What is the role of iFOBT in screening for colorectal cancer?
- SourceAvailable from: Alberto Vannelli[Show abstract] [Hide abstract]
ABSTRACT: In the present work we investigated the possible role of the native fluorescence of blood plasma in the management of colorectal cancer (CRC) and its feasibility as a new tumor marker. Sample of blood was collected from 248 asymptomatic blood donors and from 246 CRC patients. The native fluorescence of blood plasma was measured using a conventional spectrofluorimeter. The intensity of fluorescence of blood plasma at 623 nm (IF623), reasonably ascribed to endogenous porphyrins, was significantly higher in CRC patients than in healthy subjects. The diagnostic capability of IF623 in the discrimination between healthy subjects and CRC patients was tested by Receiving Operating Characteristic (ROC) curve analysis, which resulted in an Area Under the Curve (AUC) of 0.72+/-0.01. Fluorescence measurement of blood plasma might be considered diagnostically useful as a candidate for a new tumor marker for CRC management. The procedure is characterised by a great acceptability and by a very low cost, and might be used in a two-step screening wherein an IF623 positive result is followed by colonoscopy.Frontiers in bioscience (Elite edition) 01/2010; 2:694-700. · 4.25 Impact Factor
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ABSTRACT: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC). Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL. In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥ 50 to ≥ 200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively. Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present. Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers.Cancer Epidemiology Biomarkers & Prevention 03/2011; 20(2):272-80. · 4.56 Impact Factor
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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
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
important lesions ingFOBTpositive
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
sensitivity of gFOBT,
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.
they are high
Correspondence to: David F Ransohoff, CB7080,
University of North Carolina at Chapel Hill,
Chapel Hill, NC 27599-7080, USA; ransohof@
Competing interest: None declared.
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study of screening for colorectal cancer with faecal-
occult-blood test. Lancet 1996;348:1467–71.
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cancer screening and surveillance: clinical
guidelines and rationale—update based on new
evidence. Gastroenterology 2003;124:544–60.
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and rationale. Ann Intern Med 2002;137:129–31.
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detection of cancer: update of early detection
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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.
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status and challenges. Gastroenterology
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a better FIT. Gastroenterology 2005;129:745–8.
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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.
over 41 months.