okabe S, et al. Gastric mucosal changes
induced by long term infection with Helicobacter pylori in
Mongolian gerbils: Effects of bacteria eradication. J Phys-
iol Paris 2001;95:429–36.
54. Nozaki K, Shimizu N, Ikehara Y, et al. Effect of early
eradication on Helicobacter pylori-related gastric carcino-
genesis in Mongolian gerbils. Cancer Sci 2003;94:235–9.
55. Hahm KB, Song YJ, Oh TY, et al. Chemoprevention
of Helicobacter pylori-associated gastric carcinogenesis
in a mouse model: Is it possible? J Biochem Mol Biol
56. Yu E, Lee HK, Kim HR, et al. Acute inflammation of the
proliferative zone of gastric mucosa in Helicobacter pylori
gastritis. Pathol I Res Pract 1999;195:689–97.
57. Obst B, Wagner S, Sewing KF, et al. Helicobacter pylori
cause DNA damage in gastric epithelial cells. Carcinogen-
58. Jaiswal M, LaRusso NF, Gores GJ. Nitric oxide in
gastrointestinal epithelial cell carcinogenesis: Linking
2112Malfertheiner et al.
inflammation to oncogenesis. Am J Physiol Gastrointest
Liver Physiol 2001;281:626–34.
59. Wang TC, Dangler CA, Chen D, et al. Synergistic inter-
action between hypergastrinemia and Helicobacter infec-
tion in a mouse model of gastric cancer. Gastroenterology
ter pylori infections induce gastric mutations in mice. Gas-
61. Farrell J, Wang TC. The biology of gastric cancer. In:
Rustgi AK, Crawford J, eds. Gastrointestinal Cancers.
Philadelphia: W. B. Saunders, 2003:299–320.
62. Teh M, Tan KB, Seet BL, et al. Study of p53 im-
munostaining in the gastric epithelium of CagA-positive
and CagA-negative Helicobacter pylori gastritis. Cancer
63. Murakami K, Fujioka T, Kodama M, et al. Analysis of p53
mutations and Helicobacter pylori infection in human and
animal models. J Gastroenterol 2002;37(suppl 13):1–5.
64. Sung JJ, Leung WK, Go MY, et al. Cyclooxygenase-2
expression in Helicobacter pylori-associated premalignant
and malignant gastric lesions. Am J Pathol 2000;157:729–
sion of ornithine decarboxylase, cyclooxygenase-2, and
ter pylori before and after eradication therapy. Dig Dis Sci
66. Coyle WJ, Sedlack RE, Nemec R, et al. Eradication of
Helicobacter pylori normalizes elevated mucosal levels of
epidermal growth factor and its receptor. Am J Gastroen-
67. Nardone G, Staibano S, Rocco A, et al. Effect of Heli-
cobacter pylori infection and its eradication on cell prolif-
eration, DNA status, and oncogene expression in patients
with chronic gastritis. Gut 1999;44:789–99 [Erratum in:
68. Yu J, Leung WK, Ng EK, et al. Effect of Helicobacter
pylori eradication on expression of cyclin D2 and p27
in gastric intestinal metaplasia. Aliment Pharmacol Ther
Gastrointestinal and Liver Disease. 7th Ed. Philadelphia:
W. B. Saunders, 2002:829–55.
70. Genta RM. Defining atrophic gastritis and grading gas-
tric atrophy: New challenges beyond the Sydney System.
In: Hunt RH, Tytgat GN, eds. Helicobacter pylori—Basic
demic Publishers, 1998:215–23.
71. Rugge M, Correa P, Dixon MF, et al. Gastric mu-
cosal atrophy: Interobserver consistency using new crite-
ria for classification and grading. Aliment Pharmacol Ther
of gastric dysplasia: Randomized trial of antioxidant sup-
plements and Helicobacter pylori therapy. J Natl Cancer
73. Moayyedi P, Wason C, Peacock R, et al. Changing pat-
terns of Helicobacter pylori gastritis in long-standing acid
suppression. Helicobacter 2000;5:206–14.
