Factors predicting progression of gastric intestinal
metaplasia: results of a randomised trial on Helicobacter
W K Leung, S-R Lin, J Y L Ching, K-F To, E K W Ng, F K L Chan, J Y W Lau, J J Y Sung
See end of article for
Dr J Sung, Department of
Therapeutics, Prince of
Wales Hospital, 30-32,
Ngan Shing Street, Shatin,
Hong Kong; joesung@
Revised version received
1 January 2004
Accepted for publication
21 January 2004
Gut 2004;53:1244–1249. doi: 10.1136/gut.2003.034629
Background and aim: Gastric intestinal metaplasia (IM) is generally considered to be a precancerous
lesion in the gastric carcinogenesis cascade. This study identified the risk factors associated with
progression of IM in a randomised control study.
Subjects and methods: A total of 587 Helicobacter pylori infected subjects were randomised to receive a
one week course of anti-Helicobacter therapy (omeprazole, amoxicillin, and clarithromycin (OAC)) or
placebo. Subjects underwent endoscopy with biopsy at baseline and at five years. Severity of IM was
graded according to the updated Sydney classification and progression was defined as worsening of IM
scores at five years in either the antrum or corpus, or development of neoplasia. Backward stepwise
multiple logistic regression was used to identify independent risk factors associated with IM progression.
Results: Of 435 subjects (220 in the OAC and 215 in the placebo group) available for analysis, 10
developed gastric cancer and three had dysplasia. Overall progression of IM was noted in 52.9% of
subjects. Univariate analysis showed that persistent H pylori infection, age .45 years, male subjects,
alcohol use, and drinking water from a well were significantly associated with IM progression. Duodenal
ulcer and OAC treatment were associated with a reduced risk of histological progression. Progression of
IM was more frequent in those with more extensive and more severe IM at baseline. With multiple logistic
regression, duodenal ulcer (odds ratio (OR) 0.23 (95% confidence interval (CI) 0.09–0.58)) was found to
be an independent protective factor against IM progression. Conversely, persistent H pylori infection (OR
2.13 (95% CI 1.41–3.24)), age .45 years (OR 1.92 (95% CI 1.18–3.11)), alcohol use (OR 1.67 (95% CI
1.07–2.62)), and drinking water from a well (OR 1.74 (95% CI 1.13–2.67)) were independent risk factors
associated with IM progression.
Conclusion: Eradication of H pylori is protective against progression of premalignant gastric lesions.
intestinal-type, involves multistep progression from gastritis
to glandular atrophy (GA), intestinal metaplasia (IM), dys-
plasia, and ultimately to cancer.1The gastric carcinogenesis
cascade is generally considered to be triggered by Helicobacter
pylori infection. Meta-analysis shows that infection with
H pylori confers a 2–3-fold increase in the risk of gastric
cancer development.2 3In a prospective study from Japan,
2.9% of infected subjects developed gastric cancer over a
mean follow up period of 7.8 years.4In contrast, none of the
uninfected individuals developed cancer. Moreover, H pylori
infected subjects with IM were found to have a 6.4-fold
increased risk of gastric cancer.
Despite a strong causal link between H pylori infection and
gastric cancer, data showing that treatment of H pylori
infection could actually prevent cancer are lacking. This is
largely due to the long lead time in gastric cancer develop-
ment. In order to assess the potential benefits of H pylori
eradication, most studies are designed to examine regression
of precancerous changes, such as IM and GA of the stomach,
as surrogate end points of treatment success. None the less,
there are conflicting data in the literature due to differences
in study populations and design.5–10Some studies also lack a
suitable control arm and adjustment for confounding factors.
Colombian reported by Correa and colleagues,9patients were
randomised to receive eight different treatments, including
vitamin supplements and anti-Helicobacter therapy alone or in
astric cancer is the second leading cause of cancer
related mortality worldwide. Evidence shows that
the pathogenesis of gastric cancer, particularly the
combination, compared with placebo for up to six years. After
successful eradication of H pylori, there was modest regres-
sion of IM compared with placebo (15% v 6%). Interestingly,
supplementation of b-carotene or ascorbic acid resulted in a
similar degree of improvement in IM (20% and 19%). None
the less, combinations of anti-H pylori therapy and vitamins
conferred no additional benefit on gastric histology. IM
progression rates were similar in all treatment groups and the
actual benefit of anti-Helicobacter treatment was question-
able.11One of the reasons for this conflicting result may be
the lack of statistical power of this study that involved
multiple treatment arms. Additionally, the results may be
confounded by other environmental and demographic factors
that contribute to progression of premalignant gastric lesions.
