P esenceo Fleische ingandp ominen co nealne es
inke a oconus ela i esandno malcon ols
窑ClinicalResea ch窑
Depa men o Oph halmology,Uni e si yo Deb ecen
ClinicalCen e ,Deb ecen4032,Hunga y
Co espondence o: LiliTak觃cs. Depa men o
Oph halmology,Uni e si yo Deb ecenMedicalSchool,
H4032Deb ecen,Nagye deik ,98,Hunga y.l akacs@med.
unideb.hu
Recei ed:2014-09-24 Accep ed:2015-02-03
Abs ac
·AIM:Toexamine heoccu enceo commonlyknown
clinicalsignso ke a oconus (KC), Fleische ing,
p ominen co neal ne es and hinning, among
una ec ed amilymembe so KCpa ien sandheal hy
con olindi iduals.
·METHODS:Da ao bo heyeso 117 ela i eso KC
pa ien s ha ing no mani es disease based on
ideoke a og aphy indices (KC ela i es), and 142
con olswe eused o Pea sonco ela ionand - es
s a is ics.Co ela iono Fleische ing,p ominen co neal
ne esandcen alpachyme yda awe e es edwi h
eacho he andwi h ideoke a og aphyindices(KSI,
KISA,3and6mmFou ie asymme y,andI-S)
·RESULTS:Amode a eco ela ionwas oundbe ween
Fleische ingandallexamined opog aphicalindices.
Mos impo an co ela ionwasp esen wi h6mm
Fou ie asymme y,andco nealpachyme y(=0.272, <
0.001; =-0.234, =0.027, espec i ely).Simila co ela ions
we e oundwi hp ominen co nealne es(=0.234, <
0.001 o 6mmFou ie asymme yand =-0.235, =
0.0265 o pachyme y). KC amily membe s who
exhibi edFleische ingo p ominen ne eshad hinne
and mo e asymme ic co neas han hose wi hou
Fleische ingo p ominen co nealne es ( <0.05 o
pachyme yand opog aphicindiceswi h - es and
Mann-Whi ney anksum es ).Though a ely,Fleische
ingandp ominen co nealne esoccu edamong
no malcon ols,indica ing heexis enceo o me us e
casesin heno malpopula ion.Con olsubjec s,who
hadco nealFleische ingo p ominen ne eshad
co neasmo esimila oKC hano he con ols(- es :
inc eased KSI and KISA, =0.048 and 0.012,
espec i ely).
·CONCLUSION:InKC amilymembe sandheal hy
indi iduals,Fleische ingandp ominen co nealne es
a eassocia edwi h ea u eso KCandmaysugges a
possibili yo o me us eKC.Sea ching o hepossible
p esenceo Fleische ingo p ominen ne eson he
co neamayhelpin hedecisionwhe he o no o
diagnosesubclinicalKCinabo de linecase.
·KEYWORDS: o me us e/subclinicalke a oconus;
Fleische ing; co nealne es; co neal hinning;
ideoke a og aphicindices;ia ogenicke a ec asia
DOI:10.3980/j.issn.2222-3959.2015.05.12
K isz 魣,LosonczyG,Be aA,Tak觃csL.P esenceo Fleische ing
andp ominen co nealne esinke a oconus ela i esandno mal
con ols. 2015;8(5):922-927
INTRODUCTION
Ke a oconus(KC,OMIM#148300)isap og essi e,
bila e al,p ima yec a icdiseaseo heco nea,
cha ac e izedbynon-in lamma o y hinningandconical
p o usion [1].In hegene alpopula ion,i ses ima ed
p e alenceliesbe ween50and230pe 100000 [2],bu
dependingondiagnos icc i e iaande hnici y,i can each
2.34%[3].KCis equen lyanisola edcondi ion,bu i may
associa ewi ho he sys emico ocula diso de s [1,4].The eis
awell- ecognisedgene iccomponen oKC,ase idencedby
win [5] and amilys udies [1,6-8];howe e , hee iologyo he
diseaseiscomplex,mul i ac o ialwi hbo hgene icand
en i onmen al ac o splayinga ole[9,10].