74. Annibale BE, Di Giulio. The long-term effects of cure of
gastritis. Aliment Pharmacol Ther 2002;16(10):1723–31.
75. Blot WJ. Preventing cancer by disrupting progression of
precancerous lesions. J Natl Cancer Inst 2000;92(23):
76. Ito M, Haruma K. Helicobacter pylori eradication therapy
improves atrophic gastritis and intestinal metaplasia: A 5-
year prospective study of patients with atrophic gastritis.
Aliment Pharmacol Ther 2002;16(8):1449–56.
77. Kim N, Lim SH. Long-term effects of Helicobacter
pylori eradication on intestinal metaplasia in patients
with duodenal and benign gastric ulcers. Dig Dis Sci
78. Kokkola A, Sipponen P. The effect of Helicobacter pylori
eradication on the natural course of atrophic gastritis with
dysplasia. Aliment Pharmacol Ther 2002;16(3):515–20.
in patients with reflux oesophagitis treated with long-term
omeprazole reverses gastritis without exacerbation of re-
flux disease; results of a randomised controlled trial. Gut
80. Kyzekova J, Mour J. The effect of eradication therapy
on histological changes in the gastric mucosa in patients
with non-ulcer dyspepsia and Helicobacter pylori infec-
tion. Prospective randomized intervention study. Hepato-
81. Larkin CJ, Watson P. Gastric corpus atrophy following
eradication of Helicobacter pylori. Eur J Gastroenterol
82. Morales TG, Sampliner RE. Inability to noninvasively di-
83. Ohkusa T, Fujiki K. Improvement in atrophic gastritis and
intestinal metaplasia in patients in whom Helicobacter py-
lori was eradicated. Ann Intern Med 2001;134:380–6.
and intestinal metaplasia after eradication of Helicobacter
pylori. Helicobacter 1998;3(4):236–40.
86. Stolte M, Meining A. Eradication of Helicobacter py-
lori heals atrophic corpus gastritis caused by long-term
treatment with omeprazole. Virchows Arch 1999;434:91–
87. Sung JJY, Lin SR. Atrophy and intestinal metaplasia one
year after cure of H. pylori infection; a prospective, ran-
domized study. Gastroenterology 2000;119:7–14.
88. Van der Hulst RWM, Van der Ende A. Effect of Heli-
A prospective 1-year follow-up study. Gastroenterology
89. Yamada T, Miwa H. Improvement of gastric atrophy after
Helicobacter pylori eradication therapy. J Clin Gastroen-
90. Zerbib F, Lenk C. Long-term effects of Helicobacter py-
lori eradication on gastric antral mucosa in duodenal ulcer
patients. Eur J Gastroenterol Hepatol 2000;12:719–25.
91. Forbes GM, Warren JR. Long-term follow-up of gastric
terol Hepatol 1996;11:670–3.
92. Haruma K, Mihara M. Eradication of Helicobacter pylori
increases gastric acidity in patients with atrophic gastritis
of the corpus-evaluation of 24 h pH monitoring. Aliment
Pharmacol Ther 1999;13(2):155–62.
93. Kimura A, Tsuji S. Expression of cyclooxy-genese-2 and
Fatty Acids 2000;63:315–22.
ication on gastric histology, serum gastrin and pepsinogen
I levels, and gastric emptying in patients with gastric ulcer.
Am J Gastroenterol 1997;92:1844–8.
tion and its eradication on cell proliferation, DNA status,
and oncogene expression in patients with chronic gastritis.
96. Orihara T, Wakabayashi H. Effect of Helicobacter py-
lori eradication on gastric mucosal phospholipid content
and its fatty acid composition. J Gastroenterol Hepatol
vent gastric cancer in a high-risk region of China: A ran-
domized controlled trial. JAMA 2004;291:187–94.