We have recently completed a five year prospective
randomised control study in Yantai county of Shandong
Province where gastric cancer incidence is among the highest
in China.10 12In this study, H pylori infected subjects were
randomised to receive either anti-Helicobacter therapy or
placebo. The results of the one year and five year follow up
have been reported previously.10 12In summary, we concluded
that there was a dramatic improvement in acute and chronic
gastritis in the treated (omeprazole, amoxicillin, and clari-
thromycin) group. Five years after H pylori eradication,
progression of gastric IM was retarded in the eradication
group. However, a considerable proportion of subjects in both
Abbreviations: IM, intestinal metaplasia; GA, glandular atrophy; OAC,
omeprazole, amoxicillin, and clarithromycin; OR, odds ratio
treatment arms still had histological progression of IM. It
thus appears that progression of gastric IM may be
influenced by factors in addition to H pylori eradication. In
fact, previous studies showed that factors such as smoking,13
age of patients,10and pattern or severity of gastritis4 14may
influence the progression of precancerous gastric lesions.
Studies that fail to adjust for these factors may undermine
the real benefits of H pylori eradication. In the present study,
we attempted to identify independent risk factors associated
with progression of gastric IM in this prospective study. We
also aimed to identify a subgroup of high risk subjects that
might warrant more intensive surveillance.
Study design and study population
Details of subject characteristics and the results of the one
year and five year follow up study were reported pre-
viously.10 12Briefly, volunteers residing in the Yantai county
of Shandong Province were invited for screening endoscopy
in 1996. This is a rural region with a very high gastric cancer
incidence (50 per 100 000 population). The residents are
predominantly comprised of farmers of lower socioeconomic
class. Written informed consent was obtained from all
participants and the study protocol was approved by the
clinical research ethics committee of the Chinese University
of Hong Kong. All participants were interviewed on their
medical and family histories, followed by a brief physical
examination. A structured questionnaire elicited information
on demographic data, smoking habits (active smoker, non-
smoker, or ex-smoker), alcohol use (active drinker, non-
drinker, or ex-drinker) and source of drinking water (tap or
During gastroscopy, the presence of peptic ulcer or tumour
was noted. In all subjects, three antral biopsies were taken
from the greater and lesser curvatures 2–3 cm from the
pylorus, and two corpus biopsies were obtained from the
lesser curvature and the greater curvature at the mid corpus.
One antral biopsy was used for determination of H pylori
status using the rapid urease test (CLOtest; Ballard, Draper,
Utah, USA) whereas the remaining gastric biopsies were used
for histological examination. Samples from the antrum and
corpus were stored in separate bottles that were readily
H pylori infection was diagnosed when both the rapid
urease test and histology were positive. H pylori positive
subjects were then randomised to receive either a one week
course of anti-Helicobacter therapy (OAC: omeprazole 20 mg,
amoxicillin 1 g, and clarithromycin 500 mg, all given twice
daily) or placebo. Medications had identical appearances.
Exclusion criteria included pregnancy, allergy to the pre-
scribed medication, suspected gastric malignancy, prior
gastric surgery, concomitant use of proton pump inhibitors
or non-steroidal anti-inflammatory drugs, and comorbid
illnesses that might increase the risk of complications from
Follow up gastroscopy was arranged at one year and five
year intervals after randomisation. Gastric biopsies were
taken from the same sites as described above for both
endoscopies. The rapid urease test was repeated to monitor H
pylori status. Subjects who defaulted follow up were traced by
the local village doctors to document their outcome,
particularly in the development of gastric cancer. Hospital
records and death certificates were retrieved to document the
nature of any illnesses and causes of death in those who
underwent surgery or died within the five year study period.
