Review Article Confocal Laser Endomicroscopy in ...downloads.hindawi.com/journals/bmri/2016/4638683.pdfCancer Research Lab. ECM, Universit ´eParis-Est,ValdeMarneUPEC, C r ´eteil,

Review ArticleConfocal Laser Endomicroscopy inGastrointestinal and Pancreatobiliary Diseases:A Systematic Review and Meta-Analysis

Alessandro Fugazza,1 Federica Gaiani,1 Maria Clotilde Carra,2

Francesco Brunetti,3 Michaël Lévy,4 Iradj Sobhani,4,5 Daniel Azoulay,3

Fausto Catena,6 Gian Luigi de’Angelis,1 and Nicola de’Angelis3,5,7

1Unit of Gastroenterology and Digestive Endoscopy, University of Parma, 43100 Parma, Italy2University Paris VII-Denis Diderot, 75006 Paris, France3Unit of Digestive, Hepato-Pancreato-Biliary Surgery and Liver Transplantation,HenriMondorHospital, AP-HP, 94010Créteil, France4Department of Gastroenterology and Digestive Endoscopy, Henri Mondor Hospital, AP-HP, 94010 Créteil, France5Cancer Research Lab. EC2M3, Université Paris-Est, Val de Marne UPEC, 94010 Créteil, France6Emergency Surgery Department, University of Parma, 43100 Parma, Italy7Department of Advanced Biomedical Sciences, University Federico II of Naples, 80138 Naples, Italy

Correspondence should be addressed to Alessandro Fugazza; [email protected]

Received 6 September 2015; Accepted 31 December 2015

Academic Editor: Gerald J. Wyckoff

Copyright © 2016 Alessandro Fugazza et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Confocal laser endomicroscopy (CLE) is an endoscopic-assisted technique developed to obtain histopathological diagnoses ofgastrointestinal and pancreatobiliary diseases in real time.The objective of this systematic review is to analyze the current literatureon CLE and to evaluate the applicability and diagnostic yield of CLE in patients with gastrointestinal and pancreatobiliary diseases.A literature search was performed on MEDLINE, EMBASE, Scopus, and Cochrane Oral Health Group Specialized Register, usingpertinent keywords without time limitations. Both prospective and retrospective clinical studies that evaluated the sensitivity,specificity, or accuracy of CLE were eligible for inclusion. Of 662 articles identified, 102 studies were included in the systematicreview. The studies were conducted between 2004 and 2015 in 16 different countries. CLE demonstrated high sensitivity andspecificity in the detection of dysplasia in Barrett’s esophagus, gastric neoplasms and polyps, colorectal cancers in inflammatorybowel disease, malignant pancreatobiliary strictures, and pancreatic cysts. Although CLE has several promising applications, its usehas been limited by its low availability, high cost, and need of specific operator training. Further clinical trials with a particular focuson cost-effectiveness andmedicoeconomic analyses, as well as standardized institutional training, are advocated to implement CLEin routine clinical practice.

1. Introduction

Confocal laser endomicroscopy (CLE) is an endoscopicmodality that was developed to obtain very high magnifica-tion of the mucosal layer of the gastrointestinal (GI) tract [1],and it has the potential to enable histological diagnosis in realtime [2]. CLE is based on tissue illumination using a low-power laser and the subsequent detection of fluorescent light

that is reflected back from the tissue through a pinhole [3].The term “confocal” refers to the alignment of both illumi-nation and collection systems in the same focal plane [4, 5].In brief, the laser light is focused at a selected depth in thetissue of interest and reflected light is then refocused ontothe detection system by the same lens. Only the returninglight that is refocused through the pinhole is detected. Anylight that is reflected or scattered at other geometric angles

Hindawi Publishing CorporationBioMed Research InternationalVolume 2016, Article ID 4638683, 31 pageshttp://dx.doi.org/10.1155/2016/4638683

2 BioMed Research International

from the illuminated object or any light that is refocused outof plane with the pinhole is excluded from detection. Thisdramatically increases the spatial resolution of CLE andenables cellular imaging and evaluation of tissue architectureat the focal plane to be performed during endoscopy [1].

To obtain confocal images, exogenous fluorescence agentscan be administered either topically or systemically [6]. Themost common topical contrast agents that are applied by aspraying catheter are acriflavine and cresyl violet [7], whereasthe most widely used systemically administered fluorescentagent is intravenous fluorescein sodium. Fluoresceins are non-toxic, and their administration has been associated with onlyrare adverse events, including transient hypotension with-out shock (0.5%), nausea (0.39%), injection site erythema(0.35%), self-limited diffuse rash (0.04%), andmild epigastricpain (0.09%) [8].

There are two types of CLE: endoscope-based (eCLE) andprobe-based (pCLE) endomicroscopy. To perform eCLE, adedicated endoscope with a miniaturized confocal scannerintegrated into the distal tip is employed [9]. This systemwas developed by Pentax (Tokyo, Japan) and enables simul-taneous endoscopic imaging to be performed. Additionally,it frees the endoscopic working channel, and it can be usedfor targeted biopsies or combined enhancement techniques[9, 10]. Images can be collected by sectioning down throughthe mucosa in 7 𝜇m increments to a depth of 250𝜇m. Imagestabilization is necessary to obtain good quality images [11].The second system is pCLE (Cellvizio, Mauna Kea Tech-nologies, Paris, France). In this system, confocal miniprobescan be passed down the accessory channel of any standardendoscope [12], providing rapid image capture and “stitching”of adjacent images to create a “mosaic image” in real time [11].The advantages of pCLE are its versatility and the possibilityof combining it with other imaging modalities such as virtualchromoendoscopy or magnification [9]. Image stabilizationcan be achieved by using a plastic cap on the endoscope tip.There are several types of probes that are characterized bydifferent imaging depths, fields of view, and lateral resolutions(Supplementary Table S1 in Supplementary Material avail-able online at http://dx.doi.org/10.1155/2016/4638683). Morerecently, a novel needle-based CLE (nCLE) miniprobe (AQ-Flex 19; Mauna Kea) has been developed which can passthrough a 19G needle to perform endoscopic ultrasound-guided fine-needle aspiration (EUS–FNA) on solid organsand lymph nodes [13–16]. The probes can be reused after dis-infection for as many as 10 to 20 examinations [1].

