University of Groningen Medullary Thyroid Carcinoma ......3 ((thyroid* or thyreoid) adj6 (neoplas or cancer or carcinoma* or macrocarcinoma* or microcarcinoma* or tumo?r*)).tw,ot

University of Groningen

Medullary Thyroid CarcinomaVerbeek, Hans

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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.


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.


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


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.


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


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.



Did the study avoid inappropriate exclusions? Yes



Patient

characteristics

and setting


Clinical features: Patients with nodular goiter.



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.


review question?

Low concern

Index Test

Index tests Index test: Basal calcitonin.


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: -


Basal: Reported: 30 pg/ml; extracted:30 pg/ml, 50 pg/ml, 100 pg/ml.

Stimulated: -

A. Risk of Bias




Appendices

165



Low concern

Reference Standard

A. Risk of Bias

Target condition and

reference standard(s)


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.


Number FNAB: 669 patients.



Number FNAB: 4 patients.



Were the reference standard results interpreted without knowledge of the results

of the index tests?

Unclear


bias?

Unclear risk


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


Type: -

Duration: -

Follow-up calcitonin positive: Described for 3 MTC patients.

Type: Basal and stimulated calcitonin levels.

Duration: 14-18 months







Publication

details




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.







Patient

characteristics

and setting




Sex (female%)(n): 80,3% (1163).

Age (mean/SD): 46 years Range: 14-86 years.


Type of thyroid nodules: Not reported.

Thyroid nodules detected by palpation or US: Not reported.




FNA procedures performed through ultrasound guidance or palpation: Not reported.

Setting: Thyroid clinic of Samsung Medical Center.

Country: Korea.


review question?

Low concern

Index Test


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.


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.


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






Low concern

Appendices

167

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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)



Calcitonin positive (n = 56 patients)





of the index tests?

Unclear


bias?

Unclear risk




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:







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.


Was a consecutive or random sample of patients enrolled? Unclear



Could the selection of patients have introduced bias? High risk


Patient

characteristics

and setting




Sex (female%)(n): 78,8% (3073).

Age (mean/SD): 54.6 (+11.2) yrs range: 6 - 90 yrs.






Sonographic morphology of thyroid nodules: Only reported for MTC patients.


Setting: Outpatient ward of the department of Nuclear Medicine and Endocrinology of the

General Hospital Linz.

Country: Austria.


review question?

Low concern

Index Test



Used calcitonin assay: a two-site chemoluminesence immunoassay, Nichols institute diagnostics.

Sensitivity: 0.7 pg/ml


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.


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






Low concern

Appendices

169

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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 (?)



of the index tests?

Unclear


bias?

Unclear risk




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



Were all patients included in the analysis? No




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


Inclusion criteria: Patients with nodular thyroid disease.







Patient

characteristics

and setting




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.







Country: Italy


review question?

Low concern

Index Test



Used calcitonin assay: Solid phase 2 site immunoradiometric assay (ELSA-hCT, CIS, Gif Sur

Yvette, France).

Sensitivity: 14 pg/ml.


Indication: Patients with detectable levels of basal CTand twice confirmed.


Dose: 0.5 ug/kg.

Time: before, 2, 5, 15 and 30 min.


Basal: reported: 20 pg/ml; extracted: 20 pg/ml.

Stimulated: reported 60 pg/ml; extracted: 60, 100 pg/ml.

A. Risk of Bias






Low concern

Appendices

171

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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









of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -

Follow-up calcitonin positive: Only reported of MTC patients.

Type: Not reported.


Duration: Mean 6.2 + 2.5 yr (range, 3-10 yr).







Publication

details


FUNDING: Non-commercial.


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.







Patient

characteristics

and setting




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.


Nodule size: Only for patients with elevated CT; volume 21 + 10 ml.




Setting: Out-patient department.

Country: Austria.


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)



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.


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






Low concern

Appendices

173

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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.


Number FNAC: -



Number FNAC: -

Number operated: 1 patient.



of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -

Follow-up calcitonin positive: Only for MTC patient.

Type: Basal and stimulated CT.

Number with follow-up: 1.

Duration: Not reported







Publication

details




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


Inclusion criteria: Patients with suspected thyroid disorders.

Exclusion criteria: Patients with a known elevation of hCT.






Patient

characteristics

and setting




Sex (female%)(n): 79.9% (8114).

Age (mean/SD): Not reported range: Not reported.

MTC: 36 patients.


Thyroid nodules detected by palpation or US: Both.

Nodule size: Only reported of MTC patients.




Setting: Thyroid outpatient clinic.

