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PSA ECLIA Prostatic neoplasia Accuracy Immunochromatography Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative determination of prostate-specific antigen (PSA) in patients from the "Novembro Azul" campaign

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Prostate cancer is the most common non-cutaneous tumor and the second cause of death due to tumor among men. The high incidence of clinically diagnosed prostate cancer in the last twenty years reflects the result of an effective screening using pros-tate-specific antigen (PSA) tests. Electro-chemiluminescence (ECLIA) still remains the gold standard method for determining serum PSA. However, faster and more straightforward methods are available on the market, which are usually based on the qualitative immunochromatographic me-Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative determination of prostate-specific antigen (PSA) in patients from the "Novembro Azul" campaign 157 thod that informs whether serum PSA levels are above 4 ng / mL, whose concentrations are present in 70 to 80% of the patients with malignant prostate tumors. The aim of this work is to demonstrate the accuracy of the qualitative immunochromatographic method in comparison with the results from the quantitative ELISA tests. 212 men aged between 39 and 101 were used in this study, where three blood aliquots were withdrawn , one for the ECLIA test and the other two for the immu-nochromatographic tests with kits from two different manufacturers. 3.3% of the individuals had PSA content within the range of 4 to 7 ng / mL (values with prediction of malignancy of 30%). In this range, 42.9% of the immunochro-matographic tests of brand A and 71.4% of brand B showed positive results. In the range above 7 ng / mL (2.8% of the samples), 100% of both tests were positive. Immunochromatographic tests had an average sensitivity of 77.5% at those PSA contents near their detection limits and 100% in samples with PSA contents at an upper range, where 95% of prosta-te tumors can be detected in association with other tests. Therefore, the immunochromatographic tests seem to be satisfactory when used in screening patients with prosta-tic neoplasia, especially if we take into account the simplicity and the low cost of this method.
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156
Keywords:
PSA
ECLIA
Prostatic neoplasia
Accuracy
Immunochromatography
Naiche Abdon Miranda¹, Jonathan Jenzer², Irami de Araújo-Filho¹,
Fausto Pierdoná Guzen¹, Eduardo Pereira de Azevedo¹*
¹Graduate Program of Biotechnology, Laureate International Universities - Universida-
de Potiguar (UnP), Natal, RN, Brazil
²Departament of Biomedicine, Universidade Federal do Rio Grande do Norte (UFRN),
Natal, RN, Brazil
Running tittle: Accuracy of the qualitative rapid test for PSA determination
*Author for correspondence: Eduardo Pereira de Azevedo. Email: eduardo.azevedo@unp.br
Abstract
Prostate cancer is the most common non-
-cutaneous tumor and the second cause of
death due to tumor among men. The high
incidence of clinically diagnosed prostate
cancer in the last twenty years reects the
result of an eective screening using pros-
tate-specic antigen (PSA) tests. Electro-
chemiluminescence (ECLIA) still remains
the gold standard method for determining
serum PSA. However, faster and more
straightforward methods are available on
the market, which are usually based on the
qualitative immunochromatographic me-
Accuracy assessment of the immunochromatographic method
(rapid test) for the qualitative determination of prostate-specic
antigen (PSA) in patients from the “Novembro Azul” campaign
Vol.: 1(1). pp. 156-167, July-Aug
DOI: 10.36619/2674886x.2019.1.156.167
ISSN: 2674-886X
Copyright © 2019
Journal of Pharmacological, Chemistry and Biological Sciences
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
157
thod that informs whether serum
PSA levels are above 4 ng / mL,
whose concentrations are present
in 70 to 80% of the patients with
malignant prostate tumors. The
aim of this work is to demonstra-
te the accuracy of the qualitative
immunochromatographic method
in comparison with the results
from the quantitative ELISA tests.
212 men aged between 39 and
101 were used in this study, whe-
re three blood aliquots were wi-
thdrawn, one for the ECLIA test
and the other two for the immu-
nochromatographic tests with kits
from two dierent manufacturers.
