Are concurrent systematic cores needed at the time of targeted biopsy in patients with prior negative prostate biopsies?

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ORIGINAL ARTICLE

Are concurrent systematic cores needed at the time of targeted biopsy in patients with prior negative prostate biopsies?

Les biopsies systématiques sont-elles nécessaires dans le même temps que les biopsies ciblées chez les patients ayant des biopsies de prostate initialement négatives ?

S. Albisinni

^a^,^b^,∗

, F. Aoun

^a^,^c

, A. Noel

^a

, E. El Rassy

^d

, M. Lemort

^e

, M. Paesmans

^f

, R. van Velthoven

^a

, T. Roumeguère

^a^,^b

, A. Peltier

^a^,^b

aDepartmentofurology,institutJules-Bordet,universitélibredeBruxelles(ULB),Brussels, Belgium

bDepartmentofurology,cliniquesuniversitairesdeBruxelles,hôpitalErasme,ULB,Brussels, Belgium

cDepartmentofurology,Hôtel-DieudeFrance,Beirut,Lebanon

dDepartmentofoncology,Hôtel-DieudeFrance,Beirut,Lebanon

eDepartmentofradiology,institutJules-Bordet,ULB,Brussels,Belgium

fDepartmentofstatistics,institutJules-Bordet,ULB,Brussels,Belgium

Received5August2017;accepted6October2017 Availableonline6December2017

KEYWORDS Prostatecancer;

MRI/USfusion;

Targetedprostate biopsies;

Cancerdetection

Summary

Introductionandobjectives.—MRI-guidedtargetedbiopsiesareadvisedinpatientswhohave undergoneaninitial seriesof negativesystematicbiopsies, inwhomprostatecancer (PCa) suspicionremainselevated.Theaimofthestudywastoevaluatewhether,inmenwithprior negativeprostatebiopsies,systematiccoresarealsowarrantedatthetimeofanMRI-targeted repeatbiopsy.

∗Corresponding authorat: Département d’urologie, cliniques universitairesde Bruxelles, hôpitalErasme-ULB, routede Lennik 808, Bruxelles,Belgium.

E-mailaddress:Simone.albisinni@erasme.ulb.ac.be(S.Albisinni).

https://doi.org/10.1016/j.purol.2017.10.001

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Materialandmethods.—Weenrolledpatientswithpriornegativebiopsyundergoingrealtime MRI/TRUSfusionguidedprostatebiopsyatourinstitutebetween2014and2016.Patientswith atleastoneindexlesiononmultiparametricMRIwereincluded.Alleligiblepatientsunderwent bothsystematicrandombiopsies(12—14cores)andtargetedbiopsies(2—4cores).

Results.—Thestudyincluded74menwithamedianageof65years,PSAlevelof9.27ng/mL, andprostaticvolume of45ml. The overallPCa detectionrateandthe clinicallysignificant cancerdetectionratewere56.7%and39.2%,respectively.Targetedcoresdemonstratedsimilar clinicallysignificantPCadetectionratecomparedtosystematiccores(33.8%vs.28.4%,P=0.38) withsignificantlylesstissuesampling.Indeed,acombinationapproachwassignificantlysuperior toatargeted-onlyinoverallPCadetection(+16.7%overalldetectionrate,P=0.007).Although differencesinclinicallysignificantPCadetectionwerestatisticallynon-significant(P=0.13),a combinationapproachdidallowdetecting7extraclinicallysignificantPCas(+13.8%).

Conclusions.—InpatientswithelevatedPSAandpriornegativebiopsies,concurrentsystematic samplingmaybeneededatthetimeoftargetedbiopsyinordertomaximizePCadetection rate.Largerstudiesareneededtovalidateourﬁndings.

Levelofevidence.—4.

MOTSCLÉS Cancerdeprostate; Fusion

RMN/échographie; Biopsiescibléesde prostate;

Diagnostic

Résumé

Introductionetobjectifs.—Des biopsies ciblées guidées par IRM sont conseillées chez les patients quiontsubiunesérieinitiale debiopsies systématiquesnégativespour lesquelsle soupc¸ondecancerdela prostate(CaP)resteélevé.L’objectifdel’étude étaitd’évaluersi, chezleshommesayantdesbiopsiesantérieuresnégativesdelaprostate,denouvellesbiopsies systématiquessontégalementjustiﬁéesaumomentdesbiopsiesrépétéescibléesparIRM.

