intestinal cancer development. Nature
30 Prokhortchouk A, Sansom O, Selfridge J, et al.
Kaiso-deficient mice show resistance to intestinal
cancer. Mol Cell Biol 2006;26:199–208.
31 Perreault N, Sackett SD, Katz JP, et al. Foxl1 is a
mesenchymal modifier of Min in carcinogenesis of
stomach and colon. Genes Dev 2005;19:311–5.
32 Oster H, Leitges M. Protein kinase C alpha but not
PKCzeta suppresses intestinal tumor formation in
ApcMin/+ mice. Cancer Res 2006;66:6955–63.
33 Wilson CL, Heppner KJ, Labosky PA, et al. Intestinal
tumorigenesis is suppressed in mice lacking the
metalloproteinase matrilysin. Proc Natl Acad
Sci U S A 1997;94:1402–7.
34 Sansom OJ, Mansergh FC, Evans MJ, et al.
Deficiency of SPARC suppresses intestinal
tumourigenesis in APCMin/+mice. Gut
35 Hanahan D, Weinberg RA. The hallmarks of
cancer. Cell 2000;100:57–70.
36 Framson PE, Sage EH. SPARC and tumor growth:
where the seed meets the soil? J Cell Biochem
37 Murphy-Ullrich JE. The de-adhesive activity of
matricellular proteins: is intermediate cell adhesion
38 Bradshaw AD, Sage EH. SPARC, a matricellular
protein that functions in cellular differentiation and
tissue response to injury. J Clin Invest
39 Brekken RA, Puolakkainen P, Graves DC, et al.
Enhanced growth of tumors in SPARC null mice is
associated with changes in the ECM. J Clin Invest
40 Sangaletti S, Stoppacciaro A, Guiducci C, et al.
Leukocyte, rather than tumor-produced SPARC,
determines stroma and collagen type IV deposition
in mammary carcinoma. J Exp Med
... ............ ............. ............ ............. ............ ............. ............
What is the role of iFOBT in screening
for colorectal cancer?
David F Ransohoff
Policy makers will need to consider if it has one, not only as an
adjunct to gFOBT screening, but also as a primary screening test
randomised controlled trials (RCTs) to
reduce CRC mortality.1–3gFOBT testing is
endorsed as an option for CRC screening
in the United States4–7and is being
implemented in the United Kingdom.
People with a positive gFOBT receive
colonoscopy to detect early cancers and
advanced adenomas that, if untreated,
might cause CRC mortality. Because
gFOBT has a high rate of false positive
results, however, gFOBT screening can
incur substantial cost and use of colono-
scopy resources. A method that could
determine which people with a positive
gFOBT have false positive results—and do
notneed colonoscopy—would make
gFOBT screening more practical.
A study in this issue of Gut8Fraser et al
(see p 1415) shows that doing iFOBT
(human haemoglobin immunochemical
based FOBT) in people with a positive
gFOBT will detect almost all clinically
individuals, while reducing false positive
results and the need for colonoscopy. In
this study, both iFOBT and colonoscopy
were done in those with a positive gFOBT,
defined as one to four positive gFOBT
ovals (people with five or six positive
ovals were automatically referred for
colonoscopy). The sensitivity of iFOBT
among people with positive gFOBT was
95.9%, while specificity was 59.2%, result-
ing in a 30% reduction of colonoscopy
use. The mechanism by which iFOBT
achieves higher specificity than gFOBT
creening for colorectal cancer (CRC)
using gFOBT (guaiac based faecal
occult blood test) has been shown in
presumably is elimination of false posi-
tives that occur in guaiac based testing
from sources other than human haemo-
globin, like diet.
Learning that iFOBT may have a role in
a programme of gFOBT screening is
practical and important, but it raises a
larger question that will need to be sorted
out over time. Should iFOBT replace
gFOBT as the primary test in a pro-
gramme of FOBT screening? The authors
note that the unit cost for iFOBT is higher
than for gFOBT, but that is only one
increased benefit that might be achieved,
additional costs (including false posi-
tives), and the public’s willingness to
pay for greater benefit.
The potential usefulness of iFOBT vs
gFOBT screening depends largely on the
‘‘absolute sensitivity’’ of each FOBT, a
question not addressed in this study that
assessed iFOBT sensitivity only among
those who already had a positive gFOBT.
Used in this way, iFOBT can never do
better than gFOBT.
