Mortality study of 18 000 patients treated with
D N Bateman, D Colin-Jones, S Hartz, M Langman, R F Logan, J Mant, MMurphy, K R Paterson, R Rowsell, S Thomas and M Vessey
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Mortality study of 18 000 patients treated withomeprazole
D N Bateman, D Colin-Jones, S Hartz, M Langman, R F Logan, J Mant, M Murphy,K R Paterson, R Rowsell, S Thomas, M Vessey, for the SURVEIL (Study of UndetectedReactions. Vigilance Enquiry into Links) Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Background: The long term safety of potent gastric acid suppressive therapy has yet to be established.
Method: General practice record review at a median interval of 26 months followed by retrieval ofdetails of all deaths within four years using the UK National Health Service Central Registers in 17 936patients prescribed omeprazole in 1993–1995. Death rates were compared with general populationrates.
Results: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received fur-ther scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. Allcause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals(CI) 1.34–1.55); p<0.0001) but had fallen to population expectation by the fourth year. There weresignificant mortality increases in the first year, falling to or below population expectation by the fourthyear, for deaths ascribed to neoplasms (1.82 (95% CI 1.58–2.08); p<0.0001), circulatory diseases(1.27 (95% CI 1.13–1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12–1.64);p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87–3.43); p<0.0001)persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60–
6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84–2.18); p=0.075), and trachea, bronchus,
and lung (1.64 (95% CI 1.19–2.19); p<0.01) seen in the first year had disappeared by the fourth year
. . . . . . . . . . . . . . . . . . . . . . .
but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20–10.09) (p<0.0001) in year
1; 2.88 (95% CI 1.62–4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer
had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of
Barrett’s disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17–4.80)). Six
deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37–2.22)) and five
in patients without oesophageal disease (O/E 0.77 (95% CI 0.25–1.80)). No relationships were
detected with numbers of omeprazole scripts received.
Conclusions: Increases in mortality associated with treatment are due to pre- existing illness, includ-
Accepted for publication:20 February 2002
ing pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesopha-
. . . . . . . . . . . . . . . . . . . . . . .
geal adenocarcinoma in those without oesophageal mucosal damage recorded at registration.
proton pump inhibitors (PPIs), where usage is likely to be
We sought to register a cohort of 18 000 patients prescribed
widespread and prolonged, requires that safety during
omeprazole in the six UK conurbations of or surrounding Bir-
chronic treatment is assured. The need for such assessment is
mingham, Glasgow, Newcastle, Nottingham, Oxford, and
emphasised by claims that omeprazole treatment might
Portsmouth. Using the computerised registers of cooperating
adversely affect the management of upper gastrointestinal
general practitioners, we identified takers of omeprazole in the
period 1993–1995. Records of patients who were still alive andwho had received at least one prescription for omeprazole
epithelialisation of the cancer might be promoted, so hinder-
were examined and details taken of, inter alia, the patient’s
ing disease recognition.1 It has also been suggested that raised
age, sex, and NHS number, prescription data, and the reasons
serum gastrin concentrations in response to reduced acidity
for any prescription, together with details of any prior diagno-
might act as growth promoters,2 or that treatment might
sis of malignant disease, any previous upper abdominal surgi-
accelerate the onset of atrophic gastritis, so predisposing to
cal procedures, and any other recorded antisecretory drug use
gastric cancer.3 Moreover, as omeprazole is commonly used to
in the previous 12 months. We excluded from consideration all
treat gastro-oesophageal reflux disease, it is important to
those dying prior to the registration date.
determine whether treatment influences the frequency of
Clinical diagnoses were those recorded in individual case
oesophageal adenocarcinoma, a tumour known to complicate
notes and were not re- interpreted, but details of investiga-
oesophageal metaplasia (Barrett’s disease), which occurs in
tions were recorded. Individual diagnoses of ulcer, oesoph-
association with oesophageal reflux associated damage.
agitis, Barrett’s oesophagus, hiatal hernia or reflux, and cancer
We examined mortality rates from any cause over a four
required specific mention of these following investigation.
year period during or after treatment with omeprazole in sixcities in England and Scotland. Death rates were compared
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
with those expected nationally. Data have strength in relating
Abbreviations: O/E, observed/expected; PPI, proton pump inhibitor;
risks to those observed in the general population, as done pre-
NHSCR, National Health Service Central Register; ICD, International
Major diagnostic groups of patients prescribed omeprazole
Diagnostic figures add up to more than 100% because some patients had more than one diagnosis.