3.3% of the individuals had PSA
content within the range of 4 to 7
ng / mL (values with prediction
of malignancy of 30%). In this
range, 42.9% of the immunochro-
matographic tests of brand A and
71.4% of brand B showed posi-
tive results. In the range above 7
ng / mL (2.8% of the samples),
100% of both tests were posi-
tive. Immunochromatographic
tests had an average sensitivity of
77.5% at those PSA contents near
their detection limits and 100% in
samples with PSA contents at an
upper range, where 95% of prosta-
te tumors can be detected in asso-
ciation with other tests. Therefore,
the immunochromatographic tests
seem to be satisfactory when used
in screening patients with prosta-
tic neoplasia, especially if we take
into account the simplicity and the
low cost of this method.
Introduction
Prostate cancer is the most
common non-cutaneous malig-
nancy and the second cause of
death by tumor among men, with
61,200 new reports in Brazil,
14,290 in the Northeast region
and only second to lung cancer in
lethality among male cancer pa-
tients (BRASIL, 2019). The like-
lihood of prostate cancer increases
with age. In fact, hyperplastic al-
terations are present in more than
90% of individuals older than 80
and malignant alterations are ob-
served in more than 70% of this
population (DAN L, 2013). The
average biannual incidence is
66.12 new cases per 100,000 men.
About 1 in 9 men will be diagno-
sed with prostate cancer during
their lifetime (BRASIL, 2018).
The risk of prostate cancer
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
158
increases by a factor of two when
a rst degree relative is aected
and by a degree of four if two or
more are aected. Within the same
age group, African-American men
have a higher number of multifo-
cal and highly unstable prostatic
intraepithelial neoplasia (NIP)
lesions, which are precursors of
cancer, and higher volume tumors,
possibly due to higher levels of
testosterone (WEIN, 2012).
The high incidence of cli-
nically diagnosed prostate cancer
reects the eectiveness of scre-
ening by using the prostate-spe-
cic antigen (PSA) test. Before
the PSA test was available, about
19,000 new cases of prostate can-
cer were reported each year in
the United States. This number
reached 84,000 in 1993, with a
peak of around 300,000 in 1996
(GOLDMAN, 2014).
PSA is a kallikrein-related
serine protease that causes semi-
nal clot liquefaction. It is produ-
ced by non-malignant and malig-
nant epithelial cells and therefore
is prostate-specic, even though
it is not specic to prostate can-
cer as its serum levels might also
increase due to prostatitis and be-
nign prostatic hyperplasia (BPH)
(CARTER et al., 2013). Regarding
the serum PSA level, the cuto
point for normal male is 4.0 ng /
mL. Values above this threshold
should be investigated and may
typically represent BPH, prostate
cancer or acute prostatitis. Values
greater than 10 ng / mL are more
frequently associated with prosta-
te cancer, although other causes
might be involved such as prosta-
titis (RODDAM et. al., 2006).
In Brazil, a government-
-sponsored screening campaign
named “Novembro Azul” oers
free PSA tests for population with
the purpose of nding new cases
of prostate cancer in early stages
so that treatment can be initiated
as soon as possible. The Brazilian
Ministry of Health accepts a PSA
level up to 4 ng / mL as normal,
although it does rule out the exis-
tence of tumors with PSA below
this value. When the PSA level is
above 10 ng / mL, there is a for-
mal recommendation for biopsy
(BRASIL, 2018). For values be-
tween 4-10 ng / mL, one should
also consider the rate of increase
in the level of PSA and the free/
total PSA ratio (ZERATI et al.,
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
159
2010).
Among the analytical me-
thods available to determine the
serum PSA levels, the electroche-
miluminescence assay (ECLIA)
is considered the gold standard,
however, it requires sophisticated
kits and equipment that is usually
available only in reference labo-
ratories. On the other hand, there
are the rapid tests that are based
on the immunochromatographic
method, which are able to predict
whether PSA levels are above or
below 4 ng / mL. Such tests are
easier, faster and cheaper than
ECLIA. In addition, it can be done
regularly in the site of attendance
without the need of specic equi-
pment (ROBLES, 2006) Although
the immunochromatographic test
(also known as rapid test) is fre-
quently performed, studies that in-
vestigate its accuracy is still scar-
ce.
The aim of this work is to
investigate the accuracy of the
immunochromatographic method
(rapid test) for qualitative determi-
nation of PSA by using the quan-
titative data obtained from ECLIA
as the standard values. The outco-
me of this study might give more
condence to the results given by
the rapid tests, which are routinely
used in the screening protocols for
prostate cancer, especially during
the Blue September campaign.