Amsle [11] demons a edsimila bu lessp onouncedco neal
opog aphicalchangesbyPlacidodiscin ela i eso KC
pa ien s,andcalled hisqui e equen phenomenon o me
us eKC.Hep o ed ha classicand o me us eKC
cons i u ed hesameen i yand ha mus beconside edin
gene ics udies.Topog aphicexamina iono ela i eso KC
pa ien s e ealedagg ega iono asymme icco nealpa e ns
andinc eased ideoke a oscopyindices [7,12].Topog aphic
ea u essimila o o me us eKCwe eobse edamong
some e ac i esu ge ycandida es,especiallyamong he
ones su e ing omp og essi eke a ec asia a e he
in e en ion [13].Rela i eso pa ien swi hKCha eahigh
p e alenceo undiagnosedKCandKC ai s, he e o e,
ke a o e ac i esu ge yshouldbeconside edcau iouslyin
heseindi iduals[14,15].
KCse e i ywas ound obeassocia edwi haninc easing
a eo sli -lampbiomic oscopicsigns, Vog s iae,
Fleische inginke a oconus ela i es
922
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Fleische ing,p ominen ne es,hazeand hinningo he
co nea.Fleische ingisp esen inmos KCco neaswhe eas
p ominen ne esa eless equen andspeci ic o KC[1,16].
Diagnosing o me us eo subclinicalKCiss illchallenging
inmanycases.Howe e ,iden i yingsuchcasesisnecessa y
bo h o gene ics udiesandsc eeningpo en ialhigh isk
e ac i esu ge ycandida es.Inou p e iouswo k,we
obse ed heoccu enceo Fleische ingandp ominen
co nealne esinuna ec edKC amilymembe s [9].Fo me
us eKCisknown ooccu equen lyamongKC amily
membe s, he e o emanys udiesexamineKC amily
membe s ode inesub lecha ac e is icsassocia edwi h
o me us eo subclinicalKC [15,17].In hep esen s udy,we
in es iga ed heco ela iono co nealFleische ingand
p ominen ne eswi h ideoke a og aphicsignso KCbo h
amonguna ec ed amilymembe sandheal hycon ol
indi iduals o indou i hesesignscanbeused obe e
iden i y o me us eKC.
SUBJECTSANDMETHODS
Subjec s Ou s udy'sdesign ollowed he ene so he
HelsinkiDecla a ionwi hins i u ional esea che hicsboa d
app o al,in o medconsen o pa ien sandcon olswas
ob ainedbe o eexamina ion.KC amilieswe e ec ui edby
mailingle e s opa ien s ea edinou depa men o KC,
in o ming hemabou heaimso hes udyandasking o
pa icipa iono he ela i es, oo.Heal hycon olswe e
ec ui ed oms uden s,pe sonnelandpa ien so he
depa men wi hheal hyco neas.Allo heen olledsubjec s
we eHunga ianpa ien swi hCaucasianances y.Table1
shows heg oupso indi idualsen olledin hes udy.
Non-a ec edKC amilymembe swe ede inedasha ing 臆
3Das igma ismo 臆6Dsphe ical e ac i ee o andno
ha ingKCbasedonke a oconusse e yindex(KSI)o
KISA( aluesbelow30%and100%, espec i ely).Noneo
he amilymembe shadanyo heknowngene ic
associa ionso KC( Downsynd ome,Ma ansynd ome
).O 142con olindi idualswi hou amilyhis o yo KC
andwi hou his o yo co nealdiseaseo eyesu ge ywe e
selec ed,wi h 臆3Das igma ismo 臆6Dsphe ical
e ac i ee o .Onlyeyes ha hadnop e iousco nealinju y
andsu ge y,including pe o a ing ke a oplas y,we e
in ol edin hes udy.
Me hods Fo eachKCp oband,diagnosiswasbasedon
clinicalexamina ion,includingmeasu emen o isualacui y,
sli -lampbiomic oscopy,di ec oph halmoscopy, e inoscopy
and ideoke a og aphy.
AllKC amilymembe sandcon olindi idualsconsen ed
co neal opog aphy,sli -lampclinicalexamina ion,and86
consen edul asonicpachyme y(27eyeso 15KCpa ien s,
89eyeso 45 amilymembe sand52eyeso 26con ols;
Table1).
Bysli -lampbiomic oscopy, hep esenceo Fleische ingin
heepi helium,p ominen co nealne eswe esea ched o
in amilymembe so KCpa ien sandcon ols.Fleische
ingwasconside edasp esen whena leas 2mmcu ed
pa acen alsubepi heliali ondeposi (incomple e)o a
comple eFleische ingwasde ec ed(Figu e1).