Matérieletméthodes.—Patientsayantbénéﬁciédebiopsies deprostateguidéesparfusion IRM/échographie en temps réel entre 2014 et 2016 après un set de biopsies négatives antérieures. Les patients avec aumoins une lésion index sur l’IRM multiparamétrique ont étéinclus.Touslespatientsadmissiblesonteuàlafoisdesbiopsiesaléatoiressystématiques (12—14)etdesbiopsiesciblées(2—4).

Résultats.—L’étudecomprenait74hommesavecunâgemédiande65ans,untauxdePSAde 9,27ng/mLetunvolumeprostatiquede45mL.LetauxglobaldedétectiondeCaPetletaux dedétectiondecancercliniquementsigniﬁcatifétaientrespectivementde56,7%et39,2%.

LesciblesontdémontréuntauxdedétectiondeCaPcliniquementsignificatifsimilaireàcelui desbiopsiessystématiques(33,8%contre28,4%,p=0,38)avecunéchantillonnagedetissus beaucoupmoinsimportant.UneapprochecombinéepermettaitunedétectionglobaledeCaP supérieureàuneapprochecibléeseule(+16,7%detauxdedétectionglobal,p=0,007).Bien quelesdifférencesdansladétectiondeCaPcliniquementsignificatifsoientstatistiquementnon significatives(p=0,13),uneapprochecombinéeapermisdedétecter7PCasupplémentaires cliniquementsignificatifs(+13,8%).

Conclusions.—Chezlespatientsprésentantdespremièresbiopsiesnégatives,laréalisationde biopsiessystématiques simultanéessemblenécessairedanslemêmetempsquedesbiopsies cibléesaﬁnd’améliorerletauxdedétectiondePCasigniﬁcatifs.

Niveaudepreuve.— 4.

Introduction

Prostate cancer (PCa) is the most frequent male non- cutaneous malignancy across Europe [1]. After multiple yearsofoverlyaggressivetreatment evenincasesoflow- risk, indolent cancer, today the urologic community is driving its attention to the identiﬁcation and treatment of clinically signiﬁcant PCa, advising to reduce detection

andpractice less morbid therapeutic options for indolent prostate PCa, in the light of the results of recent large, prospectivestudies[2].Inthissetting,multiparametricMRI (mp-MRI)has emergedasapromising tooltodiscriminate indolent from clinically signiﬁcant PCa, and recent trials [3]havereportedintriguingﬁndingswhichcouldreducethe numberofbiopsiesperformedacrossurologicdepartments, aswellasitsassociatedmorbidity.

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MRI-guidedtargetedprostatebiopsieshaveemergedasa promisingtechniquetoadequatelysampletheindexlesion detectedonmp-MRI,identifyingmoremenwithsignificant diseaseasopposedtosystematic biopsies.Severalstudies have demonstrated more homogeneousmapping and precise targeting of the index lesion in contemporary series [4,5]. Moreover,MRI-targetedbiopsiesallow amore accu- ratediagnosis of anterior andapical tumors [6].As such, inpatientsinwhominitialprostate biopsiesyieldednega- tiveresultsandpresentingnonethelessahighsuspicionfor neoplasia,currentguidelinesadvisetoperformmp-MRIand MRI-guidedbiopsies[7].However,inthisscenario,itremains poorlyunderstoodwhethermenshouldundergopurelyMRI- targetedbiopsies,orifanovelsystematicsamplingofthe prostaticglandshouldbeperformedalongwithMRI-guided targeted biopsies, in order toobtain the maximal detection of clinically significant PCa. Supporter of repeating systematicbiopsiesadvocatethepotentialaddedvalueof suchspecimensin ordertoavoid missingclinicallysignifi- cantPCa[8];ontheotherhand,someinvestigatorsdidnot findanyaddedvalueofreperformingstandardsamplingof theprostate,while thiscouldpotentially increase patient discomfort,bleeding,infectionrateandeventuallyleadto indolentcanceroverdiagnosis[9].Aimofthecurrentstudy wastoexploresuchclinicaldilemmainaprospectivebiopsy cohortatJules-BordetInstitute,whereMRI-targetedbiop- sieshavenowbeenimplementedforover5years.

