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University of Groningen
Medullary Thyroid CarcinomaVerbeek, Hans
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Publication date:2015
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Verbeek, H. (2015). Medullary Thyroid Carcinoma: from diagnosis to treatment. [S.n.].
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Appendices
Appendices
154
Appendix 1
Search strategy
Search terms
Unless otherwise stated, search terms are free text terms.
Abbreviations:
'$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words
within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE
medical index term); pt: publication type; sh: MeSH; tw: text word.
The Cochrane Library
#1 MeSH descriptor Thyroid Neoplasms explode all trees
#2 MeSH descriptor Goiter, Nodular explode all trees
#3 ( (thyroid* in All Text near/6 neoplas* in All Text) or (thyroid* in All Text near/6 cancer in All Text)
or (thyroid* in All Text near/6 carcinoma* in All Text) or (thyroid* in All Text near/6
macrocarcinoma* in All Text) or (thyroid* in All Text near/6 microcarcinoma* in All Text) )
#4 ( (thyreoid* in All Text near/6 neoplas* in All Text) or (thyreoid* in All Text near/6 cancer in All
Text) or (thyreoid* in All Text near/6 carcinoma* in All Text) or (thyreoid* in All Text near/6
macrocarcinoma* in All Text) or (thyreoid* in All Text near/6 microcarcinoma* in All Text) )
#5 ( (thyroid* in All Text near/6 tumor* in All Text) or (thyroid* in All Text near/6 tumour* in All Text)
or (thyreoid* in All Text near/6 tumor* in All Text) or (thyreoid* in All Text near/6 tumour* in All
Text) )
#6 ( (thyroid* in All Text near/6 nodul* in All Text) or (thyroid* in All Text near/6 multinodul* in All
Text) or (thyreoid* in All Text near/6 nodul* in All Text) or (thyreoid* in All Text near/6 multinodul*
in All Text) )
#7 MTC in All Text
#8 MeSH descriptor Carcinoma, Medullary explode all trees
#9 (carcinoma* in All Text near/6 medull* in All Text)
#10 (#8 or #9)
#11 (thyroid* in All Text or thyreoid* in All Text)
#12 (#10 and #11)
#13 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #12)
#14 MeSH descriptor Calcitonin explode all trees
#15 (calcitrin* in All Text or calcitonin* in All Text or thyrocalcitonin* in All Text)
#16 (#14 or #15)
#17 (#13 and #16)
#18 MeSH descriptor Diagnostic Tests, Routine explode all trees
#19 MeSH descriptor Biopsy, Fine-Needle explode all trees
#20 MeSH descriptor Diagnostic techniques, endocrine explode all trees
#21 MeSH descriptor Magnetic resonance imaging explode all trees
#22 MeSH descriptor Ultrasonography explode all trees
#23 MeSH descriptor Biological markers explode all trees
#24 MeSH descriptor Carcinoembryonic antigen explode all trees
#25 MeSH descriptor Diagnostic imaging explode all trees
#26 MeSH descriptor Immunoassay explode all trees
#27 MeSH descriptor Chemiluminescent measurements explode all trees
Appendices
155
#28 diagnos* in All Text
#29 ( (tumor in All Text near/6 marker* in All Text) or (biological in All Text near/6 marker* in All
Text) or (tumour in All Text near/6 marker* in All Text) )
#30 ( (calcitonin* in All Text and test* in All Text) or (pentgastrin* in All Text and test* in All Text) )
#31 (PET-CT in All Text or RET in All Text or MRI in All Text)
#32 (fine in All Text and (needle in All Text near/6 biops* in All Text) )
#33 (MRI in All Text or FNAC in All Text or FNAB in All Text)
#34 CEA in All Text
#35 (cytology in All Text or immunohistochem* in All Text or ultrasonograph* in All Text or
echograph* in All Text)
#36 (imaging in All Text and technique* in All Text)
#37 (RIA in All Text or IRMA in All Text or ILMA in All Text)
#38 (#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31
or #32 or #33 or #34 or #35 or #36 or #37)
#39 (#17 and #38)
MEDLINE
1 exp Thyroid Neoplasms/
2 exp Goiter nodular/
3 ((thyroid* or thyreoid*) adj6 (neoplas* or cancer or carcinoma* or macrocarcinoma* or
microcarcinoma* or tumo?r*)).tw,ot.
4 (nodul* adj3 (thyroid* or thyreoid* or goiter)).tw,ot.
5 ((thyroid* or thyreoid*) adj3 (multinodul* or multi nodul*)).tw,ot.
6 MTC*.ab.
7 or/1-6
8 exp Carcinoma, medullary/
9 (medullary adj6 (thyroid* or thyreoid*)).tw,ot.
10 8 or 9
11 (thyroid* or thyreoid*).tw,ot.
12 10 and 11
13 7 or 12
14 exp Calcitonin/
15 (Calcitrin* or calcitonin*).tw,ot.
16 thyrocalcitonin*.tw,ot.
17 9007-12-9.rn.
18 or/14-17
19 (screen* or detect*).tw,ot.
20 exp Diagnostic Tests, Routine/
21 exp Biopsy, Fine-Needle/
22 exp Diagnostic Techniques, Endocrine/
23 exp Magnetic Resonance Imaging/
24 exp Ultrasonography/
25 exp Biological markers/
26 exp Carcinoembryonic antigen/
27 exp diagnostic imaging/
28 exp Pentagastrin/du [Diagnostic Use]
29 exp Immunoassay/
30 Carcinoma, medullary/di [diagnosis]
31 chemiluminescent.mp.
32 ((tumo?r or biological) adj6 marker*).tw,ot.
33 diagnos*.tw,ot.
Appendices
156
34 (RIA or IRMA or ILMA).tw,ot.
35 calcitonin* test*.tw,ot.
36 PET-CT.mp.
37 RET.mp.
38 fine needle aspiration*.tw,ot.
39 pentagastrin-test*.tw,ot.
40 MRI.tw,ot.
41 (MRI or FNAC or FNAB).tw,ot.
42 (cytology or immunohistochem* or ultrasonograph* or echograph*).tw,ot.
43 CEA.tw,ot.
44 imaging technique*.tw,ot.
45 or/19-44
46 13 and 18 and 45
47 (animals not (animals and humans)).sh.
48 46 not 47
EMBASE
1 thyroid tumor/
2 exp thyroid cancer/
3 exp thyroid nodule/
4 exp thyroid medullary carcinoma/
5 exp nodular goiter/
6 ((thyroid* or thyreoid*) adj6 (neoplas* or cancer or carcinoma* or macrocarcinoma* or
microcarcinoma* or tumo?r)).tw,ot.
7 ((thyroid* or thyreoid*) adj6 medullary carcinoma*).tw,ot.
8 (nodul* adj3 (thyroid* or thyreoid*)).tw,ot.
9 ((thyroid* or thyreoid*) adj3 (multinodul* or multi nodul*)).tw,ot.