*A single script is equivalent to one month of treatment at a standard dosage.
Records of patients registered were re-examined after two
years, and new diagnoses of oesophageal cancer at hospital
A total of 17 936 patients had been registered by December
attendance and details of subsequent omeprazole and other
1995 when entry was completed, and clinical follow up data
antisecretory drug prescribing were recorded. Patients trans-
were available after two years in 17 489 (97.5%) patients.
ferring to another general practitioner were followed by post
Mean age of the patients at registration was 59.6 years
or visit to the practice if nearby. The records of cohort
(median 61.5; range 7–105) with 46.9% being men. In the
members were also flagged at the National Health Service
year prior to registration, 38% had received 1–2 omeprazole
Central Register (NHSCR) in England and Scotland, providing
prescriptions while 25% had received six or more. Table 1
data on all causes of death and confirmation of cancer
shows the major diagnostic groupings in patients prescribed
omeprazole. Oesophageal disease and gastrointestinal symp-
Observed death rates, classified according to the ninth revis-
toms of uncertain cause formed the bulk of the indications.
ion of the International Classification of Disease (ICD), were
There were 12 501 diagnoses of oesophageal disease recorded.
compared with expected population rates in England and
Oesophagitis (3664), reflux not otherwise specified (3842),
Scotland using published data from the Office of National
and hiatal hernia (3142) were the commonest recorded but
Statistics. For this purpose, rates were based on those
with substantial numbers of patients with stricture (791),
individuals dying in 1996, the approximate midpoint of the
ulcer (441), or Barrett’s disease (417) of the oesophagus.
study period, taking account of age, within five year groups,
Oesophageal disease was pre-existing cancer in 40 and was
and sex. In addition, death rates were examined in relation to
not clearly specified in the remaining 164.
the number of scripts received by patients for omeprazole, as
We found that 2096 patients (11.7%) had undergone a total
of 2477 upper abdominal procedures in the past. Commoner
noted at the time of registration. Relative risks presented are
procedures were cholecystectomy (1014 (5.3%)), oesophageal
the ratios of observed to expected deaths, together with their
surgery (489 (2.7%)) and elective ulcer surgery (439 (2.4%)).
95% confidence intervals (CI) throughout, alongside the
Further prescriptions for antisecretory treatments had been
observed and expected numbers of deaths.
received by 12 703 (72.6%) of 17 489 patients with two year
The study was approved by local ethics committees and by
follow up data; 10 929 (62.5%) had received at least one
the Office of National Statistics. It was also constructed to
further prescription for omeprazole with 8097 having omepra-
conform to the guidelines for safety assessment of marketed
medicines (SAMM guidelines),7 and was registered with the
Table 2 shows that observed mortality tended to be higher in
the first year after registration and then fell overall to population
Observed (O) deaths from all causes and observed deaths divided by deaths expected* (O/E) in each study
*Expected deaths based on national (England and Wales) rates for 1996, except for Glasgow which is based on Scottish rates for 1996, and total rateswhich are based on pooled Scotland, England, and Wales expected deaths. Calculations made for each sex separately within five year age groupings.
Observed and expected number of deaths for individual ICD (International Classification of Disease) chapters
Observed/expected (O/E) ratios in parentheses.