Materials and methods Study population

Between 2012 and 2016, we prospectively enrolled all patientsundergoingMRI-guidedtargetedprostate biopsies in the Jules-Bordet Institute. The study wasapproved by the ethics committee of our institute (reference number CE2548).Theentirecohortincludes433men.Afterexclud- ing192biopsy-naïvepatients,153menwithknownPCaand 14patientswithnoidentiﬁablelesiononMRI,weselected 74meninwhomMRI-targetedbiopsywasperformeddueto prior negativebiopsy and persistent suspicion of PCa.All the patients included in the present study had only one negativebiopsy before inclusion. Patients had undergone a mp-MRI 3.0-T MRI with 4 sequences —– triplanar T2- weighted, dynamic contrast-enhanced, diffusion-weighted imaging,andMRspectroscopyeitherpriortotheinitialset ofbiopsiesofatleast8weeksafter.Imageswerereviewed byourcentralradiologist(ML),whoproceededtothedelim- itation of the regionof interest (ROI), and described the lesion(s)usingthePiRADSv2.0score[10].

Biopsy technique

MRI-guided targeted biopsies were performed by a single operator(AP),performing>100targetedbiopsies/yearand with>20yearsofexperienceinprostatebiopsy[11].Patients received ﬂuoroquinolone antibiotic prophylaxis following currentguidelines.Atransrectal,3Delasticfusionapproach wasusedtoperformthebiopsiesvia theKoelisUrostation [11].First,anelasticfusionofMRIandultrasoundvolumesis performed.Then,withtheROIhiddenandnotvisualized,a

12—14-coresystematicschemeisapplied,taking2biopsies atthebase,2atthemidand2attheapexforeachprostatic lobe.Moreover,2biopsiesareperformedinthetransitional zone.Oncethesystematicbiopsiesareperformed,theROI isﬁnallydisplayed,and2to4targetedbiopsiesaretakenin theROI.Thisapproachwasimplementedtoreduceobserver bias,astheoperatorislessawareofthelocalizationofthe ROIwhileperformingthestandard,systematicbiopsies.

Specimens were labeledseparately, fixed in paraffine, and sections were cut at 3␮m intervals. If cancer was detected,cancerlengthwasdescribedinmmandhistologic gradingwasaccordedfollowingGleasonscorebyadedicated uro-pathologist.ClinicallysignificantPCawasdefinedasany cancerGleason≥7and/orcancerlength≥6mmonasingle biopsy[12].This thresholdallowstodetectedover95% of PCapresentingavolume>0.5ml[12].

Statistical analysis

Inthepresentstudy,eachpatientwasusedasitsowncon- trol,inordertolimitselectionbias.Assuch,foreachpatient we identified systematic biopsies (TRUS B), MRI-guided fusiontargetedbiopsies (TargetedB)andthecombination ofthetwotechniques(TRUSB+TargetedB).McNemar’stest was used tocompare categoric variables, such as cancer detectionrate,numberofclinicallysignificantPCaaswell asindolent PCa. Univariate logistic regressionswere con- structedtoassessriskfactorsforthedetectionofclinically significant PCa. Variables explored included age (continuous), PSA (continuous, log transformed), DRE (categoric), prostatevolume(continuous),numberofpreviousbiopsies (categoric), high-grade prostatic intraepithelial neoplasia (HGPIN)onpreviousbiopsy(categoric)andaPiRADSscore of4—5onmp-MRI(categoric).AssociationswithP-valueless than0.05wereconsideredstatisticallysignificant.Allstatis- ticalanalyseswereperformedusingStata13.1(StataCorp, CollegeStation,TX).

Results

Overall characteristics of the cohort are illustrated in Table 1. Global PCa detection rate in this repeat biopsy

Table1 Generalcharacteristicsofthecohort.