98. Malfertheiner P, Bayerd¨ orffer E, Diete U, et al. The GU-
MACH study: The effect of one-week omeprazole triple
therapy on Helicobacter pylori infection. Eradication heal-
Pharmacol Ther 1999;14:703–12.
99. Malfertheiner P, Kirchener T, Kist M, et al. Helicobacter
pylori eradication and gastric ulcer healing—Comparison
macol Ther 2003;17:1125–35.
100. Wright NA. Aspects of the biology of regeneration and
repair in the human gastrointestinal tract. Philos Trans R
Soc Lond B Biol Sci 1998;353:925–33.
cer and Helicobacter pylori: A combined analysis of 12
and gastric cancer: Current status of the Austrian Czech
German gastric cancer prevention trial (PRISMA study).
World J Gastroenterol 2001;7:243–7.
103. Forman D. Lessons from ongoing intervention studies. In:
anisms to clinical cure 1998. Dordrecht, The Netherlands:
Kluwer Academic Publishers, 1998:354–61.
104. Danesh J, Forman D, Collins R, et al. Helicobacter pylori
105. Parsonnet J, Harris RA, Hack HM, et al. Modeling cost ef-
fectiveness of H.pylori screening to prevent gastric cancer:
A mandate for clinical trials. Lancet 1996;348:150–4.
106. Leung WK, Sung JJ. Review acrticle: Intestinal meta-
plasia and gastric carcinogenisis. Aliment Pharmaol Ther
107. Uemura N, Mukai T, Okamoto S, et al. Effect of Heli-
cobacter pylori eradication on subsequent development of
cancer after endoscopic resection of early gastric cancer.
Cancer Epidemiol Biomarkers Prev 1997;6:639–42.
108. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter
pylori infection and the development of gastric cancer. N
Engl J Med 2001;345:784–9.
109. Lepper PM, Grusa E, Reichl H, et al. Consumption
of imipenem correlates with beta-lactam resistance in
Pseudomonas aeruginosa. Antimicrob Agents Chemother
110. Harthug S, Jureen R, Mohn SC, et al. Norwegian Ente-
rococcal Study Group. The prevalence of faecal carriage
of ampicillin-resistant and high-level gentamicin-resistant
enterococci among inpatients at 10 major Norwegian hos-
pitals. J Hosp Infect 2002;50:145–54.
crob Drug Resist 2001;7:383–9.
Microb Drug Resist 2002;8:209–14.
113. Garcia-Rey C, Aguilar L, Baquero F, et al. Pharmacoepi-
demiological analysis of provincial differences between
consumption of macrolides and rates of erythromycin re-
sistance among Streptococcus pyogenes isolates in Spain.
J Clin Microbiol 2002;40:2959–63.
114. Garcia-Rey C, Aguilar L, Baquero F, et al. Importance
of local variations in antibiotic consumption and geo-
graphical differences of erythromycin and penicillin re-
sistance in Streptococcus pneumoniae. J Clin Microbiol
115. Svetlansky I, Liskova A, Foltan V, et al. Increased con-
sumption of fluoroquinolones is not associated with resis-
tance in Escherichia coli and Staphylococcus aureus in the
community. J Antimicrob Chemother 2001;48:457–8.
116. Granizo JJ, Aguilar L, Casal J, et al. Streptococcus pneu-
moniae resistance to erythromycin and penicillin in rela-
tion to macrolide and beta-lactam consumption in Spain
(1979–1997). J Antimicrob Chemother 2000;46:767–73.
macrolide consumption on macrolide resistance of com-
mon respiratory pathogens. Eur J Clin Microbiol Infect
118. Baquero F. Evolving resistance patterns of Streptococcus
pneumoniae: A link with long-acting macrolide consump-
tion? J Chemother 1999;11(suppl 1):35–43.
119. Ena J, Lopez-Perezagua MM, Martinez-Peinado C, et al.
Emergence of ciprofloxacin resistance in Escherichia coli
isolates after widespread use of fluoroquinolones. Diagn
Microbiol Infect Dis 1998;30:103–7.