The cagA status of these individuals was determined by
serological response against CagA on entry to the study, as
Gastric biopsy specimens were fixed in buffered formalin and
embedded in paraffin. Paraffin sections were stained with
haematoxylin and eosin and modified Giemsa techniques. All
histological assessment was made by a single experienced
pathologist (KFT). Slides were coded in a random manner
such that the pathologist was blinded to the identity of
subjects, treatment assignment, and year at which biopsies
were obtained. Histological sections of the antrum and
corpus tissue were graded for H pylori density, intensity of
acute (polymorphonuclear cells) infiltrates, intensity of
chronic (mononuclear cells) infiltrates, GA, and IM, as
stipulated by the updated Sydney system (Houston).15All
parameters were graded as none (0), mild (1), moderate (2),
or marked (3). IM was recognised morphologically by the
presence of goblet cells, absorptive cells, and cells resembling
colonocytes. Dysplasia (or intraepithelial neoplasia) was
defined as stipulated in the Padova international classifica-
tion.16Briefly, diagnosis of dysplasia was restricted to cases
showing both altered glandular architecture and abnormal-
ities in cytology and differentiation but lacking any infiltrat-
ing features. Carcinoma was diagnosed when tumours
invaded the lamina propria or were through the muscularis
To determine intraobserver variation in histological assess-
ments over the five year study period, the same pathologist
(KFT) was asked to re-score 30 randomly selected cases taken
from various follow up endoscopies. Consistent results were
obtained in acute inflammation (86%), chronic inflammation
(96%), GA (92%), and IM (96%). Moreover, interobserver
variability was assessed by asking a second pathologist to
score gastric biopsies from 224 randomly selected cases.
Kappa statistics were used to compute the consistency of
scoring between the two pathologists. The kappa value for
antral IM was 0.898 (95% confidence interval (CI) 0.87–0.97)
and for body IM 0.84 (95% CI 0.77–0.91).
All subjects included in this analysis either had completed
the two endoscopic examinations at baseline and at five
years, or had developed gastric cancer within the five year
follow up period. Histological scores of IM at entry and at five
years were compared. Progression of IM was defined as a
higher score at five years compared with baseline in either
the antrum or corpus. Moreover, subjects who had developed
gastric dysplasia or cancer were regarded as having histol-
Statistical analysis was performed using SPSS software
(version 11.5; SPSS Inc, Chicago, Illinois, USA). Possible
baseline covariables associated with progression of IM were
(.45 years v (45 years), sex (male v female), tobacco use
(smokes v non-smokers+ex-smokers), alcohol use (drinkers v
non-drinkers+ex-drinkers), source of drinking water (well v
tap), and presence of peptic ulcer. The effect of H pylori
eradication was assessed in three separate analyses: (1) the
odds ratio (OR) for progression in those who received OAC
treatment versus placebo, (2) the OR for progression in those
who received OAC with confirmed H pylori clearance versus
those who received placebo with persistent infection, and (3)
those with persistent H pylori infection versus those who
remained negative for H pylori infection at five years,
regardless of treatment allocation. Possible associations
between the baseline distribution of IM and severity of IM
in the antrum and risk of IM progression were also assessed.
ORs (with 95% CI) are presented. Factors with a trend
towards affecting progression of histology (p,0.10) were
included in the backward stepwise multiple logistic regres-
sion model to identify significant predictors associated with
Progression of intestinal metaplasia 1245
IM progression. All p values were two sided and statistical
significance was taken at p,0.05.
Five hundred and eighty seven H pylori infected subjects were
randomised in this study. A total of 295 received a one week
course of OAC whereas 292 received placebo. Seventy five
patients in the OAC group and 77 in the placebo group were
lost to follow up. Data from 435 subjects (220 in the OAC
group and 215 in the placebo group) were available for the
five year analysis. There were 208 males and 227 females
with a mean age of 52.0 (8.1) years.
Clearance of H pylori infection was confirmed at five years
in 164 (74.5%) subjects who had received OAC whereas 20
(9.3%) subjects in the placebo group were negative for H
pylori by histology at five years. Twenty six (6.0%) subjects
were diagnosed as having duodenal ulcer and 16 (3.7%)
gastric ulcer. Ten (2.3%) subjects developed invasive gastric
cancers during the five year follow up period. Four cancers
were in the OAC group whereas the remaining six cancers
were in the placebo group. As not all cancer patients had
undergone surgery, data on pathological staging and final H
pylori status were incomplete. However, all 10 cancer patients
died from gastric cancer, suggesting that they were of
advanced staging. Additionally, three subjects in the placebo
group were noted to have dysplasia during the five year
follow up endoscopy.