Material and Methods
Patients
212 men between the ages of
39 and 101 were selected from the
Health Basic Units of six districts
of the Mata Norte region of the
State of Pernambuco during the
“Novembro Azul” campaign (No-
vember 1st to 30th). As inclusion
criteria, men aged 50 or older with
no risk factors for prostate can-
cer were selected. Under the age
of 50, only those with risk factors
(afro-descendants and positive fa-
mily history) were able to partici-
pate. The exclusion criteria were
patients who: 1- ejaculated in the
last 48 hours; 2- did exercise on a
bicycle (ergometric or not) in the
last two days; 3- have been riding
a motorcycle for the past two days;
4- have practiced riding a horse in
the past two days; 5- have used
suppository for the last three days;
6- have received urethral catheter
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
160
or have had rectal examination in
the past three days; 7- have been
submitted to cystoscopy in the
last ve days; 8- have performed
transrectal ultrasonography in the
last seven days; 9- have submitted
to colonoscopy or rectosigmoidos-
copy in the last 15 days; 10- have
performed a urodynamic study in
the last 21 days; 11- have submit-
ted to prostate biopsy in the last
30 days. This study was submitted
and approved by the Research and
Ethics Committee of Universida-
de Potiguar (UnP), according to
protocol number 2.837.029. All
participants received a clear ex-
planation about the study and had
to signed an informed consent.
Sampling
Blood samples were collec-
ted from each individual by veni-
puncture. After centrifugation and
serum separation, three aliquots
were separated from each sample:
one for the ECLIA test, which was
performed in a reference labora-
tory, and the other 2 for the immu-
nochromatographic tests, which
were performed with kits from
two dierent brands, both with a
detection limit of 4 ng / mL.
Electrochemiluminescence
(ECLIA) test
The ECLIA test consists of
rst subjecting the sample to a
medium composed of biotinylated
PSA-specic monoclonal antibo-
dy and anti-Ruthenium-labeled
antibody, allowing the formation
of a complex (sandwich). After the
addition of the streptavidin-coated
microparticles, this complex binds
to the solid phase through a bio-
tin-streptavidin interaction. In the
measurement cell, the microparti-
cles are magnetically captured on
the surface of the electrode, where
the application of a voltage indu-
ces chemiluminescent emission,
whose intensity is directly propor-
tional to the concentration of PSA
in the sample, which is measured
by a photomultiplier (DEW et. al.,
1999).
Immunochromatographic
test (rapid test)
The rapid test uses the solid
phase immunochromatographic
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
161
method for the qualitative detec-
tion of serum PSA levels. This test
essentially predicts whether the-
se levels are below or above the
detection threshold of 4 ng / mL.
The kits consist of tapes made of
a nitrocellulose membrane ma-
trix with anti-PSA antibody and
a cushion impregnated with the
color-anti-PSA antibody conjuga-
ted in a matrix protein containing
0.1% sodium azide and a desic-
cant. One drop of sample and one
drop of buer are used in the as-
say. If two parallel red lines appe-
ar (positive result) it means serum
PSA level is above 4 ng / mL. On
the other hand, PSA levels are
below this threshold if only one
red line appears (negative result)
(CAPLAN & KRATZ, 2002).
Data analysis
Data analysis was perfor-
med using statistical software R
version 3.5.0, where mean, me-
dian and standard deviations of
the data were calculated. In ad-
dition, sensitivity, specicity as
well as positive predictive values
and negative predictive values of
both immunochromatographic
kits were evaluated. Graphing was
performed using GraphPadPrism
software (version 7.0).
Results
This current study analyzed
the concentrations of total PSA
by electrochemiluminescence and
immunochromatography methods
in 212 patients aged between 39
and 101 years old. Table 1 shows
the distribution of PSA levels de-
termined by ECLIA according the
age. The mean PSA concentration
was 2.43 ng / mL and half of the
patients had levels lower than 0.8
ng / mL. The minimum PSA level
was 0.04 and the maximum was
134 ng / mL (Table 1).
By analyzing the PSA ran-
ges according to the age groups
it can be observed that the PSA
levels increase as the age progres-
ses, as none of the 50 analyzed in-
dividuals between 39 and 49 years
old presented levels above 4 ng/
mL, whereas 25% of the individu-
als above 70 years old presented
PSA levels above this cuto value.