*O/E significantly >1.0, p<0.05.
expectation, with similar trends in the six conurbations. Table 3
To examine results for oesophageal cancer in more detail, we
shows the mortality observed for individual ICD chapters by
stratified data in those without oesophageal cancer at
year, together with their associated relative risks (observed/
registration according to whether patients were recorded ini-
expected (O/E)). Mortality was initially higher than expected
tially as having Barrett’s disease, oesophageal ulcer, stricture,
for neoplasms (observed 217, expected 119; O/E 1.82; 95% CI
or oesophagitis (categorised as severe disease), or whether
1.58–2.08; p<0.0001) and also for diseases of the circulatory
they had reflux or hiatal hernia without Barrett’s disease,
(observed 284, expected 224; O/E 1.27; 95% CI 1.13–1.43;
ulcer, stricture, or oesophagitis (categorised as mild disease).
p<0.0001), respiratory (observed 112, expected 82; O/E 1.37;
Table 5 shows the types of non- malignant oesophageal disease
95% CI 1.12–1.64; p<0.001), and digestive (observed 45,
present in the 38 patients diagnosed as having oesophageal
expected 18; O/E 2.56; 95% CI 1.87–3.43; p<0.0001) systems.
cancer after registration. Among those with severe oesopha-
Death rates from neoplasms fell to population expectation by
geal disease, 27 died of oesophageal cancer (expectation 8.2 in
year 4, as did those for the circulatory and respiratory systems.
four years; O/E 3.30; 95% CI 2.17–4.80). In contrast, of those
Greater mortality than expected was also initially recorded for
with mild oesophageal disease, evidenced by clinical diag-
infectious and parasitic disease (O/E 3.09; 95% CI 1.33–6.08;
noses of reflux or hiatal hernia, only six died of oesophageal
p<0.01), falling to population expectation by the fourth year of
cancer (expectation 5.9; O/E 1.02; 95% CI 0.37–2.22). In those
the study. Initially increased mortality from musculoskeletal
without initial clinical diagnoses of oesophageal disease, five
disorders, upper gastrointestinal disorders, and chronic liver
patients died (against expectation 6.5; O/E 0.77; 95% CI 0.25–
disease, although falling with time towards population expecta-
1.80). Of the 417 who had Barrett’s disease identified at some
tion, still tended to remain raised.
time and recorded at registration, nine had died of oesopha-
Table 4 shows the observed and expected deaths for selected
geal cancer (O/E 11.25; 95% CI 5.14–21.36).
ICD rubrics, including major gut epithelial cancers and cancer
In those with severe oesophageal disease, the risk of devel-
of the lung, breast, and blood forming tissues, ischaemic and
oping oesophageal cancer was slightly lower (observed 8,
cerebrovascular disease, and upper gastrointestinal causes. For
expected 2.8; O/E 2.86; 95% CI 1.23–5.63) in those who had
all selected causes, initial increases in mortality declined
received six or more scripts in the year before registration than
towards or below population expectation, except for oesopha-
in those who had received fewer (observed 19, expected 5.2;
geal cancer and liver disease which remained significantly
O/E 3.65; 95% CI 2.20–5.71). Examination of mortality from
all other neoplasms, and from all other (non-neoplastic)
Observed and expected number of deaths for selected ICD (International Classification of Disease) rubrics
Observed/expected (O/E) ratios in parentheses.
*O/E significantly >1.0, p<0.05.
Observed and expected deaths from cancer of the oesophagus in successive years according to initial
oesophageal disease diagnosis in those cancer free at registration
Barrett’s disease/ulcer/stricture/oesophagitis (n=5517)
(Barrett’s disease cases only)* (n=417)
*Includes all diagnoses of the condition, irrespective of date of diagnosis.
causes, likewise showed no relationship with the intensity of
oesophageal cancer in the first year after registration. This
treatment. Clear histological diagnoses were available in 29 of
almost certainly represents confounding by indication rather
38 oesophageal cancer cases diagnosed after the study enrol-
than an adverse drug effect, or masking of disease by
ment date. Fifteen (83%) of 18 patients with adenocarcino-
treatment. The patterns are similar to those seen with cimeti-
mata had initial clinical diagnoses of oesophagitis, oesopha-
dine; no dose relationship was seen with treatment, and death
geal ulcer, stricture, and/or Barrett’s oesophagus. In contrast,
rates fell progressively with time. Persisting increases into the
only five (45%) of 11 patients with squamous cancers had
fourth year were only seen for oesophageal cancer. The major-
such initial diagnoses (p=0.086, Fisher’s exact test).