Changes in gastric histology of each individual over the five
year follow up period are summarised in table 1. Both
forward and backward movements from one stage to the
other were frequently noted during the follow up examina-
tion. Eight patients with IM at baseline developed gastric
cancer. Conversely, IM was no longer detected in 26 patients
with baseline IM. Progression or deterioration of gastric IM
was also frequently noted during the five years of follow up.
Of the 435 subjects, 230 (52.9%) had progression of gastric
IM which included 13 subjects with gastric cancer or
Baseline demographic and histological progression
Table 2 summarises the results of the univariate analysis of
baseline demographic and clinical data in the risk of IM
progression. Univariate analysis showed that male subjects
had a higher risk of progression of IM than female subjects
(OR 1.51 (95% CI 1.03–2.20); p=0.034). The risk of
progression was also higher in subjects aged .45 years (OR
1.95 (95% CI 1.24–3.07); p=0.004). Alcohol users or those
who obtained drinking water from a well had significantly
higher risks of IM progression. Tobacco smokers tended to
have a higher risk of IM progression compared with non-
smokers and ex-smokers but the difference did not reach
p=0.06). In contrast, subjects who had duodenal ulcers on
first endoscopy had a reduced risk of progression of IM (OR
0.28 (95% CI 0.12–0.67)) but the presence of gastric ulcer did
not have any effect on IM progression. Family history of
gastric cancer or the presence of anti-CagA antibody were not
associated with IM progression.
Baseline histology and histological progression
We assessed the severity and patterns of gastric histology at
baseline and its association with the risk of IM progression.
As shown in fig 1, there was a significant difference in the
distribution patterns of IM at baseline between those with
and without progression (p=0.01). Subjects with IM
progression tended to have more severe IM in the antrum
at baseline (p=0.08, fig 2). In contrast, there was no
association between the pattern of gastritis and IM progres-
sion (fig 3). The risk of progression was comparable in those
with antral predominant gastritis, corpus predominant, or
pangastritis (OR 0.89 (95% CI 0.57–1.38)).
to baseline pathology results
Frequency of gastric pathology changes after five years of follow up according
5 year follow up pathology
Dys, dysplasia; GA, glandular atrophy; IM, intestinal metaplasia; Inflammation, active and/or chronic
*As all subjects were infected with Helicobacter pylori, there was no normal histology at baseline.
metaplasia (IM) according to baseline variables: univariate analysis
Odds ratio (OR with 95% confidence interval (CI)) for progression of intestinal
No IM deterioration
(n=205) OR (95% CI)p Value
Age .45 y
Drinking water from well
Family history of stomach cancer
1246 Leung, Lin, Ching, et al
Effect of H pylori eradication on histological
Table 3 summarises the risk of IM progression with regard to
treatment allocation and final H pylori statuses. Eradication of
H pylori infection was significantly associated with reduction
in the risk of IM progression. Patients assigned to receive
OAC had a significantly lower risk of IM progression
compared with those who received placebo (OR for histol-
ogical progression 0.63 (95% CI 0.43–0.93); p=0.018)).
Comparing those in the OAC group with H pylori eradicated
with those with persistent H pylori infection in the placebo
group, the OR of histological progression was further reduced
to 0.48 (95% CI 0.32–0.74); p,0.001). Also, the risk of IM
progression was significantly higher in those with persistent
H pylori infection at five years, regardless of treatment
allocation (OR 2.14 (95% CI 1.45–3.16); p,0.001).
Multivariate logistic regression
Table 4 summarises the risks of IM progression with the
following factors entered into the logistic regression model:
age, sex, smoking, alcohol, source of drinking water, presence
of duodenal ulcer, severity of baseline antral IM, treatment
allocation, and final H pylori status. After stepwise logistic
regression, five factors remained statistically significant:
subject age .45 years, alcohol use, source of drinking water,
presence of duodenal ulcer, and final H pylori status (table 4).