10 MTC*.tw,ot.
11 or/1-10
12 exp calcitonin/
13 (calcitrin* or calcitonin* or thyrocalcitonin*).tw,ot.
14 9007-12-9.rn.
15 or/12-14
16 11 and 15
17 exp diagnostic test/
18 exp needle biopsy/
19 exp endocrine system examination/
20 exp nuclear magnetic resonance imaging/
21 exp echography/
22 exp biological marker/
23 exp carcinoembryonic antigen/
24 exp diagnostic imaging/
25 exp immunoassay/
26 exp chemiluminescent/
27 pentagastrin test.mp.
28 exp medullary carcinoma/di [Diagnosis]
29 ((tumo?r or biological) adj6 marker*).tw,ot.
30 diagnos*.tw,ot.
31 (RIA or IRMA or ILMA).tw,ot.
32 ((calcitonin* or pentagastrin*) adj6 test*).tw,ot.
33 (screen* or detect*).tw,ot.
Appendices
157
34 PET-CT.mp.
35 RET.mp.
36 needle biop*.tw,ot.
37 (MRI or FNAC or FNAB).tw,ot.
38 (cytology or immunhistochem* or ultrasonograph* or echograph*).tw,ot.
39 CEA.tw,ot.
40 imaging technique*.tw,ot.
41 or/17-40
42 16 and 41
43 limit 42 to human
Web of Science
# 1 Topic=(thyroid* tumor*) OR Topic=(thyroid* cancer) OR Topic=(thyroid* neoplas*) OR
Topic=(thyroid* carcinoma*) OR Topic=(thyroid* microcarcinoma*) OR Topic=(thyroid*
macrocarcinoma) OR Topic=(thyroid* medullary carcinoma*) OR Topic=(thyroid* nodul*) OR
Topic=(thyroid* multinodul*) OR Topic=(nodul* goiter*)
# 2 Topic=(thyreoid* tumor*) OR Topic=(thyreoid* cancer) OR Topic=(thyreoid* neoplas*) OR
Topic=(thyreoid* carcinoma*) OR Topic=(thyreoid* microcarcinoma*) OR Topic=(thyreoid*
macrocarcinoma) OR Topic=(thyreoid* medullary carcinoma*) OR Topic=(thyreoid* nodul*) OR
Topic=(thyreoid* multinodul*) OR Topic=(nodul* goiter*) OR Topic=(MTC)
# 3 Topic=(calcitonin*) OR Topic=(calcitrin*) OR Topic=(thyrocalcitonin*)
# 4 #1 OR #2
# 5 #3 AND #4
# 6 Topic=(diagnostic test*) OR Topic=(needle biopsy) OR Topic=(endocrine examination*) OR
Topic=(echograph*) OR Topic=(ultrasonograph*) OR Topic=(magnetic resonance imaging) OR
Topic=(MRI) OR Topic=(biological marker*) OR Topic=(diagnostic imaging) OR Topic=(immunoassay)
OR Topic=(chemiluminescent*) OR Topic=(tumor marker*)
# 7 Topic=(carcioembryonic antigen) OR Topic=(CEA) OR Topic=(pentagastrin test*) OR
Topic=(diagnos*) OR Topic=(calcitonin* test*) OR Topic=(screen*) OR Topic=(detect*) OR Topic=(RIA)
OR Topic=(IRMA) OR Topic=(ILMA) OR Topic=(PET-CT) OR Topic=(RET)
# 8 Topic=(FNAC) OR Author=(FNAB) OR Publication Name=(cytology) OR Topic=(immunhistochem*)
OR Topic=(imaging technique*)
# 9 #6 OR #7 OR #8
# 10 #5 AND #9
# 11 Topic=(animal*)
# 12 #10 NOT #11
'My NCBI' alert service
("thyroid nodule"[MeSH Terms] OR ("thyroid"[All Fields] AND "nodule"[All Fields]) OR "thyroid
nodule"[All Fields]) AND ("calcitonin"[MeSH Terms] OR "calcitonin"[All Fields])
Appendices
158
Appendix 2
Additional Table 2 Data extraction form
Design
Design:
Inclusion criteria:
Exclusion criteria:
Patient characteristics
and setting
Number of participants:
Number with NTD:
Number with NTD and calcitonin testing:
Sex (female%):
Age (mean/SD): range:
MTC:
Type of thyroid nodules:
Thyroid nodules detected by palpation or US:
Nodule size:
Number of nodules:
Sonographic morphology of thyroid nodules:
FNA procedures performed through ultrasound guidance or palpation:
Setting:
Country:
Index test
Index test:
Calcitonin as a triage or add-on test:
Used calcitonin assay:
Stimulated calcitonin performed:
Indication stimulated calcitonin:
Stimulative:
Dose:
Time:
Reported and extracted cut-off values
Basal:
Stimulated:
Reference standard
Target condition:
Reference standards:
Indication surgical treatment:
Type of surgical treatment:
Calcitonin negative (n)
Number FNA:
Number operated:
Calcitonin positive (n)
Number FNA:
Number operated:
Flow and timing
Follow-up calcitonin negative:
Type:
Duration:
Follow-up calcitonin positive:
Type:
Duration:
Appendices
159
Appendix 3
QU
AD
AS
-2 S
ign
all
ing
qu
est
ion
s fo
r b
ias
Do
ma
in
Sig
na
llin
g q
ue
stio
n
Cri
tera
Ye
s U
ncl
ea
r N
o
Pa
tie
nt
sele
ctio
n
1.
Co
nse
cuti
ve
or
ran
do
m s
am
ple
en
roll
ed
?
A c
on
secu
tive
or
ran
do
m s
am
ple
of
pa
tie
nts
we
re e
nro
lle
d in
th
e
stu
dy.
It is
un
cle
ar
wh
eth
er
a
con
secu
tive
or
ran
do
m s
am
ple
of
pa
tie
nts
wa
s e
nro
lled
in t
he
stu
dy.
Th
ere
wa
s n
o c
on
secu
tive
or
ran
do
m s
am
ple
incl
ud
ed
in
the
stu
dy
(e.g
. o
nly
pa
tie
nts
alr
ea
dy
in s
usp
icio
n o
f
(me
du
llary
) th
yro
id
ma
lign
an
cy a
nd
pa
tie
nts
wit
h
hig
h r
isk
for
(fa
mili
al)
MT
C.
2.
Ca
se c
on
tro
l d
esi
gn
av
oid
ed
?
Th
ere
wa
s n
o c
ase
co
ntr
ol d
esi
gn
. It
is u
ncl
ea
r if
th
ere
wa
s a
ca
se
con
tro
l de
sig
n
Th
ere
wa
s a
ca
se c
on
tro
l
de
sig
n
3.
Ina
pp
rop
ria
te
ex
clu
sio
ns
av
oid
ed
?