ity of those dying with oesophageal cancer had initialdiagnoses suggesting severe oesophageal disease, namely Bar-rett’s disease, stricture, ulcer, or oesophagitis. Observed
mortality was more than three times as great as expected in
By registering patients with the NHSCR, we systematically
these patients whereas it was not increased in those with ini-
collected information on the causes of death over four years in
tial diagnoses of hiatal hernia or reflux, or in those initially
nearly 18 000 patients prescribed omeprazole. Mortality was
considered to have disease outside the oesophagus as the rea-
significantly greater than population expectation in the first
son for omeprazole prescription. Patients with adenocarcino-
year after registration, falling progressively to that expectation
mata were six times as likely to have initial clinical diagnoses
by the fourth year. Increased mortality in the first year is
suggesting severe underlying oesophageal disease as those
unlikely to reflect drug effects because it was detectable for a
with squamous tumours. Observed mortality was more than
wide variety of causes and was unrelated to the duration of
10 times as high in patients in whom Barrett’s disease had
initial treatment. Furthermore, very similar patterns were
been detected at some time in their clinical course whether or
observed in our previous studies of cimetidine takers
not found at registration. However, findings of high propor-
conducted in the same way.5 6 We deduce therefore that
tions of Barrett’s disease in this group may reflect the results
confounding by indication for treatment explains the general
of differences in intensity of surveillance in those with and
patterns observed. Thus treatment of chest pain attributed to
reflux, but actually anginal in origin, could well explain
Although in the long term follow up of approximately
increased cardiovascular disease mortality. Use of omeprazole
10 000 patients prescribed cimetidine we found no evidence
in those perceived to be at high risk of ulcer complications is
that treatment was likely to cause gastric or other varieties of
also likely to explain raised risks of death from peptic ulcer
gastrointestinal cancer,4–6 it has recently been suggested that
disease and musculoskeletal disease.8 This finding should not
histamine receptor antagonist treatment might predispose to
be taken to imply that such treatment fails in its objectives:
cardio-oesophageal adenocarcinoma .18 That claim was based
there is strong evidence from controlled trials to indicate that
on comparing prior drug intake in cardio-oesophageal cancer
treatment is appropriate and successful.9–11 In the same way,
patients with that in individuals with myocardial infarction.
increased mortality from musculoskeletal diseases seems
The nature of the control would seem to make sensible deduc-
likely to reflect use of omeprazole in those perceived as at risk
tions about causation impossible. Our findings indicate
of ulcer complications.12 The increased mortality observed
strongly that the nature of the underlying oesophageal disease
from infectious and parasitic disease in the first two years of
is the major, and probably sole, cause of the raised risk of
observation lacks a plausible explanation but may represent
oesophageal cancer death in our omeprazole takers. This con-
the play of chance in small numbers. PPI use is known to be
clusion is reinforced by evidence that death rates were
associated with an increased frequency of dysenteric infec-
unrelated to the number of omeprazole scripts received at
tions but not with death from this cause.13 14 Persistently
registration. This finding is consonant with findings that the
increased mortality from chronic liver disease in our cohort
proportions of patients receiving acid suppressant therapy for
seems likely to represent deaths in patients with upper
Barrett’s oesophagus, and oesophagitis without Barrett’s
gastrointestinal symptoms coincident liver disease, and
disease, did not differ significantly.19 The data in our study
suggest strongly that underlying oesophageal disease explains
drinking.15 16 Scrutiny of our cases revealed none where a
the increased risk of oesophageal cancer but it should be noted
causal relationship with antisecretory treatment seemed
that classification depended upon reports available to us in
likely. Prescribing of omeprazole to attendees at general prac-
practice case records, these not being produced to standard-
titioner surgeries with other main complaints, a form of Berk-
ised criteria. The actual strength of risk is therefore uncertain.