Videoke a og aphy Topog aphicexamina ionwas
pe o medonbo heyeso eachs udypa icipan ,usinga
TMS-4 ideoke a oscope(TomeyCo po a ion,Nagoya,
Japan).A leas ou imagespe eyewe e aken,disca ding
hose ha we emisaligned,ou o ocuso o poo quali y.
Ca ewas aken oa oida i ac sdu ing heexamina ion
whichcouldbe esponsible o pseudoke a oconusimages[18].
Da aob ained om hebes imageo eacheye,selec edupon
hequali yo heke a oscopymi esby isualinspec ion,
we eused.Topog aphicalimagesandpa ame e so ope a ed
eyeswe eigno ed.
Videoke a og aphyindiceso ke a oconus Videoke a o-
g aphyindicesyieldedby heTMS-4so wa eand hose
calcula ed om hemwe eselec ed o u he analysis.
KISA Valueso KISAabo e100we e aken oindica e
mani es KC,below60heal hyeyes,and hein e al
be ween he wobeingconside ed o me us ecases[19].
Ke a oconusse e i yindex KSIexp esses hese e i yo
hediseaseinpe cen age, KCsuspec >15%,mani es
KC>30%[20].
Th eeandsixmilime e Fou ie asymme yindices
Decen a ion( i s ha monic)componen ,onmi e ings1-9,
Table 1 Cha ac e is ics o he examined 47 KC amilies and con ol indi iduals
KC amilies (n=47) KC pa ien s KC amily membe s Heal hy con olsc
No. o subjec s 49 (87 eyes) a 117 (233 eyes) a 142 (279 eyes) b
Age (a): ( ange) 33.3 ± 11.7 (15-64)
41.3 ± 18.6 (9-81) 35.9 ± 13.7 (14-74)
No. o subjec s ha ing addi ional cen al co neal pachyme y
measu emen s 15 (27 eyes) 45 (89 eyes) 26 (52 eyes)
No. o subjec s ha ing Fleische ing 33 (71.7%) 36 (30.8%) 3 (2.1%)
No. o subjec s ha ing p ominen co neal ne es 7 (15.2%) 17 (14.5%) 4 (2.8%)
All subjec s unde wen sli -lamp and opog aphic examina ion, and a subpopula ion had addi ional cen al co neal pachyme y
measu emen s. a In wo amilies, wo membe s we e a ec ed. Da a o ope a ed eyes we e excluded (3 and 5 p obands unde wen bila e al
and unila e al ke a oplas y, espec i ely, and one ela i e had p e ious eye inju y); bFi e eyes ha ing p e ious inju ies we e excluded;
cCon ols we e no signi ican ly di e en om he membe s o KC amilies, conce ning age (P=0.11) and gende dis ibu ion (P=0.153).
s
x
±
923
and ings1-20whichapp oxima ely ep esen hecen al3o
6mmo heco nea[21,22].
I-S Absolu e alueso heI-S (in e io -supe io diop ic
asymme y)[23].[I-S]逸1.4wasconside edabno mal.
Co nealpachyme y Co nealul asonicpachyme ywas
used omeasu e hecen alco neal hicknessonbo heyeso
86indi iduals:15KCp obands,45non-a ec ed ela i es
and26con ols(Table1).
S a is icalAnalysis Fo calcula ings a is ics,da ao bo h
he igh andle eyeso eachindi idualwe eincluded.In
KC amilymembe s,3se ieso co ela ions a is icswe e
es ed: hep esenceo Fleische ing,cen alco neal
pachyme yda aand hep esenceo p ominen co neal
ne es,wi honeano he andwi h ideoke a og aphyindices.
Co ela ions a is icswe e no pe o medincon ol
indi idualsbecause helownumbe o caseswi hFleische
ingo p ominen co nealne es.Thep esenceo Fleische
ingandp ominen ne esin heco neawe ebina y
a iables. Cen alco nealpachyme yda aandall
ideoke a og aphyindiceswe econ inuous a iables.
Co ela ionbe ween a iableswascalcula edusingPea son
co ela ion s a is ic, alueand heco ela ion
coe icien ( )we ede e mined.Pa ame e aluesbe ween
g oupswe ecompa edwi h - es o Mann-Whi ney ank
sum es .Thep og amSigmaS a 3.5 e sionwasused o
s a is icsand 琢=0.05was hele elo signi icance.