What is the absolute sensitivity for
each FOBT? Obtaining absolute sensitiv-
ity for any FOBT is logistically difficult,
requiring administration of both the
FOBT and a ‘‘gold standard’’ exam (like
colonoscopy). In asymptomatic indivi-
duals the prevalence of CRC is so low,
roughly 1–3 per 1000, that thousands of
people need to be studied. In one report,
gFOBT sensitivity for CRC was about
30%9; in another it was 13%.10
different results might be explained by
use of centralised FOBT processing in the
former study (as is also done in the
current study, in RCTs, and in the UK
screening programme being implemen-
ted), while in the latter study processing
was done in each physician’s office.
While these are low values for absolute
enough, as shown in RCTs, to reduce
CRC mortality by 33% in a US1trial and
by about 16% in two European trials.2 3
FOBT in a programme of screening.
gFOBT screening is considered not only
an ‘‘option’’ for CRC screening, but when
combined with sigmoidoscopy, it may be
competitive, in terms of effectiveness,
with a programme of colonoscopy screen-
ing.11 12This seeming paradox—that a less
sensitive test like FOBT might be as
effective or more effective than a ‘‘gold
standard’’ test like colonoscopy—can be
explained by considering how a ‘‘pro-
gramme’’ of screening works. If a test
with lower sensitivity at any one applica-
tion is applied repeatedly over time in a
programme of screening, it may result in
a higher ‘‘programme’’ sensitivity than
when a more sensitive test (like colono-
scopy) is applied less frequently, because
a more frequently applied test can detect
fast growing CRC that would be missed
by a less frequently applied test.11–13
If gFOBT is not simply ‘‘acceptable’’ but
perhaps is even competitive with colono-
scopy in some settings, then what would
be the impact of a better FOBT? The
absolute sensitivity of iFOBT in recent
studies has been shown to be roughly
60% for CRC,14–17much higher than for
gFOBT. Even without new RCT data to
assess CRC mortality reduction, policy
decisions may be based on data about
the sensitivity and specificity of newer
tests, existing RCT results, and model-
ling.7Policy makers will need to consider
whether iFOBT has a role not only as an
adjunct to gFOBT screening, but also as a
primary screening test.
Correspondence to: David F Ransohoff, CB7080,
University of North Carolina at Chapel Hill,
Chapel Hill, NC 27599-7080, USA; ransohof@
Competing interest: None declared.
1 Mandel JS, Bond JH, Church TR, et al. Reducing
occult blood. N Engl J Med 1993;328:1365–71.
2 Hardcastle JD, Chamberlain JO, Robinson MHE, et
al. Randomised controlled trial of faecal-occult-
blood screening for colorectal cancer. Lancet
3 Kronborg O, Fenger C, Olsen J, et al. Randomised
study of screening for colorectal cancer with faecal-
occult-blood test. Lancet 1996;348:1467–71.
4 Winawer S, Fletcher R, Rex D, et al. Colorectal
cancer screening and surveillance: clinical
guidelines and rationale—update based on new
evidence. Gastroenterology 2003;124:544–60.
5 Screening for colorectal cancer: recommendation
and rationale. Ann Intern Med 2002;137:129–31.
6 Smith RA, von Eschenbach AC, Wender R, et al.
American Cancer Society Guidelines for the early
detection of cancer: update of early detection
guidelines for prostate, colorectal, and
endometrial cancers. CA Cancer J Clin
7 Winawer SJ, Fletcher RH, Miller L, et al. Colorectal
cancer screening: clinical guidelines and rationale.
8 Fraser CG, Mathew CM, Mowat NAG, et al.
Evaluation of a card collection-based faecal
immunochemical test in screening for colorectal
cancer using a two-tier reflex approach. Gut
9 Ahlquist DA, Wieand HS, Moertel CG, et al.
Accuracy of fecal occult blood screening for
colorectal neoplasia. A prospective study using
Hemoccult and HemoQuant tests. JAMA
10 Imperiale TF, Ransohoff DF, Itzkowitz SH, et al.
Fecal DNA versus fecal occult blood for colorectal-
cancer screening in an average-risk population.
N Engl J Med 2004;351:2704–14.
11 Pignone M, Saha S, Hoerger T, et al. Cost-
effectiveness analyses of colorectal cancer
screening: a systematic review for the US Preventive
Services Task Force. Ann Intern Med
12 Pignone M, Russell L, Wagner J. Economic models
of colorectal cancer screening in average-risk
adults: workshop summary http://www.nap.edu/
catalog/11228.html, Washington, DC: National
Academies Press 2005.