120. Cars O, M¨ olstad S, Melander A. Variation in antibiotic use
in the European Union. Lancet 2001;357:1851–3.
121. Glupczynski Y, M´ egraud F, Lopez-Brea M, et al. Euro-
in Helicobacter pylori. Eur J Clin Microbiol Infect Dis
122. Loivukene K, Maaroos HI, Kolk H, et al. Prevalence of
antibiotic resistance of Helicobacter pylori isolates in Es-
tonia during 1995-2000 in comparison to the consumption
of antibiotics used in treatment regimens. Clin Microbiol
123. Grove DI, Koutsouridis G. Increasing resistance of He-
licobacter pylori to clarithromycin: Is the horse bolting?
124. Perez Aldana L, Kato M, Nakagawa S, et al. The relation-
ship between consumption of antimicrobial agents and the
prevalence of primary Helicobacter pylori resistance. He-
125. Leibovici L, Berger R, Gruenewald T, et al. Departmental
126. Fridkin SK, Edwards JR, Tenover FC, et al. Intensive Care
National Nosocomial Infections Surveillance (NNIS) Sys-
tem Hospitals. Antimicrobial resistance prevalence rates
in hospital antibiograms reflect prevalence rates among
pathogens associated with hospital-acquired infections.
Clin Infect Dis 2001;33:324–30.
127. Cizman M, Pokorn M, Seme K, et al. The relation-
ship between trends in macrolide use and resistance to
macrolides of common respiratory pathogens. J Antimi-
crob Chemother 2001;47:475–7.
tance in intensive care units: Impact of computer-assisted
decision support. J Chemother 1999;11:530–5.
2114Malfertheiner et al.
129. Saez-Llorens X, Castrejon de Wong MM. Impact of an an-
terial susceptibilities: A lesson from a pediatric institution
in a developing country. Pediatr Infect Dis J 2000;19:200–
130. Kristinsson KG. Effect of antimicrobial use and other risk
factors on antimicrobial resistance in pneumococci. Mi-
crob Drug Resist 1997;3:117–23.
131. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effect
of changes in the consumption of macrolide antibiotics on
J Med 1997;337:441–6.
132. Enne VI, Livermore DM, Stephens P, et al. Persis-
tence of sulphonamide resistance in Escherichia coli in
the UK despite national prescribing restriction. Lancet
133. Arason VA, Gunnlaugsson A, Sigurdsson JA, et al. Clonal
spread of resistant pneumococci despite diminished an-
timicrobial use. Microb Drug Resist 2002;8:187–92.
134. Austin DJ, Kristinsson KG, Anderson RM. The relation-
ship between the volume of antimicrobial consumption in
human communities and the frequency of resistance. Proc
Natl Acad Sci U S A 1999;96:1152–6.
135. Bruinsma N, Hutchinson JM, van den Bogaard AE, et al.
Influence of population density on antibiotic resistance. J
Antimicrob Chemother 2003;51:385–90.
136. Adamsson I, Nord CE, Lundquist P, et al. Compara-
tive effects of omeprazole, amoxycillin plus metronida-
zole versus omeprazole, clarithromycin plus metronida-
zole on the oral, gastric and intestinal microflora in Heli-
137. Sjolund M, Wreiber K, Andersson DI, et al. Long-term
persistence of resistant Enterococcus species after antibi-
otics to eradicate Helicobacter pylori. Ann Intern Med
disease: Systematic review. BMJ 2003;326(7392):737.
139. Labenz J, Blum AL, Bayerdorffer E, et al. Curing He-
licobacter pylori infection in patients with duodenal ul-
cer may provoke reflux esophagitis. Gastroenterology
140. Hamada H, Haruma K, Mihara M, et al. High incidence of
reflux esophagitis after eradication therapy for Helicobac-
ter pylori: Impacts of hiatal hernia and corpus gastritis.
Aliment Pharmacol Ther 2000;14:729–35.