RESULTS
Table1shows hecha ac e is icso heexaminedpopula ion.
Con olswe eno signi ican lydi e en om hemembe so
KC amilies,conce ningage(=0.11)andgende
dis ibu ion(=0.153).InKCpa ien s,Fleische ingwas
de ec edin71.7%,andp ominen ne eso heco neain
15.2%.InKC amilymembe s,co nealFleische ingwas
obse edin30.8%andp ominen ne eswe ede ec edin
14.5%.
Amongcon olindi iduals,Fleische ingandp ominen
ne eswe eno comple elyabsen bu occu edin2.1%and
2.8%, espec i ely(Table1;Figu e1).
Co ela ions a is icsinKC ela i esamongKC amily
membe s, he ewasasigni ican nega i eco ela ion
be weencen alco nealpachyme yandFleische ing(=
-0.234;Table2).Fo each opog aphicindex, he ewasa
signi ican posi i eco ela ionwi hFleische ing(Table2).
Theseco ela ion esul simply ha Fleische ingoccu edin
hinne andmo easymme icco neaso KC ela i es.The e
wasasigni ican posi i eco ela ionwi hp ominen co neal
ne es o all opog aphicindices,excep o I-S.Signi ican
nega i eco ela ionbe weenp ominen ne esandcen al
Figu e1Sli -lampand ideoke a og aphicimageso wo
heal hycon olindi iduals A:Sli -lamppho og aphyo a39
yea -oldmanwhohasco nealFleische ing(a ows)andp ominen
ne es(a owheads);B:Videoke a og aphicimageo hesameman
showsasymme icco nealpa e n;C:Sli -lamppho og aphyo a32
yea -oldwomanwhohasco neali ondeposi ion,whichdidno
each2mmleng h, he e o ei wasno conside edasFleische ing
(a ow),bu shehasp ominen co nealne es(a owheads);D:
Videoke a og aphicimageo hesamewomanshowsasymme ic
co nealpa e nwi hskewed adialaxis.
Table 2 Co ela ion s a is ics in KC ela i es
Pea son co ela ion
Pa ame e s
P
Fleische ing
Pachyme y -0.234 0.027
KSI 0.169 0.00958
KISA 0.155 0.0178
3 mm Fou ie asymme y 0.214 0.001
6 mm Fou ie asymme y 0.272 0.0000261
I-S 0.229 0.000419
Pachyme y
P ominen ne es -0.235 0.0265
KSI -0.377 0.000271
KISA -0.342 0.00104
3 mm Fou ie asymme y -0.425 0.0000328
6 mm Fou ie asymme y -0.427 0.0000303
I-S -0.338 0.00119
P ominen ne es
Fleische ing 0.00437 0.947
KSI 0.237 0.000261
KISA 0.246 0.000148
3 mm Fou ie asymme y 0.228 0.000463
6 mm Fou ie asymme y 0.234 0.000308
I-S -0.0287 0.663
The p esence o Fleische ing in KC ela i es showed signi ican
co ela ion wi h cen al co neal pachyme y da a and all opog aphic
indices. Cen al co neal pachyme y da a displayed signi ican
co ela ion wi h he p esence o p ominen ne es and all opog aphic
indices. The p esence o p ominen co neal ne es showed signi ican
co ela ion wi h all opog aphic indices excep o I-S. : Co ela ion
coe icien .
Fleische inginke a oconus ela i es
924
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co nealpachyme yda aindica ed ha p ominen ne es
we emo elikely oappea in hinne co neas(=-0.235;
Table2).
Cen alco nealpachyme y aluesnega i elyco ela edwi h
allexamined opog aphicindices(<-0.3 o allindices,
co ela ionwas hehighes o Fou ie asymme yindices3
and6mm =-0.425,-0.427, espec i ely).
The ewasnosigni ican co ela ionbe weenFleische ing
andp ominen ne esin heseco neas,indica ing ha
p ominen ne esandFleische ingdidno equen lyoccu
in hesameindi iduals(Table2).