Age(years)median(IQR) 65(62—69) PSA(ng/ml)median(IQR) 9.27(6.84—13.4) DRE

Normal,n(%) 59(80)

Abnormal,n(%) 15(20)

Prostatevolume(ml)median(IQR) 45(36—60) Timefromlastnegativebiopsy

(mo)median(IQR)

27(12—48) NumberofMRIdetectedlesionsper

patient(PiRADS>3)median(IQR)

Histologyofpriorbiopsy 1(1—2)

BPH,n(%) 37(50)

Chronicprostatitis,n(%) 21(28)

HGPIN,n(%) 13(18)

ASAP,n(%) 3(4)

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Table2 Detectionratesaccordingtobiopsyspecimenanalyzed.

OverallPCadetection IndolentPCa ClinicallysigniﬁcantPCa

TRUSBonly 44.6%(33/74) 16.2%(12/74) 28.4%(21/74)

TargetedBonly 47.3%(35/74) 13.5%(10/74) 33.8%(25/74)

Combination 56.8%(42/74) 17.6%(13/74) 39.2%(29/74)

TRUSB:randomizedTRUSbiopsiesonly;TargetedB:MRIguidedfusiontargetedbiopsiesonly;Combination:TRUSB+TargetedB.

Figure1. ProstatecancerdetectionrateofsystematicTRUSandcombinationbiopsies(TRUSB+TargetedB).

cohortwas57%(42/74),ofwhich69%(29/42)wereclinically signiﬁcant and 31% (13/42) wereindolent PCas (Table 2).

DetectionrateforPCaandforclinicallysignificantPCawas higher in the Combination(TRUS B+Targeted B)group as opposedtotheTRUSBgroupalone(Fig.1).Inparticular,our combinedapproachdetected 11% (29/42 vs. 21/42) more clinicallysignificantPCa,withastatisticallysignificantdif- ference(P=0.013),aswell asan increasedoverallcancer detection,withoutincreasingthenumberofindolentPCas detected.

When comparingonly biopsy specimens obtained via a standard systematic approach(TRUS B)tothose obtained onlywithaMRI-targetedstrategy(targetedB),wedidnot findanysignificantdifferencebetweenthetwotechniques (Fig.2). Although targeted biopsies did yield an absolute highernumberofclinicallysignificantPCadiagnoses(25vs.

21),thisdifferencewasnon-signiﬁcant(P=0.34).

Finallywe evaluatedthedetectiondifferencebetween a pure, MRI-targetedstrategy (TargetedB), andour combination technique (targeted B+TRUSB), inthe effort to explore whetheranovel setof systematicbiopsies should be performed at the moment of repeat targeted biopsy.

Indeed,acombination approachwassignificantlysuperior toatargeted-onlyinoverallPCadetection(+16.7%overall detectionrate,P=0.007) (Fig.3). Althoughdifferencesin clinically significant PCa detection were statistically non- significant (P=0.13), a combination approach did allow

to detect 7 extra clinically signiﬁcant PCas (+13.8%).

The increased detection rate obtained via a combination approachwas accompanied by a non-signiﬁcant (P=0.25) increaseinindolentcancerdetection,inparticular3extra indolentPCa(Table3).

Onunivariatelogisticregression(Table4),theonlysig- niﬁcantriskfactorforthedetectionofclinicallysigniﬁcant prostatecancerwasthepresenceofaPiRADS4—5lesionon mp-MRI.

Discussion

Currently,inpatients witha highsuspicionof PCaaftera firstsetof negativebiopsies,guidelinesadvisetoundergo mp-MRI,followedbysystematicandtargetedrepeatbiop- sies[7].Logically,itcouldseemobviousthatifcancerisnot detectedonafirstsetofsystematicbiopsies,itisunlikely tobefoundonasubsequentsetduringwhichtissueissam- pledfrom,theoretically,thesameglands.Indeed,multiple studieshavedemonstratedthesuperiorityofanMRIguided approachtorepeatsystematicbiopsy,inordertoenhance PCadetectionandreducemorbidity[13].Onecouldimagine thatifapatientistoundergoasecond,targetedprocedure, systematicbiopsiescouldprobablybeavoided,asprostatic tissuehasalreadybeen sampledin thefirst,negative,set ofbiopsies[8].Althoughthisreasoningmayseemcorrecton

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Figure2. ProstatecancerdetectionrateofsystematicTRUSandtargeted-onlybiopsies(TargetedB).