Th
ere
are
no
pa
tie
nts
ina
pp
rop
ria
te e
xclu
de
d (
e.g
.
pa
tie
nts
wit
h s
usp
icio
us
US,
wh
o
will
alr
ea
dy
be
op
era
ted
on
)
It is
un
cle
ar
if t
he
re w
as
avo
ida
nce
of
ina
pp
rop
ria
te
exc
lusi
on
s
Th
ere
is
ina
pp
rop
ria
te
exc
lusi
on
of
pa
tie
nts
(e
.g.
exc
lusi
on
of
pa
tie
nts
wit
h
hig
h r
isk
of
ma
lign
an
cy)
Ind
ex
te
st
1.
Ind
ex
te
st r
esu
lts
inte
rpre
ted
wit
ho
ut
kn
ow
led
ge
re
sult
s
refe
ren
ce s
tan
da
rd?
Th
is it
em
will
be
om
itte
d a
s o
nly
stu
die
s a
re in
clu
de
d in
wh
ich
th
e r
efe
ren
ce s
tan
da
rd
(his
top
ath
olo
gic
al e
xam
ina
tio
n)
is p
erf
orm
ed
aft
er
calc
ito
nin
te
stin
g.
Furt
he
rmo
re c
alc
ito
nin
te
stin
g i
s
a o
bje
ctiv
e t
est
(a
lth
ou
gh
inte
rpre
tati
on
de
pe
nd
s o
n t
he
th
resh
old
, b
ut
this
will
be
ass
ess
ed
in t
he
ne
xt it
em
)
2.
Pre
-sp
eci
fie
d
thre
sho
ld?
Th
ere
wa
s a
pre
-sp
eci
fie
d
calc
ito
nin
cu
t-o
ff l
eve
l.
It is
un
cle
ar
if t
he
re w
as
a p
re-
spe
cifi
ed
cu
t-o
ff l
eve
l
Th
ere
wa
s n
o p
re-s
pe
cifi
ed
calc
ito
nin
cu
t-ff
le
vel.
Appendices
160
Q
UA
DA
S-2
Sig
na
llin
g q
ue
stio
ns
for
bia
s
Do
ma
in
Sig
na
llin
g q
ue
stio
n
Cri
tera
Ye
s U
ncl
ea
r N
o
Re
fere
nce
sta
nd
ard
1.
Re
fere
nce
sta
nd
ard
lik
ely
to
co
rre
ctly
cla
ssif
y
targ
et
con
dit
ion
?
In p
ati
en
s re
ceiv
ing
su
rge
ry
the
re is
ad
eq
ua
te
his
top
ath
olo
gic
al e
xam
ina
tio
n
of
thyr
oid
tis
sue
.
In p
ati
en
ts r
ece
ivin
g f
oll
ow
-up
,
the
re is
at
lea
st t
hre
e y
ea
rs
follo
w-u
p y
ea
rs in
clu
din
g a
t
lea
st o
ne
US
exa
min
ati
on
an
d if
ind
ica
ted
FN
AC
.
In p
ati
en
ts r
ece
ivin
g s
urg
ery
it's
un
cle
ar
ho
w h
isto
pa
tho
log
ica
l
exa
min
ati
on
is p
erf
orm
ed
.
In p
ati
en
ts r
ece
ivin
g f
oll
ow
-up
the
tim
e a
nd
pro
toco
l fo
r
follo
w-u
p is
un
cle
ar
In p
ati
en
ts r
ece
ivin
g s
urg
ery
his
top
ath
olo
gic
al e
xam
ina
tio
n
is n
ot
ad
eq
ua
te.
In p
ati
en
ts w
ith
ou
t su
rge
ry,
follo
w-u
p is
to
sh
ort
or
do
es
no
t
incl
ud
e a
t le
ast
on
e U
S
exa
min
ati
on
an
d F
NA
C.
2.
Re
fere
nce
sta
nd
ard
resu
lts
inte
rpre
ted
wit
ho
ut
kn
ow
led
ge
resu
lts
ind
ex
te
st?
Th
e o
utc
om
e a
sse
sso
r o
f
his
top
ath
olo
gic
al a
nd
fo
llow
-up
resu
lts
wa
s n
ot
aw
are
of
calc
ito
nin
te
stin
g r
esu
lts
It is
no
t cl
ea
r if
th
e o
utc
om
e
ass
ess
or
of
his
top
ath
olo
gic
al
an
d f
ollo
w-u
p r
esu
lts
wa
s
aw
are
of
calc
ito
nin
te
stin
g
resu
lts
Th
e o
utc
om
e a
sse
sso
r o
f
his
top
ath
olo
gic
al a
nd
fo
llow
-up
resu
lts
wa
s a
wa
re o
f ca
lcit
on
in
test
ing
re
sult
s
Flo
w a
nd
tim
ing
1.
Ap
pro
pri
ate
in
terv
al
be
twe
en
in
de
x t
est
an
d
refe
ren
ce s
tan
da
rd?
Tim
e b
etw
ee
n c
alc
ito
nin
te
stin
g
an
d h
isto
pa
tho
log
ica
l
exa
min
ati
on
is <
3 m
on
ths
It is
un
cle
ar
wh
at
the
tim
e
pe
rio
d b
etw
ee
n r
efe
ren
ce
sta
nd
ard
an
d in
de
x te
st is
.
Tim
e b
etw
ee
n c
alc
ito
nin
te
stin
g
an
d h
isto
pa
tho
log
ica
l exc
ee
ds
3
mo
nth
s.
2.
All
pa
tie
nts
re
ceiv
ed
refe
ren
ce s
tan
da
rd?
All
pa
tie
nts
re
ceiv
ed
su
rge
ry,
an
d p
ati
en
ts w
ho
did
no
t
rece
ive
su
rge
ry h
ave
clin
ica
l
follo
w-u
p o
f a
t le
ast
th
ree
yea
rs.
It is
no
t cl
ea
r if
th
e w
ho
le
sam
ple
did
re
ceiv
e s
urg
ery
or
follo
w-u
p.
On
ly a
se
lect
ed
su
bse
t o
f th
e
pa
tie
nts
re
ceiv
ed
or
surg
ery
or
no
t a
ll p
ati
en
ts h
ave
clin
ica
l
follo
w-u
p.
3.
Pa
tie
nts
re
ceiv
ed
sam
e r
efe
ren
ce
sta
nd
ard
?
All
pa
tie
nts
we
re o
pe
rate
d a
nd
his
top
ath
olo
gic
al e
xam
ina
tio
n
of
the
th
yro
id w
as
pe
rfo
rme
d.
It is
no
t cl
ea
r if
all
pa
tie
nts
we
re
op
era
ted
an
d r
ece
ive
d
his
top
ath
olo
gic
al e
xam
ina
tio
n.
No
t a
ll p
ati
en
ts w
ere
op
era
ted
or
his
top
ath
olo
gic
al
exa
min
ati
on
wa
s n
ot
pe
rfo
rme
d in
all
pa
tie
nts
.