In summary, subjects who remained positive for H pylori at
five years had a significantly higher risk of IM progression
than those with successful eradication (adjusted OR 2.13
(95% CI 1.41–3.24); p,0.001). Duodenal ulcer patients were
less likely to have IM progression (adjusted OR 0.25 (95% CI
0.09–0.66); p=0.005). IM progression was more frequently
noted in subjects aged .45 years (adjusted OR 1.92 (95% CI
1.18–3.11); p=0.009). The rate of progression was highest
among subjects .45 years with persistent H pylori infection
(62.8%) and lowest in younger subjects with successful H
pylori eradication (28.6%) (fig 4). Environmental factors,
including alcohol use and drinking well water, were also
independent risk factors for IM progression.
In this five year prospective study, 53% of subjects were noted
to have progression of gastric IM. Moreover, it was noted that
2.3% of H pylori infected subjects developed gastric cancer
over the five year follow up period. Thus the mean annual
risk of gastric cancer development in our cohort was 0.46%.
This value is slightly higher than that reported in the study by
Uemura et al (0.37%) which included both H pylori infected
and uninfected individuals.4We also showed that eradication
of H pylori infection significantly retarded progression of IM.
As shown in table 3, subjects randomised to receive anti-H
pylori therapy had a significantly lower risk of IM progression
than those who received placebo, regardless of the final H
pylori status (OR 0.63). The risk of progression was further
reduced in those with successful H pylori eradication in the
OAC group (OR 0.48). After adjusting for various confound-
ing factors, it was determined that subjects with persistent H
pylori infection had more than a twofold increased risk of IM
progression than those who were negative for H pylori,
irrespective of treatment allocation. This finding strongly
supports the notion that successful eradication of the
bacterium could prevent progression of precancerous gastric
As in our previous analysis,10results from this five year
analysis further confirmed that age is an important factor
governing the rate of histological progression. Subjects
.45 years had about a twofold increased risk of IM
progression than younger subjects. The highest risk of
progression was in subjects .45 years of age with persistent
H pylori infection. In keeping with this finding, You et al
concluded that the risk of progression to gastric cancer was
threefold higher in subjects .45 years compared with those
,45 years.14Although it appeared that eradication of H pylori
would most benefit subjects .45 years, our analysis showed
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with IM progression. p,0.01.
Baseline distribution of intestinal metaplasia (IM) in subjects
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progression of gastric IM. p=0.084.
Severity of antral intestinal metaplasia (IM) at baseline and
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intestinal metaplasia (IM). Antrum versus corpus/pangastritis, p=0.69.
Pattern of gastritis at baseline and progression of gastric
Progression of intestinal metaplasia 1247
that eradication of the bacterium also significantly retarded
the rate of progression in younger subjects (fig 4). Thus
eradication of H pylori should be considered in all age groups
to prevent deterioration in gastric histology.
In our analysis, modifiable environmental factors, includ-
ing alcohol use and drinking water from a domestic well,
increased the risk of IM progression. While there are a
number of studies addressing the role of tobacco and alcohol
on premalignant gastric lesions,13 18the role of the source of
drinking water has received little attention. A previous study
from Changle, China, showed that the source of drinking
water may have a strong correlation with gastric cancer
incidence.19Gastric cancer mortality was highest among
those drinking river water, which was significantly higher
than those drinking shallow well water and tap water. One of
the plausible explanations for this observation may be related
to the mineral and trace element concentrations of drinking
water. It has been shown that higher concentrations of
selenium and zinc in drinking water may aid in preventing
gastric carcinogenesis.20Alternatively, the use of well water
may just be a surrogate indicator of the lower socioeconomic
class of these study subjects.
It is well known that not all subjects infected with H pylori
develop gastric cancer. In fact, duodenal ulcer and gastric
cancer, both aetiologically linked to chronic H pylori infection,
are considered to be two ends of the clinical spectrum of H
pylori infection. While duodenal ulcer is characterised by
antral predominant gastritis and acid hypersecretion, gastric
cancer is characterised by corpus predominant or pangastritis
with acid hyposecretion. This divergent clinical outcome may
be related to the genetic makeup of the host and polymorph-
ism in the proinflammatory cytokines.21 22In this study, we
found that duodenal ulcer patients had a lower rate of IM
progression and the risk of progression was approximately
75% lower than those without duodenal ulcer. Uemura et al
also found that the risk of gastric cancer development was
lower in patients with duodenal ulcers but higher in patients
with gastric ulcers and non-ulcer dyspepsia.4With the lower
progression rate of gastric precancerous lesions in patients
with duodenal ulcer, our finding may offer a plausible
explanation for the reduced risk of gastric cancer develop-
ment in these patients.