Figure3. Prostatecancerdetectionrateoftargeted-only(TargetedB)andcombinationbiopsies(TRUSB+TargetedB).

Table3 Comparingdetectionratesacrossbiopsytechniques.

Detectionrate,% Differenceacrosstechniques,%(95%CI) P Overallcancer(n=42)

TRUSBvs.targetedB 78.6vs.83.3 4.7(0—11.1) 0.8

Combinationvs.targetedB 100vs.83.3 16.7(9—33.8) 0.007

ClinicallysigniﬁcantPCa(n=29)

TRUSBvs.targetedB 72.4vs.86.2 13.8(1.2—33.8) 0.39

Combinationvs.targetedB 100vs.86.2 13.8(1.2—26.4) 0.13

Indolentprostatecancer(n=13)

TRUSBvs.targetedB 92.3vs.76.9 15.4(0—35) 0.79

Combinationvs.targetedB 100vs.76.9 23.1(0.2—46) 0.25

TRUSB:ranbdomizedTRUSbiopsiesonly;TargetedB:MRIguidedfusiontargetedbiopsiesonly;Combination:TRUSB+TargetedB.

atheoreticalbasis,wehypothesizedthatsystematicbiop- siesremainvitalincombinationwithatargetedapproach.In thepresentstudy,wepresentourpreliminaryresultsﬁnding thatindeedacombinedapproachtorepeatbiopsyis clin- icallymoreaccurateandshouldbepursued,asitallowsa signiﬁcantincreaseinPCadetection(+16%comparedtotar-

getedalone,P=0.007).CompletemappingofPCa,including theindexlesionandindolent cancer,mayhavesigniﬁcant impactoftherapeuticstrategy,includingactivesurveillance andfocaltherapy.

Initially,wewerequiteperplexedbythecurrentﬁndings:

indeedinourdepartmentweareﬁrmsupportersofmp-MRI

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Table4 Univariate logistic regression analyzing risk factorsforclinicallysigniﬁcantprostatecancer.

Univariate

OR 95%CI P

Age 1.05 0.97—1.13 0.27

PSA 1.04 0.96—1.12 0.36

DRE 2.82 0.89—9.0 0.08

Prostatevolume 0.98 0.96—1.01 0.22 HGPINonpreviousBx 0.85 0.23—3.08 0.8 NumberofpreviousBx 1.23 0.47—3.24 0.67

PiRADS4-5 28.7 6—138.4 <0.001

which we have been performingfrom>10 years; yet, the reportedresultssupportthe useof systematic biopsiesto targeted ones, which alone arenot signiﬁcantly superior.

The reasons for such ﬁndings areprobably multifactorial:

first, our singleoperator performingall biopsies (AP) has a vast experienceinprostate ultrasound and3D prostatic reconstruction.UsingtheKoelisUrostation,weareperform- ing3D reconstructionsoftheprostate, possiblyincreasing qualityand spatial distribution of thesystematic biopsies within the gland. As such, even standard, systematic 12- core biopsies could be more precise compared to those performedbyaurologistwithoutsuchbackground.Indeed, 3Dprostaticmapping hasdemonstrateditsinterestin the detectionof clinicallysignificant PCa[14,15].Infact, our detectionrates arehighertothosereportedbyinvestiga- torsusinga2Dtargetedsystem [16]:Sonnetal.reported anoverallcancerdetectionrateof34%(vs.56.8%inthecurrentstudy)and25%ofclinicallysignificantPCa(versus34%).

Second, patient and prostatic movementsmay determine modifications in the positioningof the ROI,thus reducing accuracyoftargetedbiopsies;Xuetal.havedemonstrated thepresence ofamodificationof upto4.3mmevenwith robot-assistedbiopsies[17].However,thankstotheorgan- trackingsystemofKoelis,thesemodifications areminimal andreducedto1.2mmbetweenthetheoreticalandthetrue target.Finally,mp-MRImaypresentfalsepositiveresultsin upto32%cases[18],thustargetedbiopsiesinfalselyposi- tiveareaswillinevitablyyieldinaccurateresults,rendering repeatsystematicbiopsiesstillfundamental.