4.
All
pa
tie
nts
in
clu
de
d i
n
the
an
aly
sis?
All
pa
tie
nts
en
roll
ed
we
re
incl
ud
ed
in t
he
an
aly
sis
It is
no
t cl
ea
r if
all
pa
tie
nts
we
re
incl
ud
ed
in t
he
an
aly
sis.
No
t a
ll p
ati
en
ts e
nro
lled
we
re
incl
ud
ed
in t
he
an
aly
sis
(e.g
.
pa
tie
nts
lost
to
fo
llow
-up
)
Appendices
161
Appendix 4
Characteristics of included studies
Rieu 1995 Patient Selection
A. Risk of Bias
Patient Sampling Design: Prospective cohort study.
Inclusion criteria: Pts with thyroid nodules detected by clinical examination or with
abnormal TSH levels or both.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 657 patients.
Number with NTD: 469 patients.
Number with NTD and calcitonin testing: 469 patients.
Sex (female%): 88,1% (579/657); only reported of whole study population.
Age (mean/SD): 45, SD: Not reported range: 15-87 years; only reported of whole study
population.
MTC: 4 patients.
Type of thyroid nodules: non toxic uninodular goitre (n = 136), autonomously functioning
thyroid nodule (n = 14), non toxic multinodular goitre (n = 224), toxic multinodular goitre (n =
15), nodular Hashimoto thyroiditis (n = 53), nodular Graves' disease (n = 25), nodular
formation related to subacute thyroiditis in a hyperthyroid phase (n = 2).
Thyroid nodules detected by palpation or US: both, number not specified.
Nodule size: not reported.
Number of nodules: Uninodular (n = 150), multinodular (n = 239), not reported (n = 80).
Sonographic morphology of thyroid nodules: A localized thyroid area was considered
nodular when it had a distinctive rim at two different incidences. When this rim was absent, a
thyroid area with round or oval patterns, and also echogenicity different from that of the
surrounding normal tissue, was classified as nodular.
FNA procedures performed through ultrasound guidance or palpation: Not
reported.
Setting: Not reported.
Country: France
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay:
01-1989 – 12-1989, RIA (Mallinckrodt Medical SA, Evry, France).
01-1990 – 12- 1993: IRMA (CIS-Oris International, Saint Quentin en Yvelins, France.
Stimulated calcitonin: Yes.
Indication: Patients with basal serum CT above normal range.
Stimulative: Pentagastrin.
Dose: 0.5 ug/kg.
Appendices
162
Time: 0, 3, 5, 15 and 30 min after injection.
Reported and extracted cut-off values
Basal: reported: RIA: 35 ng/l, IRMA 10 ng/l; extracted 50 ng/l; 100 ng/l.
Stimulated: reported: 100 ng/l; extracted 100 ng/l.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNA in patients whose nodular formation was accessible to such a
procedure, in selected patients histopathological examination after surgery.
Indication surgical treatment: Patients with increased basal serum CT values, pentagastrin
stimulated CT levels > 100 pg/l, regardless of FNAC result, FNAC suggestive of thyroid
carcinoma (n = 7), compressive goitre (n = 4).
Type of surgical treatment: For suspected MTC total thyroidectomy and central neck
dissection. Bilateral modified neck dissection was performed only in the presence of evident
lymph node involvement in one or both sides. For all other types of thyroid carcinoma, total
thyroidectomy and lymph node dissection on the side of the thyroid nodule(s) or bilaterally
(as appropriate).
Calcitonin negative (n = 465)
Number FNAC: Not reported.
Number operated: 11 patients.
Calcitonin positive (n = 4)
Number FNAC: 4 patients.
Number operated: 4 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results of
the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Not reported.
Type: -
Duration: -
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Appendices
163
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Not reported.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: "to asses the prevalence of sporadic MTC in nodular and non -
nodular thyroid diseases by routine basal serum CT measurements"
Abbreviations FNAC: fine needle aspiration cytology, CT: calcitonin.
Notes
Appendices
164
Ozgen 1999
Patient Selection
A. Risk of Bias
Patient Sampling Design: Prospective study.
Inclusion criteria: Patients with nodular goiter.
Exclusion criteria: Patients with previously known medullary
carcinoma and their relatives.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Yes
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 773 patients.
Clinical features: Patients with nodular goiter.
Number with NTD: 773 patients.
Number with NTD and calcitonin testing: 773 patients.
Sex (female%)(n): 75,8% (586).
Age (mean/SD): range: 42.1 years, range 17-78.
Number with MTC: 4 patients.
Type of thyroid nodules: Multinodular goiter (nontoxic/toxic), solitary (nontoxic/toxic)
thyroid nodules.
Thyroid nodules detected by palpation or US: Both; number not specified.
Nodule size: Not reported.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Both (US guidance in
nonpalpable nodules), number not specified.
Setting: Outpatient clinic.
Country: Turkey.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: Commercial kit; DSL-5200 Ultrasensitive calcitonin RIA kit, Diagnostic
System Laboratories Inc., Webster, Tx.
Sensitivity: Not reported.
Stimulated calcitonin: No
Indication: -
Stimulative: -
Dose: -
Time: -
Reported and extracted cut-off values
Basal: Reported: 30 pg/ml; extracted:30 pg/ml, 50 pg/ml, 100 pg/ml.
Stimulated: -
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Appendices
165
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Reference Standard
A. Risk of Bias
Target condition and
reference standard(s)
Target condition: MTC.
Reference standards: FNAB and in selected cases histopathological examination after
surgery,
Indication surgical treatment: Malignant or suspicious results in FNAB, or elevated
calcitonin levels regardless of the result of FNAB.
Type of surgical treatment: Thyroid surgery.
Calcitonin negative (n = 669)
Number FNAB: 669 patients.
Number operated: 171 patients.
Calcitonin positive (n = 4)
Number FNAB: 4 patients.
Number operated: 4 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference
standard does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Described for 3 MTC patients.
Type: Basal and stimulated calcitonin levels.
Duration: 14-18 months
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Not reported.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: " To identify MTC by screening patients who have thyroid nodules
with basal calcitonin measurements and to determine whether basal serum calcitonin
measurement should be a part of the routine evaluation of a nodular goiter."
Abbreviations FNAB: Fine needle aspiration biopsy.
Notes
Appendices
166
Hahm 2001
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study.
Inclusion criteria: Patients with nodular thyroid disease.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 1448 patients.
Number with NTD: 1448 patients.
Number with NTD and calcitonin testing: 1448 patients.
Sex (female%)(n): 80,3% (1163).
Age (mean/SD): 46 years Range: 14-86 years.
Number with MTC: 10 patients.
Type of thyroid nodules: Not reported.
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Not reported.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Thyroid clinic of Samsung Medical Center.