13 Ransohoff DF. Colon cancer screening in 2005:
status and challenges. Gastroenterology
14 Allison JE. Colon cancer screening guidelines
2005: the fecal occult blood test option has become
a better FIT. Gastroenterology 2005;129:745–8.
15 Morikawa T, Kato J, Yamaji Y, et al. A comparison
of the immunochemical fecal occult blood test and
total colonoscopy in the asymptomatic population.
16 Levi Z, Rozen P, Hazazi R, et al. A quantitative
immunochemical fecal occult blood test for
colorectal neoplasia. Ann Intern Med
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Antioxidants in acute pancreatitis
C D Johnson
Antioxidant supplements may be ineffective for the treatment or
prevention of organ failure in predicted severe acute pancreatitis
followed by re-oxygenation. These extre-
mely reactive radicals combine with a
large number of different protein and
lipid molecules causing tissue damage
and cell injury. The normal defences
against such free radical attack include
the presence in the tissues of antioxidant
compounds and pathways of metabolism.
A lack of sufficient antioxidant reserve
during times of increased production of
free radicals leads to the state of oxidative
There has been increasing awareness
over the last 20 years of the role played by
oxidative stress in many inflammatory
illnesses. Acute pancreatitis is no excep-
tion and in several models it has been
demonstrated that oxygen-derived free
radicals are generated during acute pan-
creatitis. It has been suggested that free
radical generation, or the inability to
quench free radicals, is an important
factor in the pathogenesis of acute pan-
creatitis.1However, a careful experimen-
tal study suggested that oxidative stress
alone cannot cause pancreatitis.2It is
much more plausible that oxidative stress
may contribute to worsening of the local
inflammatory changes after onset of
pancreatitis.3–6Some experimental studies
xygen-derived free radicals are
produced when a period of intra-
cellular anaerobic respiration is
suggest that antioxidant therapy can
diminish tissue injury in acute pancreati-
It is also clear that oxidative
mechanisms are an integral part of the
stress may contribute to pulmonary injury
in severe acute pancreatitis.8 9Oxidative
stress is recognised as part of the patho-
physiology of adult respiratory distress
syndrome,10and there is experimental
evidence that antioxidants can protect
against lung injury in acute pancreatitis.
There is a convincing body of evidence
that antioxidant blood levels diminish
during severe acute pancreatitis,11 12and
that supplements of antioxidants can
prevent these falls in experimental3 7
and clinical13pancreatitis. However, the
evidence of clinical benefit to support the
therapeutic use of antioxidants is sparse
Given the supposed harmful nature of
oxidative stress, and observation of anti-
oxidant depletion in human pancreati-
tis,11-13, it has been postulated that the
harmful effects of oxidative stress in this
condition could be ameliorated by sup-
plementation with naturally occurring
antioxidants. Unfortunately there is little
published evidence to support this theory.
One randomised trial14reported reduced
frequency of attacks of recurrent acute
pancreatitis, in a small study population
(20 patients). This study made no obser-
vations relevant to the treatment of
patients with severe acute pancreatitis.
A case controlled series from Manchester
developed) demonstrated that although
antioxidant supplements could indeed
prevent the fall in blood levels seen in
severe acute pancreatitis, there was no
observed effect on clinical outcome.13
Until now, there has been no reliable
randomised trial that investigates the use
of antioxidants to reduce the severity of
complications in acute pancreatitis. In
this issue, Siriwardena and colleagues15
report just such a randomised controlled
trial (see page 1439).
Siriwardena et al.15report a trial that
carefully selected patients who might be
expected to benefit from antioxidant
treatment. They were recruited to the
study within 72 hours of onset of pan-
creatitis and they had an APACHE-II
score .8. That is, only patients with
predicted severe acute pancreatitis were
included, and treatment was started as
early as possible. These patients are
relatively few, and recruitment in three
Interim analyses were conducted by a
trial statistician at planned annual inter-
vals and patients were treated according
to the UK National Guidelines for the
Management of Acute Pancreatitis. This
trial therefore focuses on the patients
most at risk, who were managed to a high
standard of care. The authors are to be
congratulated on achieving a relatively
low mortality rate, below 10%, for these
potentially seriously ill patients.
Patients were randomised to receive a
placebo injection or a mixture of antiox-
C), by intravenous injection for 1 week.
The two groups were well matched except
that the active treatment group were older.