Similarresults have been foundby other investigators.

A large meta-analysisevaluating 16 studies reported that targetedbiopsies hadahigher detectionrateof clinically significantPCa,andsubanalysisconfirmedthatthisdiffer- encewasstatisticallysignificantintherepeatbiopsysetting (relativesensitivity1.62,95%CI1.02—2.57)[19].Inaran- domized study, Panebianco et al. [20] similarly reported animproveddiagnosticyieldwithMRI-targetedbiopsiesin the setting of repeat prostate biopsy. Portalez et al., in patientswithapreviousnegativebiopsy,didfindmorepos- itive cores witha targeted strategy compared torandom biopsies(36.3%comparedwith4.9%,P<0.00001),although thestudywasnotdesignedtoexplore suchoutcome [21].

Similarly, Costaetal. reportedapositive biopsyin92%of men undergoinga targeted template comparedto23% in systematicbiopsy,with77%oftumorsdetectedexclusively in suspicious zonesonmp-MRI [22]. Overall,most studies

analyzingtherepeatbiopsyscenarioyieldedsimilarresults, inthatatargetedapproachappearstobesignificantlysupe- riorfor overall cancer detection and clinically significant PCa[23,24],thoughthedefinitionofthelattermayvary.

However,todate,fewreportshaveaddressedtheissue to whether, in addition to targeted biopsies, a set of standard 12-core systematic biopsies should also be performed.Moreover,anexpertpanelrecentlyreportedonthe topic,recommendingcautioninperformingsolelytargeted biopsiesinthissetting [25].Costaetal. analyzed32men withnegativetargetedbiopsiesinspiteofhighlysuspicious MRI,ﬁndingintermediateandhigh-riskPCain42%ofcases [26].

Someinvestigatorsinsteadadvocateagainstsystematic biopsiesatthetimeofrepeattargetedprocedure,giventhe lowaddedvalueof suchspecimens:Mendhirattaetal.[9]

publishedaseriesinwhichtargeted-onlybiopsiesdetected 92.3% of all signiﬁcant cancers of their cohort. Similarly, Salami [8] investigated the need for additional template biopsies during repeat targeted biopsy. In 140 men, they reportedanoveralldetectionrateof65%,missingonly3.5%

ofcancers.

Inthecurrentstudy,theonlyriskfactorforthedetection of clinicallysignificant PCaappeared tobe a radiological image highly suspicious for PCa (i.e. PiRADS≥4). Current literaturesupportsincreasinglytheuseofmp-MRI,evenin thesettingofbiopsynaïvepatients.Recently,theresultsof thePROMIStrialhavebeenreportedbyAhmedetal.[3]:576 biopsy-naïvemenunderwentmp-MMRIfollowedbyTRUSand targetedbiopsies.Theauthorsdemonstrated,inthisbiopsy naïve cohort, that mp-MRIhas an elevated sensitivity for thedetectionofclinicallysignificantPCa(93%).Performing ascreeningmp-MRIfor patientsbeforeTRUSbiopsycould reduce by 25% the number of useless, potentially morbid biopsies.Furthermore,the diagnosticprecision ofmp-MRI isenhancedatincreasingpercentageofGleason4pattern, givenits‘‘solid’’nature,andatincreasingsizeofPCa,thus makingitareliabletooltoscreenforsignificantcancerand reduceoverdiagnosisofindolentPCa.

Ourstudy is not devoid of limitations. First,the study is based on a small sample size, thus larger studies are neededtovalidatethefindings.Second,patientsweretheir owncontrols, introducing bias.However,this reducesthe differences,whichmayinevitablyexistwhencomparingto randomizedormatchedpairgroups.Third,thedefinitionof clinicallysignificantPCaisstillamatterofdebate;clearly, settingadifferentthresholdmaymodifyourresultsinone senseortheother.Ideally,allresultsshouldbecomparedto prostatectomyspecimen,inordertobefullyabletodefine the realpresence of clinically significant prostate cancer andconfirm the localization of the indextumor. As such, ourresults should be interpreted with caution,given the assumptionthat if noclinically significant PCawas found oncombinationbiopsy,thepatientdidnotharborclinically significantPCa.