Benign and malignant changes in
the prostate gland increase with
age and hence the amount of PSA
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
162
produced by the gland. In fact,
previous reports with necropsies
of men in their eighties revealed
hyperplasic alterations in more
than 90% of the individuals and
malignant alterations in more than
70% (ANDRIOLE, 2009). A simi-
lar trend can be observed in this
current study (Figure 1), where
the PSA average increases with
the age group with a signicant
increase in this average with the
group aged between 70 and 101
years old.
Figure 7. Immunoreactive photomicro-
graphs for β-tubulina III (7A) and NF-
200 (7B) demonstrate cells treated with
SNCM + MP.
Table 2 presents the results
of the immunochromatographic
method (rapid test), determined
with 2 kits from 2 dierent brands.
The qualitative results (either po-
sitive or negative) was compared
with the quantitative results pre-
viously determined by ECLIA
and grouped in three ranges of
PSA concentrations. The results
show that at PSA concentrations
below 4 ng/mL and above 10 ng/
mL, the immunochromatographic
tests were accurate in classifying
the results at either positive or ne-
gative. On the other hand, at PSA
levels between 4.1 and 10 ng/mL,
the rapid tests were not as accura-
te. The immunochromatographic
kits from brand A displayed a ne-
gative result in 36.4% of the sam-
ples whose PSA levels fell within
the 4.1 – 10 ng/mL range, which
means that 63.6% showed real po-
sitive results and 36.4% showed a
false negative. A better accuracy
was achieved with brand B, where
only 18.2% of the results were fal-
se negative within the 4.1 – 10 ng/
mL range.
Table 3 shows the determi-
ned accuracy parameters: sensi-
tivity, specicity and negative li-
kelihood ratios as well as positive
and negative predictive values,
calculated for the rapid PSA tests
performed using kits from two di-
erent brands. Both brands used
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
163
in the study showed positive like-
lihood ratios that tended to inni-
ty as the specicities of the tests
were 1.
Discussion
The recruitment of patients
during the Novembro Azul cam-
paign occurs through the Primary
Care of the Basic Health Units
throughout Brazil, where periphe-
ral blood samples are collected
from each patient for screening
purposes. The blood samples are
then sent to a third party labora-
tory for PSA determination. One
of the drawback that prevents the
campaign from reaching a larger
contingent of people is that there
is no “lter” in the initial approa-
ch that would separate the healthy
population from those with po-
tential chance of being positively
diagnosed with prostate cancer.
All samples from the par-
ticipants of the Novembro Azul
campaign are sent for PSA quan-
tication by the most sophisti-
cated method available (electro-
chemiluminescence – ECLIA),
which is generally carried out by
laboratories located in other cities,
to which the samples are routed.
In addition to this logistic, more
time are taken to deliver the re-
sults to the patient, which makes
the whole process more expensive
and time-consuming, especially
when we consider that 95% of the
general population is healthy and
does not have altered PSA levels
(BRASIL, 2018). Therefore, one
way to overcome this problem is
to use a rapid qualitative method
that would show either a positive
or negative result. The immuno-
chromatographic test ts into this
category, as it is a fast and low cost
method that can show whether the
PSA level is below or above the
cuto value of 4 ng/mL and there-
fore, could be used as way to ini-
tially screen which patients must
go forward for a more precise
examination trough quantitative
analysis by ECLIA. However, in
order to use the rapid test during
the initial screening, one should
know about the accuracy of this
method.
Among the 212 patients
analyzed in this current study,
6.1% presented total PSA levels
above 4 ng / mL, which is consi-
dered high risk for prostate cancer
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
164
according to the Consensus of the
Ministry of Health. Thus, only
this percentage would be eligible
for further investigation by more
sophisticated and quantitative
analysis, such as total and quanti-
tative free PSA dosage (using the
ECLIA method), as well as ima-
ging and pathology examinations.
It is worth mentioning that PSA
screening alone is not enough to
conrm whether the patient has
prostate cancer, as there is a possi-
bility of neoplasia with normal le-
vels of PSA which makes the rec-
tal examination essential for men
over 45 years with risk factors or
over 50 years without risk factors
(SADI, 2017).