141. Laine L, Hopkins R J, Girrardi L. Has the impact of Heli-
cobacter pylori therapy on ulcer recurrence in the United
States been overstated? A meta-analysis of rigorously
designed trials. Am J Gastroenterol 1998;93(9):1409–
142. Malfertheiner P, Dent J, Zeijlon L, et al. Impact of
Helicobacter pylori eradication on heartburn in patients
with gastric or duodenal ulcer disease—Results from a
randomized trial programme. Aliment Pharmacol Ther
143. Veldhuyzen van Zanten SJO, Bradette M, Farley A, et al.
The DU-MACH study: Eradication of Helicobacter pylori
and ulcer healing in patients with acute duodenal ulcer
144. Moayyedi P, Bardhan C, Young L, et al. Helicobac-
ter pylori eradication does not exacerbate reflux symp-
toms in gastroesophageal reflux disease. Gastroenterolgy
145. Schwizer W, Thumshirn M, Dent J, et al. Helicobac-
ter pylori and symptomatic relapse of gastro-oesophageal
reflux disease: A randomised controlled trial. Lancet
146. Wu JC Chan FK, Wong SK, et al. Effect of Helicobac-
ter pylori eradication on oesophageal acid exposure in pa-
tients with reflux oesophagitis. Aliment Pharmacol Ther
148. Moayyedi P, Feltbower R, Brown J, et al. Effect of popu-
lation screening and treatment for Helicobacter pylori on
dyspepsia and quality of life in the community: A ran-
149. Malfertheiner P. Helicobacter pylori eradication does
not exacerbate gastro-oesophageal reflux disease. Gut
150. Warburton-Timms VJ, Charlett A, Valori RM, et al. The
significance of CagA Helicobacter pylori in reflux oe-
sophagitis. Gut 2001;49:341–6.
151. Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence
of CagA-positive Helicobacter pylori strains in the spec-
trum of gastroesophageal reflux disease. Gastroenterology
152. Weston AP, Badar AS, Topalovski M, et al. Prospective
evaluation of the prevalence of gastric Helicobacter py-
lori infection in patients with GERD, Barrett’s esophagus,
Barrett’s dysplasia, and Barrett’s adenocarcinoma. Am J
153. Chow WH, Blaser MJ, Blot WJ, et al. An inverse rela-
tion between CagA+ strains of Helicobacter pylori infec-
tion and risk of esophageal gastric cardia adenocarcinoma.
Cancer Res 1998;58:588–90.
154. Ye W, Held M, Lagergren J, et al. Helicobacter pylori in-
fection and gastric atrophy: Risk of adenocarcinoma and
ter pylori Cag A+ strains and risk of adenocarcinoma of
the stomach and esophagus. Int J Cancer 2003;103:815–
156. Lassen AT, Pedersen FM, Bytzer P, et al. Helicobacter py-
lori test-and-eradicate versus prompt endoscopy for man-
agement of dyspeptic patients: A randomised trial. Lancet
with non-invasive H. pylori testing alone in the manage-
ment for dyspepsia. BMJ 2002;324:999–1002.
158. Jones R, Tait C, Sladen G, et al. A trial of a test-and-treat
strategy for Helicobacter pylori positive dyspeptic patients
in general practice. Int J Clin Pract 1999;53:413–6.
159. Chiba N, Veldhuyzen van Zanten SJO, Sinclair P, et al.
Treating Helicobacter pylori infection in primary care
patients with uninvestigated dyspepsia: The Canadian
adult dyspepsia empiric treatment—Helicobacter pylori
positive (CADET-Hp) randomised controlled trial. BMJ
160. Chiba N, Veldhuyzen Van Zanten SJO, Escobedo S, et al.
Economic evaluation of Helicobacter pylori eradication in
the CADET-Hp randomized controlled trial of H. pylori
positive primary care patients with uninvestigated dyspep-
sia. Aliment Pharmacol Ther 2004;19:349–58.