Country: Austria


review question?

Low concern

Index Test




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.


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.


Basal: Reported: 10 pg/ml extracted: 10 pg/ml.

Stimulated: Reported 100 pg/ml extracted: 100 pg/ml.

A. Risk of Bias




Are there concerns that the index test, its conduct, or interpretation differ from Low concern

Appendices

175


Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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.


Number FNA: Not reported.

Number operated: Not reported, at least 1 pt.


Number FNAB: 15 patients (only reported for MTC patients)




of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -

Follow-up calcitonin positive: Only reported of MTC patients.

Type: stimulated hCTs.


Duration: 1-9 years.







Publication details LANGUAGE OF PUBLICATION: English.



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.






Patient

characteristics

and setting




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



FNA procedures performed through ultrasound guidance or palpation: Ultrasound.


Country: Italy.


review question?

Low concern

Index Test



Used calcitonin assay: Two-site chemiluminesence assay, Nichols instute diagnostics, San

Juan Capristano, CA92675, USA).



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.


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






Low concern

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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 positive: (n = 23)





of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -


Type: -

Duration: -






Appendices

178


Publication

details




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.







Patient

characteristics

and setting




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)


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).


Sonographic morphology of thyroid nodules: Only reported for patients with elevated

calcitonin; all nodules were hypoechic/circumscribable.


Setting: Out-patient department.

Country: Austria.


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)



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.


Basal: reported: 10 pg/ml; extracted: 10 pg/ml.

Stimulated: reported: 100 pg/ml; extracted 100 pg/ml.

A. Risk of Bias




Appendices

180



Low concern

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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.


Number FNAC: -







of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -


Type: -

Number with follow-up: -

Duration: -







Publication

details




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


Inclusion criteria: Patients diagnosed with thyroid nodules.

Exclusion criteria: Renal failure, persistent or recurrent MTC, or a family history of MTC.






Patient

characteristics

and setting




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).






Setting: A national healthcare system hospital (outpatient and inpatient) sectors.

Country: Italy.


review question?

Low concern

Index Test



Used calcitonin assay: Chemiluminesence assay (Nichols advantage Calcitonin

Chemiluminesence assay, San Juan Capistrano, CA).



Indication: Basal calcitonin levels > 20 pg/ml and < 100 pg/ml.


Dose: 0.5 ug/kg.

Time: 2 and 5 min after iv injection.


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






Low concern

Appendices

182

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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.


Number FNAB: Not reported.







of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


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.


Duration: 2-4 yr.







Publication

details




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


Inclusion criteria: Nodular thyroid disease diagnosed by high-resolution US.







Patient

characteristics

and setting




Sex (female%)(n): 76.9% (16857).

Age (mean/SD): not reported range: 8 - 97 yrs.

MTC: 28 patients.


Thyroid nodules detected by palpation or US: US.

Nodule size: Only reported for MTC patients.




Setting: Four sites in central Germany.

Country: Germany.


review question?

Low concern

Index Test



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).


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.


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






Low concern

Appendices

184

Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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.


Number FNA: -



Number FNA: -




of the index tests?

Unclear


bias?

Unclear risk




Low concern

Flow and Timing

A. Risk of Bias


Type: -

Duration: -

Follow-up calcitonin positive: In patients not having surgery and without renal insufficiency.

Type: Ultrasound and determination of basal CT.


Duration: mean observation 21 months, median 17 months, range 3-87 months.







Publication

details




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.






Patient

characteristics

and setting




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.


Nodule size: Only reported of MTC patients.



FNA procedures performed through ultrasound guidance or palpation: Ultrasound.

Setting: Secondary/tertiarry referral centre.

Country: Denmark.


review question?

Low concern

Index Test

Index tests Index test: Basal calcitonin


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: -


Basal: reported 0.10 ug/l, 0.20 ug/l, 0.50 ug/l (= 100 ng/l(pg/ml)).

Stimulated: -

A. Risk of Bias




Are there concerns that the index test, its conduct, or interpretation differ from Low concern

Appendices

186


Reference Standard

A. Risk of Bias

Target condition

and reference

standard(s)


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)






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

Documents

University of Groningen Medullary Thyroid Carcinoma ......3 ((thyroid* or thyreoid*) adj6 (neoplas* or cancer or carcinoma* or macrocarcinoma* or microcarcinoma* or tumo?r*)).tw,ot

University of Groningen Medullary Thyroid Carcinoma ......3 ((thyroid* or thyreoid) adj6 (neoplas or cancer or carcinoma* or macrocarcinoma* or microcarcinoma* or tumo?r*)).tw,ot