Country: Korea.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Used calcitonin assay: Two-site immunoradiometric assay commercial kit (MED-GENIX CT-
US.-IRMA kit) BioSource Europe S.A.,Belgium.
Sensitivity: 0.8 pg/ml.
Stimulated calcitonin: Yes.
Indication: Reported for 39 patients: basal calcitonin > 10 pg/ml (n=23), family members of
MEN2 or MTC patients (n=14) and FNAC findings suspicious for MTC (n=2).
Stimulative: Pentagastrin (Peptavlon, Ayerst Laboratories Ind. Philadelphia, PA).
Dose: 0.5 ug/kg body weight.
Time: Just before, 2, 5, and 10 min.
Reported and extracted cut-off values
Basal: Reported: 10 pg/ml (n = 56); extracted: 10, 20, 30, 50, 100 pg/ml.
Stimulated: Reported: 100 pg/ml; extracted: 100, 200 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
167
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAC in all patients with palpable or visible thyroid nodule by US, in
selected patients histopathological examination after surgery.
Indication surgical treatment: Abnormal findings suspicious of malignancy by FNAC, patients
who had basal or stimulated calcitonin concentrations of more than 100 pg/ml.
Type: Thyroidectomy.
Calcitonin negative (n = 1392 patients)
Number FNAC: Not reported.
Number operated: 169 patients.
Calcitonin positive (n = 56 patients)
Number FNAC: 55 patients.
Number operated: 25 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported
Type: -
Duration: -
Follow-up calcitonin positive: Not reported
Type:
Duration:
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English
FUNDING: OTHER FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL / JOURNAL SUPPLEMENT / FULL ARTICLE /
CONFERENCE PAPER / OTHER)
Stated aim of
study
Quote from publication: "To evaluate the usefulness of routine measurement of serum
calcitonin concentration in patients with nodular thyroid diseases, and to identify the validity
of pentagastrin simulation test and FNAC "
Abbreviations US: Ultrasonography, FNAC: Fine needle aspiration cytology.
Notes
Appendices
168
Hatzl-Griesenhofer 2002
Patient Selection
A. Risk of Bias
Patient Sampling Design: Retrospective cohort study.
Inclusion criteria: Patients with nodular thyroid disease or with evidence of nodular growth
in follow-up examinations.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Unclear
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? High risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 3899 patients.
Number with NTD: 3899 patients.
Number with NTD and calcitonin testing: 3899 patients.
Sex (female%)(n): 78,8% (3073).
Age (mean/SD): 54.6 (+11.2) yrs range: 6 - 90 yrs.
Number with MTC: 12 patients.
Type of thyroid nodules: Not reported.
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Not reported.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Only reported for MTC patients.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Outpatient ward of the department of Nuclear Medicine and Endocrinology of the
General Hospital Linz.
Country: Austria.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: a two-site chemoluminesence immunoassay, Nichols institute diagnostics.
Sensitivity: 0.7 pg/ml
Stimulated calcitonin: Yes.
Indication: Patients with slightly or moderately elevated normal calcitonin levels (< 80 pg/ml).
Stimulative: Pentagastrin, Peptavlon, Zeneca, Vienna.
Dose: 0.5 ug/kg.
Time: before, 2, 5, and 8 min.
Reported and extracted cut-off values
Basal: Reported: females: 4.6 pg/ml; males 11.5 pg/ml; extracted: females: 4.6 pg/ml; males 11.5
pg/ml.
Stimulated: Reported:100 pg/ml (males and females); extracted: 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
169
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: Histological evaluation in patients referred to surgery.
Indication surgical treatment: Markedly elevated bCT and positive pentagastrin stimulation
tests.
Type: Hemithyroidectomy, (sub)total thyroidectomy, node dissection in selected patients.
Calcitonin negative ( n = 3639 patients)
Number FNA: -
Number operated: Not reported.
Calcitonin positive (n= 230 patients)
Number FNA: -
Number operated: 39 patients (?)
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported
Type: -
Duration: -
Follow-up calcitonin positive: (1) Patients with pathological stimulation test in which the
consultant for internal medicine dissuaded against surgery because of elevated risks (n =2).
(2) patients with elevated basal calcitonin levels who declined pentagastrin stimulation (n
=41).
Type: (1) Ultrasound and determination of basal and stimulated calcitonin (2) clinical and
biochemical follow up.
Number with follow-up: 43 patients.
Duration: Not reported
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? No
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English
FUNDING: Not reported
PUBLICATION STATUS: Full article
Stated aim of
study
Quote from publication: "To evaluate retrospectively the results of routine calcitonin
measurements in patients with nodular thyorid disease "
Abbreviations bCT: basal calcitonin,
Notes
Appendices
170
Elisei 2004
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study.
Inclusion criteria: Patients with nodular thyroid disease.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 10864 patients.
Number with NTD: 10864 patients.
Number with NTD and calcitonin testing: 10864 patients.
Sex (female%)(n): 81.4% (8692).
Age (mean/SD): 49 yr SD not reported Range: 12 - 82 yr.
MTC: 44 patients.
Type of thyroid nodules: Single nodules, nontoxic multinodular goiter, autonomous
functioning thyroid nodules, and autoimmune thyroid disease associated with distinct cold
nodules.
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Not reported.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Not reported.
Country: Italy
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: Solid phase 2 site immunoradiometric assay (ELSA-hCT, CIS, Gif Sur
Yvette, France).
Sensitivity: 14 pg/ml.
Stimulated calcitonin: Yes.
Indication: Patients with detectable levels of basal CTand twice confirmed.
Stimulative: Pentagastrin.
Dose: 0.5 ug/kg.
Time: before, 2, 5, 15 and 30 min.
Reported and extracted cut-off values
Basal: reported: 20 pg/ml; extracted: 20 pg/ml.
Stimulated: reported 60 pg/ml; extracted: 60, 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
171
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAC in nodules > 1 cm or in nodules < 1 cm with suspicious aspects at
neck US, in selected patients histopathological examination after surgery.
Indication surgical treatment: Patients with elevated bCT levels (confirmed by abnormal Pg-
stimulated CT levels) regardless of the results of FNAC and in those with FNAC suspicious of
malignancy indepently from the results of serum CT.
Type:Total thyroidectomy and dissection of the central neck compartment
Calcitonin negative (n = 10817)
Number FNAC: Not reported.
Number operated: Not reported.
Calcitonin positive (n = 47)
Number FNAC: 47 patients.
Number operated: 44 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Only reported of MTC patients.
Type: Not reported.
Number with follow-up: 44 patients.
Duration: Mean 6.2 + 2.5 yr (range, 3-10 yr).
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? No
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Non-commercial.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: "To asses whether we could confirm the results of our preliminiary
study of 1991 and to compare the outcome of patients diagnosed by serum CT measurement
with that of a historical group of MTC patients diagnosed and treated before the introduction
of serum CT screening".