Serum levels of PSA betwe-
en 4 and 7 ng / mL (3.3% of the
patients) have predicted values
for malignancy of 30% (HUGOS-
SON et. al., 2010), and may be
more commonly related to benign
processes such as benign prostatic
hyperplasia (BPH). In the range
of 4.1 to 10 ng/mL, 36.4% and
18.2% of the results were false
negative by using the kits from
brand A and B, respectively (Tab-
le 2). In fact, 70 to 80% of prosta-
te cancer patients have blood PSA
levels above 7 ng / mL (GOLD-
MAN, 2014). On the other hand,
neither false negative nor false po-
sitive was observed in the PSA le-
vels below 4 ng/mL and above 10
ng/mL, respectively, regardless of
the manufacturer of the kit. This
nding was reected in the spe-
cicity equal to 1 for both brands
(Table 3).
The 2 immunochromato-
graphic kits analyzed in this stu-
dy had an average sensitivity of
77.5% near their detection limits
and 100% in samples with PSA
levels in an upper range, where
in association with other exami-
nation techniques can detect 95%
of prostate tumors (GOLDMAN,
2014). Such accuracy is satisfac-
tory when used in initial screening,
especially when the simplicity of
the method is taken into account
in addition to the fact that it can be
performed by any professional of
the multidisciplinary team.
The PSA level is considered
abnormal depending on the men’s
age, where PSA greater than 2.5
and 3.5 are considered abnormal
for man aged between 40 and 49
years and between 50 and 59, res-
pectively. On the other hand, le-
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
165
vels higher than 4.5 in men aged
between 60 and 69 mean that a
more in-depth assessment should
be requested, whereas for patients
between 70 and 79 years old,
PSA level should be 6.5 or less
(HAYES et al., 2010). The positi-
ve predictive value for cancer at a
PSA level greater than 10 ng / mL
is 60%, while positive predictive
value for a PSA level between 4
and 10 ng / mL is only about 30%
(KRUMHOLTZ et al., 2002).
Therefore, even with a low sen-
sitivity to PSA levels close to the
detection threshold of 4 ng / mL,
the rapid PSA test is eective in
screening the general population
as its sensitivity was 100% when
serum PSA levels exceed 7ng /
mL.
Table 1: Distribution of PSA levels, as
determined by ECLIA, according to the
age of the patients.
Table 2: Comparison between the quali-
tative results of the immunochromatogra-
phic method and the quantitative results
of the ECLIA method.
Table 3: Accuracy parameters of the
immunochromatographic test for qualita-
tive PSA determination
Accuracy assessment of the immunochromatographic method (rapid test) for the qualitative
determination of prostate-specic antigen (PSA) in patients from the “Novembro Azul” campaign
166
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In the United States, 192,000 men were diagnosed as having prostate cancer in 2009, the majority with low-risk, clinically localized disease. Treatment of these cancers is associated with substantial morbidity. Active surveillance is an alternative to initial treatment, but long-term outcomes and effect on quality of life have not been well characterized. To examine the quality-of-life benefits and risks of active surveillance compared with initial treatment for men with low-risk, clinically localized prostate cancer. Decision analysis using a simulation model was performed: men were treated at diagnosis with brachytherapy, intensity-modulated radiation therapy (IMRT), or radical prostatectomy or followed up by active surveillance (a strategy of close monitoring of newly diagnosed patients with serial prostate-specific antigen measurements, digital rectal examinations, and biopsies, with treatment at disease progression or patient choice). Probabilities and utilities were derived from previous studies and literature review. In the base case, the relative risk of prostate cancer-specific death for initial treatment vs active surveillance was assumed to be 0.83. Men incurred short- and long-term adverse effects of treatment. Hypothetical cohorts of 65-year-old men newly diagnosed as having clinically localized, low-risk prostate cancer (prostate-specific antigen level <10 ng/mL, stage ≤T2a disease, and Gleason score ≤6). Quality-adjusted life expectancy (QALE). Active surveillance was associated with the greatest QALE (11.07 quality-adjusted life-years [QALYs]), followed by brachytherapy (10.57 QALYs), IMRT (10.51 QALYs), and radical prostatectomy (10.23 QALYs). Active surveillance remained associated with the highest QALE even if the relative risk of prostate cancer-specific death for initial treatment vs active surveillance was as low as 0.6. However, the QALE gains and the optimal strategy were highly dependent on individual preferences for living under active surveillance and for having been treated. Under a wide range of assumptions, for a 65-year-old man, active surveillance is a reasonable approach to low-risk prostate cancer based on QALE compared with initial treatment. However, individual preferences play a central role in the decision whether to treat or to pursue active surveillance.