In addition to the grading of IM, there are data to suggest
that subtyping of IM may further stratify the risk of gastric
cancer development.23–25Patients with type III or incomplete
IM, which are characterised by the presence of columnar and
globet cells secreting sulfomucins, have the highest cancer
risk. However, this typing is not easily reproducible due to the
focal nature of gastric IM. Instead, it has been proposed that
the pattern, extent, and severity of IM may be more reliable
predictors of cancer risk.26Consistent with this, we found in
the present study that the risk of IM progression was higher
in those with more severe (fig 2) and more extensive IM
(fig 1) at baseline. On the other hand, we failed to show any
significant association between the pattern of gastritis and
rate of IM progression.
Gastric IM is multifocal and is mostly indistinguishable
from inflamed gastric mucosa by the naked eye or even by
chromoendoscopy.27One of the limitations of the present and
other interventional studies of gastric precancerous lesions is
the focal nature of these lesions which make the results
subject to sampling error. To overcome this limitation, our
protocol dictated the need to obtain gastric biopsies from the
same landmark (that is, the mid point of the antrum and
corpus in the lesser and greater curves of the stomach, during
each endoscopy). Moreover, recruiting a larger sample size,
incorporating a control group, and using paired tissue
samples from the same subjects may have partially overcome
the effects of apparent spontaneous regression of precancer-
ous gastric lesions.
In conclusion, this five year randomised study showed that
the risk of progression of gastric precancerous lesions was
significantly lower in subjects with confirmed H pylori
eradication or in those with duodenal ulcer. In contrast,
metaplasia (IM) according to Helicobacter pylori treatment and/or final H pylori status
Odds ratio (OR with 95% confidence interval (CI)) for progression of intestinal
IM deterioration No IM deterioration OR (95% CI)p Value
Hp+ve at 5 y
Hp2ve at 5 y
Hp+ve, H pylori infected; Hp2ve, H pylori negative.
OAC, omeprazole, amoxicillin, and clarithromycin.
progression: multivariate logistic regression
Factors predicting intestinal metaplasia (IM)
Factor OR (95% CI) p Value
Age .45 y
Drinking water from well
Hp+ve, H pylori infected.
Values are odds ratios with 95% confidence interval (OR (95% CI)).
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according to final Helicobacter pylori (Hp) status after age stratification.
Rate of progression of gastric intestinal metaplasia (IM)
1248 Leung, Lin, Ching, et al
subjects aged .45 years who drank alcohol or well water, Download full-text
had a higher risk of progression. Hence eradication of H pylori
and lifestyle modifications may have a protective effect
against gastric cancer development by retarding the progres-
sion of premalignant gastric lesions. We also identified a
subgroup of infected individuals who were at high risk of
histological progression that may warrant more intensive
endoscopic surveillance to detect early gastric malignancy.
This study was supported by an unrestricted research grant from the
Hong Kong Society of Digestive Endoscopy. The authors would like to
thank the endoscopists and nurses of the Third Hospital of Peking
University, Dr KF Chan for assistance on histological assessment, and
Dr Rupert Leong for proofreading of the manuscript.
W K Leung, J Y L Ching, F K L Chan, J J Y Sung, Department of Medicine
and Therapeutics, The Chinese University of Hong Kong, Hong Kong,
S-R Lin, Department of Gastroenterology, The Third Hospital of Peking
University, Beijing, China
K-F To, Department of Anatomical and Cellular Pathology, The Chinese
University of Hong Kong, Hong Kong, China
E K W Ng, J Y W Lau, Department of Surgery, Prince of Wales Hospital,
The Chinese University of Hong Kong, Shatin, Hong Kong, China
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Making Health Care Safer 2004
21–22 October 2004
Royal College of Physicians, London
A two day conference for all professionals dedicated to providing safer health care for all.
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10th European Forum on Quality Improvement in Health Care
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