Inacco dancewi hco ela ions a is ics,sigini ican
di e enceswe e oundbe ween ela i esha ingo no
ha ingclinicalsignso KC,by - es s.Table3.shows ha
ela i eswi hFleische inghadsigni ican ly hinne co neas
andhighe alueso each ideoke a og aphyindexcompa ed
o hosewi hou Fleische ing.Rela i eswi hp ominen
co nealne esdisplayedhighe KSI,3and6mmFou ie
asymme yindices han hoseha ingnop ominen ne es
(Table3).SinceFleische ingandp ominen co nealne es
we eno equen lyconcomi an ,compa isono co neaswi h
p ominen ne es oallo he amilymembe co neas
includingco neaswi hFleische ing-whichwe e hinne
andmo easymme ical-yieldedsigni ican di e encesonly
o KSIand6mmFou ie asymme y.Acco dingly,when
co neaso ela i eswi hp ominen ne eswe ecompa ed o
hosewhohadnei he p ominen co nealne esno Fleische
ingsigni ican di e enceswe e ound o allpa ame e s
excep o KISA(Table3).
Ou o 142con olindi iduals,1hadonlyFleische ing,2
hadbo hFleische ingandp ominen ne es,2hadonly
p ominen ne es.Co ea ions a is icsin hisda ase wasno
eliablebecauseo lownumbe o cases.
Con olindi idualswi hFleische ingandp ominen co neal
ne esshowedsigni ican lyhighe alueso KSI(=0.048)
andKISA ( =0.012)indices,bu we eno signi icanly
hinne hancon olswi hou Fleische ingandwi hou
p ominen ne es( >0.1).
DISCUSSION
Inou da ase o 47spo adicKC amilies,occu enceo
Fleische ingandp ominen co nealne eswasobse edon
co neaso una ec ed ela i es.O hesepa hognomicclinical
signs, hemos ema kableonewas heco nealFleische ing
whichwasp esen inalmos e e y hi d amilymembe
(30.8%).This esul issimila o heoccu enceo Fleische
ingde ec edinmildKC(27.27%in<45Dke a ome y
eadings) [24].Inmani es KC,we oundFleische ingin
71.7%o hepa ien s,whichisconsis en wi h he esul so
p e iouss udieso 57%-87% [25,26].In heheal hycon ol
popula ion,Fleische ing(2.1%),p ominen ne es(2.8%)
andco nealasymme ys illoccu ed a ely(Figu e1).In he
examinedpopula ion,Fleische ingwasmos ly ain in he
co neaso KC amilymembe sandcon ols.To hebes o
heau ho s'knowledge, hisis he i s s udyo an
examina iono Fleische ingandp ominen co nealne es
amonguna ec ed ela i eso KCpa ien s.
Basedonou co ela ionand - es esul s, hep esenceo
Fleische ingandp ominen ne eswasassocia edwi h
ea u eso KC.Familymembe swhoexhibi edFleische
ingandp ominen ne eshad hinne andmo easymme ic
co neas han hosewi hou Fleische ingandp ominen
ne es.Incon olsubjec s,co neasdisplayingaFleische
ingandp ominen ne eswe emo esimila oKCco neas
(shownbysigni ican lyhighe KSIandKISA alues),bu
we eno hinne hano he no malco neas.
Table 3 Compa ison o g oups o indi iduals in he s udied popula ion
Pa ame e s o KC
amily membe s
(n)
Pachyme y KSI KISA 3 mm Fou ie
asymme y
6 mm Fou ie
asymme y I-S
Wi h Fleische ing
(36) 510.87 (±40.23)
6.20 (±15.94) 261.37 (±1497.80)
0.43 (±0.35) 0.67 (±0.54) 2.48 (±4.91)
Wi hou Fleische
ing (81) 530.17 (±32.90)
2.49 (±9.50) 19.02 (±91.67)
0.30 (±0.23) 0.43 (±0.30) 1.06 (±2.50)
P 0.017 0.010 <0.001 <0.001 <0.001 <0.001
Wi h p ominen
ne es (17) 506.72 (±48.44)
10.45 (±23.31)
566.07 (±2163.86)
0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07)
Wi hou p ominen
ne es (100) 527.96 (±31.79)
2.48 (±8.22) 13.24 (±28.19)
0.31 (±0.24) 0.47 (±0.31) 1.51 (±3.67)
P 0.083 0.006 0.467 0.002 0.008 0.349
Wi h p ominen
ne es (17) 506.72 (±48.44)
10.45 (±23.31)
15.60 (±2163.86) 0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07)
Wi hou p ominen
ne es and wi hou
Fleische ing (70)
530.55 (±31.86)
2.02 (±8.17) 12.90 (±31.79)
0.28 (±0.21) 0.41 (±0.26) 1.03 (±1.50)
P 0.024 0.001 0.907 <0.001 <0.001 0.029
KC amily membe s ha ing co neal Fleische ing compa ed o hose wi hou Fleische ing ha e signi ican ly hinne co neas ( - es ) and
highe alues o all opog aphy indices (Mann-Whi ney ank sum es s). KC amily membe s wi h p ominen co neal ne es compa ed o
hose ha ing no p ominen ne es show signi ican ly highe alues o KSI, 3 and 6 mm Fou ie asymme y indices (Mann-Whi ney ank
sum es s). KC amily membe s ha ing p ominen co neal ne es compa ed o hose wi hou p ominen ne es and wi hou Fleische ing
ha e signi ican ly hinne co neas ( - es ) and highe alues o all opog aphy indices excep o KISA (Mann-Whi ney ank sum es s).