Abbreviations CT: Calcitonin, FNAC: fine needle aspiration cytology, US: Ultrasonography.
Notes
Appendices
172
Karanikas 2004
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study
Inclusion criteria: Patients referred for the work-up of various suspected thyroid disorders.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 414 patients.
Number with NTD: 195 patients.
Number with NTD and calcitonin testing: 195 patients.
Sex (female%)(n): 79.5% (329) NB only reported for whole study population.
Age (mean/SD): 56 year; SD not reported range: 18 - 88 years, NB only reported for whole
study population.
MTC: 1 patients. (1 MTC patient in non-nodular study population)
Type of thyroid nodules: Uni and multinodular disease.
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Only for patients with elevated CT; volume 21 + 10 ml.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Out-patient department.
Country: Austria.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Calcitonin as a triage or add-on test: Not reported.
Index test: Basal and stimulated calcitonin.
Used calcitonin assay: Commercial assay by a Nichols Advantage Chemiluminescence System
(Nichols Institute Diagnostics, San Juan Capistrano, Ca, USA)
Sensitivity: 1 pg/ml.
Stimulated calcitonin: Yes.
Indication: Basal serum CT equal to or exceeding 10 pg/ml.
Stimulative: Pengagastrin Injection BP, Cambridge Laboratories, Tyne & Wear, UK
Dose: 0.5 ug/kg
Time: Before, 2 and 5 min after injection.
Reported and extracted cut-off values
Basal: reported: 10 pg/ml; extracted: 10 pg/ml, 100 pg/ml.
Stimulated: reported: 100 pg/ml (abnormal), 500 pg/ml (pathological); extracted 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
173
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: In selected patients histological examination after total thyroidectomy,
follow-up.
Indication surgical treatment: Patients with abnormal and pathological PG tests.
Type of surgical treatment: Total thyroidectomy and lymph node dissection along both
recurrent nerves in patients.
Calcitonin negative (n = 182)
Number FNAC: -
Number operated: Not reported.
Calcitonin positive (n = 13)
Number FNAC: -
Number operated: 1 patient.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Only for MTC patient.
Type: Basal and stimulated CT.
Number with follow-up: 1.
Duration: Not reported
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Not reported.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: "To compare the distribution and relevance of elevated CT levels in
referrals with nonneoplastic and neoplastic thyroid disease (...)"
Abbreviations CT: calcitonin.
Notes
Appendices
174
Vierhapper 2005
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study.
Inclusion criteria: Patients with suspected thyroid disorders.
Exclusion criteria: Patients with a known elevation of hCT.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 25669 patients.
Number with NTD: 10292 patients.
Number with NTD and calcitonin testing: 10157 patients.
Sex (female%)(n): 79.9% (8114).
Age (mean/SD): Not reported range: Not reported.
MTC: 36 patients.
Type of thyroid nodules: Not reported.
Thyroid nodules detected by palpation or US: Both.
Nodule size: Only reported of MTC patients.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Thyroid outpatient clinic.
Country: Austria
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay:
1994-1999: A commercially available immunoradiometric assay (CIS-biointernational, Gif-Sur-
Yvette, France).
1999-2004: Acridinium-ester-labeled chemiluminescent immunoassay, running on the
‘Advantage’ auto-analyser (Nichols Institute Diagnostics, US).
Sensitivity: Not reported.
Stimulated calcitonin: Yes.
Indication: All patients with basal hCT> 10.0 pg/ml.
Stimulative: Pentagastrin (CambridgeLaboratories, Wallsend, UK).
Dose: 0.5 ug/kg.
Time: Prior to, 2, 5 and 10 min.
Reported and extracted cut-off values
Basal: Reported: 10 pg/ml extracted: 10 pg/ml.
Stimulated: Reported 100 pg/ml extracted: 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from Low concern
Appendices
175
the review question?
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAB, in selected patients histopathological examination after surgery,
follow-up.
Indication surgical treatment: Elevated basal and/or pentagastrin stimulated serum
concentrations of hCT(>100 pg/ml) or cytological findings.
Type: In patients with elevated basal and/or stimulated calcitonin a total thyroidectomy was
performed. Routinely both recurrent nerves were dissected carfully and a systematic
microdissection of the central lymph node compartment. If MTC was documented
intraoperatively a systematic bilateral microdissection of the lateral lymph node
compartments was added.
Calcitonin negative (n = 9960)
Number FNA: Not reported.
Number operated: Not reported, at least 1 pt.
Calcitonin positive (n = 507)
Number FNAB: 15 patients (only reported for MTC patients)
Number operated: 75 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference
standard does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Only reported of MTC patients.
Type: stimulated hCTs.
Number with follow-up: 32 patients.
Duration: 1-9 years.
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? No
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication details LANGUAGE OF PUBLICATION: English.
FUNDING: Non-commercial.
PUBLICATION STATUS: Full article.
Stated aim of study Quote from publication: Not reported.
Abbreviations hCT; serum calcitonin.
Notes
Appendices
176
Papi 2006
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study of consecutive patients.
Inclusion criteria: (1) male & female pts > 18 yrs (2) palpable nodules (3) non-palpable
nodules > 10 mm (4) non palpable nodule < 10 mm with malignant features on US.
Exclusion criteria: (1) patients < 18 years (2) non palpable nodules < 10 mm without
malignant US features (3) pts previously evaluated for nodular goiter by FNA and/or CT
measurement (4) patients reporting familial history of MEN and pts with known MTC (5) pts
with hyper- and hypothyroidism without thyroid nodules (6) patients in follow-up for thyroid
disease (7) patients not confirmed as having thyroid diseases.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Yes
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 1474 patients.
Number with NTD: 1474 patients.
Number with NTD and calcitonin testing: 1425 patients.
Sex (female%)(n): 80% (1144).
Age (mean/SD): 49.6(+ 6.8) yr range: 18 - 91 yr.
MTC: 9 patients.
Type of thyroid nodules: Euthyroid nodular thyroid disease (n = 1369), hypothyroid nodular
thyroid disease (n = 32), sub acute de Quervain's thyroiditis (n = 1), Graves' disease (n=2),
toxic nodular goiter (n = 21).
Thyroid nodules detected by palpation or US: both.
Nodule size: 21.8 + 4 mm
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Ultrasound.
Setting: Not reported.
Country: Italy.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: Two-site chemiluminesence assay, Nichols instute diagnostics, San
Juan Capristano, CA92675, USA).
Sensitivity: 1 pg/ml.
Stimulated calcitonin: Yes.
Indication: When basal serum CT concentrations exceeded 5 pg/ml, but not exceeded 100
pg/ml.
Stimulative: Pentagastrin (Cambridge laboratories, Walsend, Tyne and Wear, NE289NX).
Dose: 0.5 ug/kg.
Time: Before, 2, 5 and 10 min after injection.
Reported and extracted cut-off values
Basal: Reported: 5 pg/ml extracted: 5, 10, 15, 20, 30, 50,100 pg/ml.