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The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)
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Purpose: The guideline purpose is to provide the urologist with a framework for the early detection of prostate cancer in asymptomatic average risk men. Materials and methods: A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age <40; 40 to 54; 55 to 69; ≥ 70). Results: Except prostate specific antigen-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and overtreatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening. Conclusions: The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence.
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With digital rectal examination (DRE), prostate-specific antigen (PSA) is a major screening tool for prostate cancer. PSA is specific for the prostate, but not for prostate cancer. Multiple factors influence PSA value. Determination of PSA levels is not 100% sensitive for prostate cancer, as PSA levels may be normal despite presence of prostate cancer. The cutoff value for PSA of 4.0 ng/mL gives the highest sensitivity and highest specificity. Several modifications of PSA testing have been developed and may be beneficial for select populations. Uncertainty about the natural progression of prostate cancer and inherent limitations of PSA testing make it unclear whether universal screening is beneficial, and the recommendations of various organizations conflict. Randomized studies are in progress to address the role of PSA testing and of modifications of this test in the early detection of prostate cancer.
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Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate. In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243. In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death. This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs. The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.
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Previous studies have shown that chronic administration of SR-3 (a 1:4 mixture of alpha-linolenic and linoleic acid) affects spatial learning, thermoregulation, pain threshold and protection from seizures. The mode of action is unknown. One possible explanation is that the preparation induces changes in the fatty acids profile and in the cholesterol level in the neuronal membrane. This study used 15 independent groups of rats (n = 12) which were given either saline, mineral oil (vehicle) or SR-3 (25 mg/kg) for 0, 1, 2, 3, or 4 weeks. The learning performance was measured in the Morris Water tank and the fatty acids profile and the cholesterol level were examined by the GC method in synaptosomes obtained from the frontal cortex of the rats. SR-3 improved the learning performance and induced major changes in the neuronal membrane composition, such as an increase in the total level of fatty acids, an increase in the level of essential fatty acids and a decrease in the cholesterol level. Those changes occurred after 3 weeks of treatment. The biochemical variables can predict the behavioral variables but not vice versa. The changes in the neuronal membrane may result in a modification of the membrane fluidity, which may, in turn, enhance cognitive and neuropharmacological effects.
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We determined the effect of cystoscopy (flexible and rigid), transrectal ultrasonography (with and without needle biopsy of the prostate) and transurethral resection of the prostate or bladder tumour on the serum prostate-specific antigen (PSA) concentration. Samples were taken from 60 men before and up to 14 days following these procedures. Flexible cystoscopy did not result in a significant increase in serum PSA concentration, with a median increase of 0·1 μg/L ( P > 0·05). Small but statistically significant increases in serum PSA levels 1 day post-procedure were observed following rigid cystoscopy and transrectal ultrasound without biopsy. The median increase in serum PSA concentration following rigid cystoscopy was 0·15 μg/L ( P = 0·04) and following transrectal ultrasound was 0·3 μg/L ( P = 0·01). In both cases the serum PSA level had normalized by 2 days post-procedure. Transurethral resection of bladder tumours resulted in a variable rise in serum PSA, with a median increase of 2·6 μg/L after 1 day, which returned to normal over 7–14 days. Ultrasound-guided needle biopsy of the prostate and transurethral resection of the prostate produced significant increases in serum PSA levels, which took up to fourteen days to return to normal. The median increase in serum PSA following needle biopsy was 6·0 μg/L and following transurethral resection of the prostate (TURP) was 13 μg/L. Samples for PSA measurement may safely be taken within 24–48 h of flexible cystoscopy and transrectal ultrasonography (TRUS) providing prostatic biopsy is not carried out. For other procedures it is necessary to wait for at least 14 days to ensure that false positive PSA results are not obtained.
Instituto Nacional do Câncer José Alencar Gomes da Silva
  • Brasil
  • Ministério Da Saúde
BRASIL. Ministério da Saúde. Instituto Nacional do Câncer José Alencar Gomes da Silva. Rio de Janeiro, RJ: MS, 2018, http://www2.inca.gov.br.