son’s bias,17 would be expected to lead to increases in mortality
Systematic study has suggested that there may be publication
from a broad range of complaints, particularly in the early
bias in the reporting of cancer risks in Barrett’s oesophagus.20
period after prescription, a phenomenon seen in our previous
Our data show, compared with the findings of others, rather
moderate increases in the risk of oesophageal cancer. Our set
Examination of the data for neoplastic diseases showed that
has particular strengths. Firstly, patients for study were
mortality increases were particularly high for gastric and
selected prior to the outcomes being known. Secondly, the
population studied was large, and the follow up prolonged and
complete. Thirdly, the number of incident oesophageal
1 Bramble MG, Suvakovic Z, Hungin APS. Detection of upper
tumours diagnosed after enrolment (38) was large.
gastrointestinal cancer in patients taking antisecretory therapy prior togastroscopy. Gut
It has been suggested that, based on symptoms alone,
2 Thorburn CM, Friedman GD, Dickinson CJ, et al
. Gastrin and colorectal
patients with oesophageal reflux are at nearly eight fold
cancer: a prospective study. Gastroenterology
increased risk of adenocarcinoma.21 Our data indicate that in
3 Pounder RE, Williams MP. Omeprazole and accelerated onset of
atrophic gastritis. Gastroenterology
our population, any increase in oesophageal cancer risk may
4 Colin-Jones DG, Langman MJS, Lawson DH, et al.
be confined to those with evidence of mucosal structural
surveillance of the safety of cimetidine: 12 month mortality report. BMJ
damage, and that simple symptomatic reflux may not pose
5 Colin-Jones DG, Langman MJS, Lawson DH, et al.
significant risks. This conclusion is consonant with that of
surveillance of the safety of cimetidine: mortality during second, third and
Cohen and Parkman22 that structural damage, and Barrett’s
fourth year of follow-up. BMJ
oesophagus in particular, are the critical factors. Our data
6 Colin-Jones DG, Langman MJS, Lawson DH, et al.
surveillance of the safety of cimetidine: 10 year mortality report. Gut
showing a fall in gastric cancer death rates by the fourth year
of the study to slightly below population expectation suggest
7 Medicines Control Agency, Committee of Safety of Medicines, Royal
that gastric cancer risk is neither intrinsically raised in the
College of General Practitioners, British Medical Association andAssociation of the British Pharmaceutical Industry. Guidelines for
population studied nor influenced in the period under review
company sponsored Safety Assessment of Marketed Medicines (SAMM
by omeprazole or other antisecretory drug prescribing. Our
Guidelines). Br J Clin Pharmacol
results are reassuring given concern that treatment might
8 Fries JF, Miller SR, Spitz PW, et al
. Towards an epidemiology of
gastropathy associated with nonsteroidal anti-inflammatory drug use.
cause early gastric atrophy,23 24 although any increased
incidence of gastric atrophy associated with antisecretory
9 Hawkey CJ, Karrasch JA, Szcepanski L, et al
, for the Omeprazole vs
treatment might take longer than the period under review to
Misoprostol for NSAID-induced Ulcer Management (OMNIUM) StudyGroup. Omeprazole compared with misoprostol for ulcers associated
influence mortality from gastric cancer. We conclude that
with non-steroidal anti-inflammatory drugs. N Engl J Med
treatment with omeprazole per se did not increase the risks of
dying from general or neoplastic disease. Our data also suggest
10 Ekstrom P, Carling L, Wetterhus S, et al
. Prevention of peptic ulcer and
dyspeptic symptoms with omeprazole in patients receiving continuous
that raised risks of oesophageal malignancy are associated
non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study.
with underlying severe oesophageal disease.