Stimulated: Reported: 100 pg/ml extracted: 100, 200 pg/ml.
A. Risk of Bias
Appendices
177
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAC and in selected patients, histopathological examination after
surgical treatment.
Indication surgical treatment: Basal serum CT concentrations > 5 pg/ml < 100 pg/ml and Pg-
stimulated CT levels > 100 pg/ml or basal serum CT concentrations > 100 pg/ml; patients with
a suspicious or repeatedly non-diagnostic FNAC and patients with a benign FNAC and
compressive symptoms.
Type: In patients with benign FNAC and compressive symptoms a lobectomy or near-total
thyroidectomy. In patients with suspicious or non-diagnostic FNAC, surgical extent depended
on histological examination of frozen sections. In patients with malignancy other than MTC a
total thyroidectomy and in case of lymph node involvement a lymphadenectomy. In MTC
patients a total thyroidectomy and a systematic microdissection of both central neck and
bilateral neck compartments. Contralateral lymph node dissection was omitted in MTC
patients with a unilateral thyroid tumor and no ipsilateral and central lymph node
involvement.
Calcitonin negative (n = 1402)
Number FNAC: 1402 patients.
Number operated: 292 patients.
Calcitonin positive: (n = 23)
Number FNAC: 23 patients.
Number operated: 23 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Not reported.
Type: -
Duration: -
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
Appendices
178
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Not reported.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: " To assess the prevalence of hypercalcitoninemia and MTC in NTD
patients, to compare the ability of CT measurement and fine needle aspiartion cytology (FNAC)
to predict MTC, to identify age groups of NTD patients who should be better candidates than
others to undergo routine measurement of CT."
Abbreviations CT: calcitonin, FNAC: fine needle aspiration cytology.
Notes
Appendices
179
Schuetz 2006
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study
Inclusion criteria: Patients with Hashimoto's thyroiditis with documented positivity for TPOAb,
Negativity for anti-TSH receptor antibodies and thyroid ultrasound imaging suggestive of a
chronic thyroiditis.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 568 patients.
Number with NTD: 105 patients.
Number with NTD and calcitonin testing: 105 patients.
Sex (female%)(n): 88.0% (500) NB only reported for whole study population.
Age (mean/SD): 55 + Not reported range: 18 - 88 years, NB only reported for whole study
population.
MTC: 0 patients. (1 MTC patient in non-nodular study population)
Type of thyroid nodules: Not reported.
Thyroid nodules detected by palpation or US: US.
Nodule size: Only reported for patients with elevated calcitonin (13 + 5 mm; range 4.5-17 mm).
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Only reported for patients with elevated
calcitonin; all nodules were hypoechic/circumscribable.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Out-patient department.
Country: Austria.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Calcitonin as a triage or add-on test: Not reported.
Index test: Basal and stimulated calcitonin.
Used calcitonin assay: Commercial assay by a Nichols Advantage Chemiluminescence System
(Nichols Institute Diagnostics, San Juan Capistrano, Ca, USA)
Sensitivity: 1 pg/ml.
Stimulated calcitonin: Yes.
Indication: Basal serum CT equal to/or exceeded 10 pg/ml.
Stimulative: Pengagastrin Injection BP, Cambridge Laboratories, Tyne & Wear, UK
Dose: 0.5 ug/kg
Time: Before, 2,3 and 5 min after injection.
Reported and extracted cut-off values
Basal: reported: 10 pg/ml; extracted: 10 pg/ml.
Stimulated: reported: 100 pg/ml; extracted 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Appendices
180
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: In selected patients histological examination after total thyroidectomy,
follow-up.
Indication surgical treatment: Patients with abnormal and pathological PG tests.
Type of surgical treatment: Total thyroidectomy and lymph node dissection along both
recurrent nerves in patients with a abnormal PG tests and an additional lateral lymph node
dissection in patients with a pathological PG test or intraoperatively verified MTC.
Calcitonin negative (n = 100)
Number FNAC: -
Number operated: Not reported.
Calcitonin positive (n = 5)
Number FNAC: Not reported.
Number operated: 0 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: Not reported.
Type: -
Number with follow-up: -
Duration: -
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Not reported.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: " To evaluate the relevance of routine CT measurements for
detection of MTC or its premalignant associated conditions (micro MTC and neoplastic C cell
hyperplasia) in HT patients."
Abbreviations CT: calcitonin.
Notes
Appendices
181
Costante 2007
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study.
Inclusion criteria: Patients diagnosed with thyroid nodules.
Exclusion criteria: Renal failure, persistent or recurrent MTC, or a family history of MTC.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Yes
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 5817 patients.
Number with NTD: 5817 patients.
Number with NTD and calcitonin testing: 5817 patients.
Sex (female%)(n): 80.9% (4706).
Age (mean/SD): 49.7 + 16.6 yr range: 11 - 72 yr.
MTC: 15 patients.
Type of thyroid nodules: Euthryoid nodular/multinodular goiter (n = 4894), hashimoto's
thyroiditis with nodules (n = 436), autonomously functioning thyroid nodules (n = 276), toxic
nodular goiter ( n = 211).
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Not reported.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: A national healthcare system hospital (outpatient and inpatient) sectors.
Country: Italy.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: Chemiluminesence assay (Nichols advantage Calcitonin
Chemiluminesence assay, San Juan Capistrano, CA).
Sensitivity: 1 pg/ml.
Stimulated calcitonin: Yes.
Indication: Basal calcitonin levels > 20 pg/ml and < 100 pg/ml.
Stimulative: Pentagastrin.
Dose: 0.5 ug/kg.
Time: 2 and 5 min after iv injection.
Reported and extracted cut-off values
Basal: 10 pg/ml, 20 pg/ml, 50 pg/ml and 100 pg/ml; extracted 10, 20, 50 and 100 pg/ml
Stimulated: 100 pg/ml; extracted: 100 pg/ml.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
182
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAB in patients with nonautonomous nodules exceeding 10 mm in
diameter; in selected patients histological examination after surgery, follow-up.
Indication surgical treatment: 1) FNAB indicative or suggestive of thyroid malignancy, 2)
multinodular autonomous or toxic goiters, 3) large euthyroid goiters causing compression, 4)
serum CT levels (basal or PG stimulated) more than 100 pg/ml.
Type: Not reported.
Calcitonin negative (n = 5535)
Number FNAB: Not reported.
Number operated: 723 patients.
Calcitonin positive (n = 216)
Number FNAB: Not reported.
Number operated: 24 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference
standard does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: In patients with basal CT between 10-100 pg/ml and negative
Pg testing.
Type: Basal CT in patients with basal CT between 10-20 pg/ml; yearly stimulated CT in
patients with basal CT between 20-100 pg /ml.
Number with follow-up: 212 patients.
Duration: 2-4 yr.