925
In e es ingly,p ominen ne esandFleische ingdidno
alwaysoccu oge he in hesameco nea.I iswellknown
ha hesesignsoccu wi hunequal equenciesinKC [1].I is
belie ed ha KCisacomplexdisease,bo hgene icand
en i onmen al ac o splayinga oleini spa hogenesis [9].
Fleische ingissupposed ode elopasaconsequenceo
al e ed esponseo KCepi helialcells ooxida i es ess[27].
Recen co neal con ocalmic oscopys udies
consis en lyha eshown ha e eninmildKC, hesubbasal
ne emo phologyisg osslyabno mal [28].Thismigh be
explainedbyal e ed egula iono ne eg ow h ac o
ecep o exp essionin heKCco nea [29].Thesedi e en
e iological ac o smigh explainwhyFleische ingand
co nealne esdono alwaysoccu oge he inKCo o me
us eco neas.
I wasunexpec ed o indFleische inginno malcon ols.
Ne e heless,supposing ha o me us eKCisan
incomple ely de elopedKC,i soccu enceinno mal
con olsispossible.A ecen s udy epo ed hep esenceo
bila e alFleische inginasubjec whohadonlymild
opog aphicasymme y,a e agecen alco neal hickness,
lowmyopiawi hs able e ac ion,no malbes co ec ed
isualacui yandno mal e inoscopic e lexes.Theexample
o hispa ien ,whowasconside edas o me us eKC,
indica ed ha hiscondi ion, co neali on ingcanoccu
wi hou aposi i e amilyhis o yand cha ac e is ic
opog aphicsignso KC[30].
Inou amilymembe s,minimal opog aphical e a ionswe e
obse edandassocia edwi h hep esenceo Fleische ing
and p ominen co nealne es. Oneo heexamined
pa ame e sin hiss udywascen alco neal hickness
measu edbyul asound pachyme y.Cen alco neal
pachyme yaloneisun eliablein hediagnosiso KC,
ne e heless,dec eased hicknesscanbeagoodindica o o
simila i y oKCand oge he wi h he ideoke a og aphic
indices hispa ame e suppo ed ha Fleische ingand
p ominen ne es end ooccu inco neasmo esimila o
KC.Howe e , heexamina iono hepos e io co neal
su aceandpachyme ywi hmode ndiagnos icme hods(
Scheimp lugimagingo O bscan)wouldbehelp ulin u u e
s udies,since heea lies signso KCcanbemo eaccu a ely
de ec edwi h hese echniquesandco ela ionswillbegi en
u he impac wi h headdi iono pos e io opog aphical
in o ma ion[31,32].
Inspi eo sophis ica edimaging echniques,de ec ing
subclinicalKCiss illchallenginginmanycases.Iden i ying
subclinical/ o me us ecases,howe e ,isimpo an bo h o
gene ics udiesandselec inghigh isk e ac i esu ge y
candida es [13,33,34].Basedonou esul s,i canbesugges ed
ha a ho oughsea ch o Fleische ingandp ominen
ne esin heco neacanhelp odecidewhe he o no o
diagnosesubclinicalKCinbo de linecases.
ACKNOWLEDGEMENTS
Founda ions: Suppo edbyHunga ianNa ionalResea ch
FundG an sOTKAF046321andTAMOP-4.
2.1/B-09/1/KONV-2010-0007.Tak觃csLis ecipien o he
Szodo ayFellowshipo heUni e si yo Deb ecen.
Con lic so In e es :K isz 譧,None; LosonczyG,None;
Be aA,None; Tak仳csL,None.
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