Conclusions

Inthisprospective,singlecenterstudy,patientswithprior negativebiopsiesappearedtobeneﬁtfromtheinclusionof systematic biopsies to targeted cores. Although targeted

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biopsies seem to determine a superior diagnostic yield, omitting a standardized template at the time of repeat biopsycouldmissclinicallysigniﬁcantPCas.Largerstudies areneededtoconﬁrmourresults.

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol 2012;61(6):

1079—92.

[2]HamdyFC,DonovanJL,LaneJA,MasonM,MetcalfeC,Hold- ing P,et al.10-year outcomes aftermonitoring, surgery,or radiotherapy for localized prostate cancer. N Engl J Med 2016;375(15):1415—24.

[3]Ahmed HU, El-ShaterBosaily A, Brown LC,Gabe R, Kaplan R,ParmarMK,etal.Diagnosticaccuracyofmulti-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a pairedvalidatingconﬁrmatorystudy.Lancet2017;389(10071):

815—22.

[4]Volkin D, Turkbey B, Hoang AN, Rais-BahramiS, YerramN, Walton-Diaz A, et al. Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonography fusion- guided biopsy increase the detection of anteriorly located prostatecancers.BJUInt2014;114(6b):E43—9.

[5]CerantolaY,HabererE,TorresJ,AlameldinM,AronsonS,Lev- entalM,etal. AccuracyofcognitiveMRI-targetedbiopsyin hitting prostatecancer-positive regions ofinterest. World J Urol2016;34(1):75—82.

[6]Kim M,ChoiS-K, Park M,ShimM, SongC,Jeong IG,et al.

Characteristicsofanteriorlylocatedprostatecancerandthe usefulnessofmultiparametricmagneticresonanceimagingfor diagnosis.JUrol2016;196(2):367—73.

[7]MottetN,BellmuntJ,BollaM,BriersE,CumberbatchMG,De SantisM,etal.EAU-ESTRO-SIOGguidelinesonprostatecancer.

Part1:screening,diagnosis,andlocaltreatmentwithcurative intent.EurUrol2017;71(4):618—29.

[8]SalamiSS,Ben-LeviE,YaskivO,RynikerL,TurkbeyB,Kavoussi LR,etal.Inpatientswithapreviousnegativeprostatebiopsy and asuspicious lesiononmagneticresonance imaging,isa 12-corebiopsystillnecessaryinadditiontoatargetedbiopsy?

BJUInt2015;115(4):562—70.

[9]MendhirattaN,MengX,RosenkrantzAB,WysockJS,Fenster- maker M,HuangR, et al.Prebiopsy MRIandMRI-ultrasound fusion-targeted prostate biopsy in men with previous negative biopsies: impact on repeat biopsy strategies. Urology 2015;86(6):1192—8.

[10]BarentszJO,WeinrebJC,VermaS,ThoenyHC,TempanyCM, Shtern F, et al. Synopsis of the PI-RADS v2 guidelines for multiparametricprostatemagneticresonanceimagingandrec- ommendationsforuse.EurUrol2016;69(1):41—9.

[11]Peltier A, Aoun F, Lemort M, Kwizera F, Paesmans M, Van Velthoven R. MRI-targeted biopsies versus systematic transrectal ultrasound guided biopsies for the diagnosis of localizedprostatecancerinbiopsynaïvemen.BiomedResInt 2015;2015:571708.

[12]Ahmed HU, Hu Y, Carter T, Arumainayagam N, Lecornet E, Freeman A, et al. Characterizing clinically signiﬁcant prostatecancerusingtemplateprostatemappingbiopsy.JUrol 2011;186(2):458—64.

[13]SiddiquiMM,Rais-BahramiS,TurkbeyB,GeorgeAK,Rothwax J,ShakirN,etal.ComparisonofMR/ultrasoundfusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostatecancer.JAMA2015;313(4):390—7.

[14]Klein J, De Gorski A, Iselin C. [3D ultrasound guidance for prostate biopsywith MRI-image fusion]. RevMed Suisse 2013;9(409):2275—8.