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? Yes
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Non-commercial.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: " To evaluate the diagnostic accuracy of systematic CT
measurement in non-multiple endocrine neoplasia type 2 patients with nodular thyroid
disease."
Abbreviations CT: calcitonin, FNAB: fine needle aspiration biopsy, PG: pentagastrin.
Notes
Appendices
183
Rink 2009
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Cohort study.
Inclusion criteria: Nodular thyroid disease diagnosed by high-resolution US.
Exclusion criteria: Not reported.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Unclear
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 21928 patients.
Number with NTD: 21928 patients.
Number with NTD and calcitonin testing: 21928 patients.
Sex (female%)(n): 76.9% (16857).
Age (mean/SD): not reported range: 8 - 97 yrs.
MTC: 28 patients.
Type of thyroid nodules: Not reported.
Thyroid nodules detected by palpation or US: US.
Nodule size: Only reported for MTC patients.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Not reported.
Setting: Four sites in central Germany.
Country: Germany.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal and stimulated calcitonin.
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: Radioimmunoassays Calcitonin-IRMA (IBL GmbH, Hamburg, Germany)
and Calcitonin-IRMA magnum (Medipan GmbH, Dahlewith/Berlin, Germany).
Sensitivity: 0.7 ng/l (IBL), 1.5 ng/L (Medipan).
Stimulated calcitonin: Yes.
Indication: If basal CT > 10 ng/l and if renal insufficiency as well as proton pump inhibiotr
medication could be ruled out.
Stimulative: Pentagastrin (Pentagastrin Injection BP, Cambridge Laboratiries Ltd., Tyne &
Wear, England).
Dose: 0.5 ug/kg.
Time: Not reported.
Reported and extracted cut-off values
Basal: reported: 10 ng/l; extracted: 10, 15 ng/l.
Stimulated: reported males: 80 ng/l, females 50 ng/l.; extracted 50, 80 ng/l.
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from
the review question?
Low concern
Appendices
184
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: In selected patients histopathological examination after thyroid
surgery, follow-up.
Indication surgical treatment: An abnormal PGT, a basal CT exceeding 30 ng/l, increasing
basal or progressive morphologic alterations during follow-up.
Type: Not reported.
Calcitonin negative (n = 21073)
Number FNA: -
Number operated: Not reported.
Calcitonin positive (n = 855)
Number FNA: -
Number operated: 157 patients.
Is the reference standards likely to correctly classify the target condition? Unclear
Were the reference standard results interpreted without knowledge of the results
of the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced
bias?
Unclear risk
B. Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard
does not match the question?
Low concern
Flow and Timing
A. Risk of Bias
Flow and timing Follow-up calcitonin negative: Not reported.
Type: -
Duration: -
Follow-up calcitonin positive: In patients not having surgery and without renal insufficiency.
Type: Ultrasound and determination of basal CT.
Number with follow-up: 214 patients.
Duration: mean observation 21 months, median 17 months, range 3-87 months.
Was there an appropriate interval between index test and reference standard? Unclear
Did all patients receive the same reference standard? No
Were all patients included in the analysis? No
Did all patients receive the reference standard? No
Could the patient flow have introduced bias? High risk
User defined characteristics
Publication
details
LANGUAGE OF PUBLICATION: English.
FUNDING: Non-commercial.
PUBLICATION STATUS: Full article.
Stated aim of
study
Quote from publication: " the calculation and validation of upper limits for basal and
stimulated pCT-Cs in a large patient population with nodular thyroid disease, to distinguish
bewteen the subgroups with and without MTC."
Abbreviations pCT-C: plasma calcitonin concentration, PGT: pentagastrin test.
Notes
Appendices
185
Hasselgren 2010
Patient Selection
A. Risk of Bias
Patient
Sampling
Design: Retrospective study.
Inclusion criteria: Patients with non-toxic nodular goiter.
Exclusion criteria: Patients with missing data or with wrongly registered diagnosis.
Was a consecutive or random sample of patients enrolled? Yes
Was a case-control design avoided? Yes
Did the study avoid inappropriate exclusions? Yes
Could the selection of patients have introduced bias? Low risk
B. Concerns regarding applicability
Patient
characteristics
and setting
Number of participants: 959 patients.
Number with NTD: 959 patients.
Number with NTD and calcitonin testing: 702 patients.
Sex (female%)(n): 84.6% (811) NB of whole study population (n=959).
Age (mean/SD): mean not reported; median 49 yrs range: 13-93 yrs NB of whole study
population (n=959).
MTC: 6 patients.
Type of thyroid nodules: Non toxic nodular goiter.
Thyroid nodules detected by palpation or US: Not reported.
Nodule size: Only reported of MTC patients.
Number of nodules: Not reported.
Sonographic morphology of thyroid nodules: Not reported.
FNA procedures performed through ultrasound guidance or palpation: Ultrasound.
Setting: Secondary/tertiarry referral centre.
Country: Denmark.
Are there concerns that the included patients and setting do not match the
review question?
Low concern
Index Test
Index tests Index test: Basal calcitonin
Calcitonin as a triage or add-on test: Not reported.
Used calcitonin assay: (1) double-antibody radioimmunoassay technique (MediLab A/S,
Copenhagen, Denmark) (n =668) (2) solid-phase, enzyme-labelded, 2-site chemiluminescent
immunometric principle (Immulite 2000, Calcitonin, Siemens Medical Solutions Diagnostics,
Erlangen, Germany) (n=14).
Sensitivity: Not reported (1 and 2).
Stimulated calcitonin: No.
Indication: -
Stimulative: -
Dose: -
Time: -
Reported and extracted cut-off values
Basal: reported 0.10 ug/l, 0.20 ug/l, 0.50 ug/l (= 100 ng/l(pg/ml)).
Stimulated: -
A. Risk of Bias
If a threshold was used, was it pre-specified? Yes
Could the conduct or interpretation of the index test have introduced bias? Low risk
B. Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from Low concern
Appendices
186
the review question?
Reference Standard
A. Risk of Bias
Target condition
and reference
standard(s)
Target condition: MTC.
Reference standards: FNAB, in selected patients histopathological examination after surgery,
cross-linkage with the Danish Thyroid Cancer Database.
Indication surgical treatment: Based on the composition of the following variables: (1) clincal
evaluation including age, comorbidity, thyroid size, suspicion of malignancy; (2) sonographic
appearance; (3) result of FNAB; (4) result of serum calcitonin measurement; (5) patient
preference.
Type: Not reported.
Calcitonin negative: (n = 663)
Number FNAB: Not reported.
Number operated: 223 patients.
Calcitonin positive (n = 39)
Number FNAB: Not reported.
Number operated: 23 patients.
Is the reference standards likely to correctly classify the target condition? Yes
Were the reference standard results interpreted without knowledge of the results of
the index tests?
Unclear
Could the reference standard, its conduct, or its interpretation have introduced bias? Unclear risk
B. Concerns regarding applicabili
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