Scand J Gastroenterol
11 Cullen D, Bardhan KD, Eisner M, et al.
prophylaxis with omeprazole for non-steroidal anti-inflammatory drugusers. Aliment Pharmacol Ther
12 Yeomans ND, Tulassey Z, Juhasz L, et al
, for the ASTRONAUT study
group. A comparison of omeprazole and ranitidine for treating and
Group members: S Thomas, D N Bateman, Judy Bland, Fiona Ander-
preventing ulcers associated with non-steroidal anti-inflammatory drugs.
son, Elizabeth Wray, Wolfson Unit of Clinical Pharmacology,
N Engl J Med
University of Newcastle upon Tyne, UK; D Colin Jones, Shirley Wood,
13 Nwokolo CU, Loft DE, Holder R, et al.
Increased incidence of bacterial
Vivienne Barrett, Department of Gastroenterology, Queen Alexandra
diarrhoea in patients taking gastric antisecretory drugs. Eur J
Hospital, Portsmouth, UK; M Langman, J Mant, P Brettle, Theresa
Grimley, Madeleine Rowsby, Ros Salter, Departments of Medicine and
14 Neale KR, Brij SO, Slack RCB, et al.
Recent treatment with H2
antagonists and antibiotics and gastric surgery as risk factors for
General Practice, University of Birmingham, Birmingham, UK; R F
Salmonella infection. BMJ
Logan, Gwyn Campion, Margaret Edmond, Department of Epidemiol-
15 Papazian A, Braillon A, Dupas JL, et al.
Portal hypertensive gastric
ogy and Public Health, Queens Medical Centre, Nottingham, UK; M
mucosa: an endoscopic study. Gut
Murphy, M Vessey, Pauline Marshall, Division of Public Health and
16 McCormack TT, Sims I, Eyre-Brook I, et al
. Gastric lesions in portal
Primary Health Care, Institute of Health Sciences, Oxford University,
hypertension: inflammatory gastritis or congestive gastropathy? Gut
Oxford, UK; K R Paterson, Gill Paice, Department of Clinical Pharma-
cology, Royal Infirmary, Glasgow, UK; S Hartz, Sue West, Innovative
17 Berkson J. Limitations of the application of 4 fold tables to hospital data.
Clinical Solutions Ltd, UK; and R Rowsell, AstraZeneca UK Ltd, Luton,
18 Suleiman UL, Harrison M, Britton A, et al.
H2-receptor antagonists may
increase the risk of cardiothoracic adenocarcinoma: a case-control study.Eur J Cancer Prev
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19 Todd JA, Weston T, MacDonald TM, et al.
The prescribing of acid
suppressants prior to the endoscopic diagnosis of Barrett’s oesophagus
and oesophagitis. Aliment Pharmacol Ther
D N Bateman, S Thomas, Wolfson Unit of Clinical Pharmacology,
20 Shaheen NJ, Crosby MA, Bozymski EM, et al.
Is there publication bias
in the reporting of cancer risk in Barrett’s oesophagus? Gastroenterology
D Colin-Jones, Department of Gastroenterology, Queen Alexandra
21 Lagergren J, Bergstrom R, Lindgren A, et al.
S Hartz, Innovative Clinical Solutions Ltd, UK
gastro-oesophageal reflux as a risk factor for oesophagealadenocarcinoma. N Engl J Med
M Langman, J Mant, Departments of Medicine and General Practice,
Cohen S, Parkman HP. Heartburn—a serious symptom. N Engl J Med
R F Logan, Department of Epidemiology and Public Health, Queens
23 Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al
. Atrophic gastritis and
Helicobacter pylori infection in patients with reflux esophagitis treated
M Murphy, M Vessey, Division of Public Health and Primary Health
with omeprazole or fundoplication. N Engl J Med
Care, Institute of Health Sciences, Oxford University, Oxford, UK
24 Klinkenberg-Knol EC, Nelis F, Dent J, et al
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K R Paterson, Department of Clinical Pharmacology, Royal Infirmary,
treatment in resistant gastroesophageal reflux disease: efficacy, safety,
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R Rowsell, AstraZeneca UK Ltd, Luton, Beds, UK
Benjamin Arbel Ph.D. Professor of Early Modern History Incumbent of the Chair for the History and Culture of the Jewry of Salonika and Greece Department of History Tel Aviv University List of Publications June 2009 A. BOOKS AND MONOGRAPHS 1. Trading Nations. Jews and Venetians in the Early Modern Eastern Mediterranean (Leiden, 1995), xi+237 pp. 2. Cyprus, the Franks and Venice (13t
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