[15]PeltierA,AounF,AlbisinniS,MarcelisQ,LedinhD,Paesmans M,etal.Resultsofacomparativeanalysisofmagneticreso- nanceimaging-targetedversusthree-dimensionaltransrectal ultrasoundprostatebiopsies: sizedoes matter.Scand JUrol 2016;50(3):144—8.

[16]Sonn GA, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P, et al. Value of targeted prostate biopsy using magneticresonance-ultrasoundfusioninmenwithpriorneg- ativebiopsyandelevatedprostate-speciﬁcantigen.EurUrol 2014;65(4):809—15.

[17]XuH,LassoA,GuionP,KriegerA,KaushalA,SinghAK,etal.

AccuracyanalysisinMRI-guidedroboticprostatebiopsy.IntJ ComputAssistRadiolSurg2013;8(6):937—44.

[18]Bratan F, Niaf E, Melodelima C, Chesnais AL, Souchon R, Mège-Lechevallier F, et al. Inﬂuence of imaging and histo- logicalfactorsonprostatecancerdetectionand localisation on multiparametric MRI: a prospective study. Eur Radiol 2013;23(7):2019—29.

[19]Schoots IG, Roobol MJ,Nieboer D, Bangma CH, Steyerberg EW,HuninkMGM.Magneticresonanceimaging-targetedbiopsy mayenhancethediagnostic accuracyofsigniﬁcantprostate cancerdetectioncomparedtostandardtransrectalultrasound- guidedbiopsy:asystematicreviewandmeta-analysis.EurUrol 2015;68(3):438—50.

[20]Panebianco V, Barchetti F, Sciarra A, Ciardi A, Indino EL, PapaliaR,etal.Multiparametricmagneticresonanceimaging vs.standardcareinmenbeingevaluatedforprostatecancer:

arandomizedstudy.UrolOncol2015;33(1):17e1—7.

[21]Portalez D, Mozer P, Cornud F, Renard-Penna R, Misrai V, ThoulouzanM,etal.ValidationoftheEuropeanSocietyofUro- genitalRadiologyscoringsystemforprostatecancerdiagnosis onmultiparametricmagneticresonanceimaginginacohortof repeatbiopsypatients.EurUrol2012;62(6):986—96.

[22]Costa DN,Bloch BN,Yao DF,Sanda MG, NgoL, Genega EM, et al. Diagnosis of relevant prostate cancer using supple- mentary cores from magnetic resonance imaging-prompted areasfollowingmultiplefailedbiopsies.MagnResonImaging 2013;31(6):947—52.

[23]Durmus T, Stephan C, Grigoryev M, Diederichs G, Saleh M, SlowinskiT,etal.[Detectionofprostatecancerbyreal-time MR/ultrasoundfusion-guidedbiopsy:3TMRIandstateofthe artsonography].ROFO FortschrGeb Rontgenstr Nuklearmed 2013;185(5):428—33.

[24]Puech P, Rouvière O, Renard-Penna R, Villers A, Devos P, ColombelM,etal.Prostatecancerdiagnosis:multiparametric MR-targetedbiopsywithcognitiveandtransrectalUS-MRfusion guidanceversussystematicbiopsy—–prospectivemulticenter study.Radiology2013;268(2):461—9.

[25]RosenkrantzAB,VermaS,ChoykeP,EberhardtSC,EggenerSE, GaitondeK,etal. Prostatemagneticresonanceimagingand magneticresonanceimagingtargetedbiopsyinpatientswitha priornegativebiopsy:aconsensusstatementbyAUAandSAR.

JUrol2016;196(6):1613—8.

[26]CostaDN,KayFU,PedrosaI,KolskiL,LotanY,RoehrbornCG, etal. Aninitialnegative roundoftargetedbiopsies inmen with highly suspicious multiparametric magnetic resonance ﬁndingsdoesnotexcludeclinicallysigniﬁcantprostatecancer- Preliminaryexperience.UrolOncol2017;35(4):149,http://dx.

doi.org/10.1016/j.urolonc.2016.11.006 [e15-149.e21 Epub 2016Dec9].