CLE can be applied to examine luminal structures, suchas esophagus, stomach, and colon, and ductal structures, suchas bile and pancreatic ducts. Ultimately, CLE can be used tooptimize endoscopic diagnoses, thereby reducing unneces-sary resections, avoiding repeated biopsies and unnecessaryfollow-up, and indirectly decreasing the risks and costs thatare associated with repeated indiscriminative endoscopicexams. However, the interpretation of CLE images is stillchallenging. A standard classification system for distinguish-ing between normal and pathological GI conditions has onlybeen developed for p-CLE devices; it was termed the MiamiClassification, and it was based on a consensus that wasreached among p-CLE users during a meeting that was held

in Miami in 2009 [12]. Conversely, international recommen-dations and guidelines for other CLE systems have not yetbeen assessed.

The objective of the present systematic review is to sum-marize and analyze the current literature evaluating the sensi-tivity and specificity of this novel imagingmodality (i.e., CLE)in detecting mucosal abnormalities. In assessing the availableliterature, we aimed to highlight the utility of CLE in thediagnosis of gastrointestinal and pancreatobiliary diseases,particularly in the screening or surveillance of dysplastic andneoplastic lesions, and to consider its potential future impacton daily clinical practice.

2. Methods

The methodological approach included the definition ofsearch strategies, the development of selection criteria, anassessment of study quality, and the abstraction of relevantdata.The PRISMA statements checklist for systematic reviewreporting was followed.

2.1. Study Inclusion Criteria. The study selection criteria weredefined prior to initiating data collection to enable the properidentification of eligible studies for inclusion in the analysis.

The search was restricted to studies that were performedin humans and that were published in English. Prospectiveand retrospective clinical studies were both eligible for inclu-sion, and there were no limits based on trial duration. Reviewarticles, case reports, commentaries, editorials, letters, andconference abstracts were not considered. Likewise, ex vivostudies were excluded. Endoscopic applications of CLE wereonly considered if theywere being used to evaluate the follow-ing types of diseases/lesions: Barrett’s esophagus; squamouscell carcinoma; esophagitis; gastroesophageal reflux disease;gastric polyps; gastric atrophy and reactive metaplasia, dys-plasia, and neoplasia; Helicobacter pylori-related gastritis;inflammatory bowel disease (IBD); celiac disease; colonicneoplasm; colonic polyps; biliary duct disease; and benign ormalignant pancreatic diseases. To be eligible for inclusion, astudy must have included at least one of the following out-comes: sensitivity, specificity, positive predictive value (PPV),negative predictive value (NPV), accuracy, description ofCLE indications, or mucosal features found using CLE.

2.2. Literature Search Strategy. A literature search was per-formed using the following online databases: MEDLINE(through PubMed), EMBASE, Scopus, and Cochrane OralHealth Group Specialized Register. A grey literature searchwas also performed by using the OpenGrey database. Toincrease the probability of identifying all relevant articles, aspecific research equation was formulated for each database,using the following key words and/or MeSH terms: confocallaser endomicroscopy, CLE, endomicroscopy, gastrointesti-nal, esophagus, esophageal, bile duct, biliary, gastric, colon,colic, pancreatic, and pancreas. Additionally, reference listsfrom eligible studies and relevant review articles (not inclu-ded in the systematic review) were cross-checked to identifyadditional studies.

BioMed Research International 3

2.3. Study Selection and Quality Assessment. The titles andabstracts of the retrieved studies were independently andblindly screened for relevance by two reviewers (AlessandroFugazza and Federica Gaiani). A full article was retrievedwhen the information in the title and/or abstract appearedto meet the objective of this review. To enhance sensitivity,records were removed only when both reviewers excludedthe record at the title screening level. All disagreements wereresolved through discussionswith a third and fourth reviewer(Nicola de’Angelis, Michaël Lévy). Subsequently, two review-ers (Alessandro Fugazza, Federica Gaiani) independentlyperformed a full-text analysis and quality assessment of theselected articles. The Cochrane criteria, which are describedin the Cochrane Handbook for Systematic Reviews of Inter-ventions [17], were applied for randomized clinical trials,and the Newcastle-Ottawa Scale (NOS) [18] was used fornonrandomized studies.

2.4. Data Extraction and Analysis. The data that were extra-cted from the studies for inclusion in the systematic reviewwere processed for qualitative and possibly quantitative anal-yses. The data were collected and summarized based onwhether CLEwas applied for gastrointestinal or pancreatobil-iary diseases. Data that would enable us to perform “perpatient,” “per biopsy,” and “per lesion” analyses were sepa-rately extracted whenever available. A “per patient” analysiswas performed by comparing each patient’s final CLE out-come against their histopathological diagnosis; similarly, “perbiopsy” and “per lesion” analyses were conducted by com-paring images produced by CLE with the results of histologicbiopsies. All data extraction was performed by one author(Alessandro Fugazza) and was verified by a second author(Federica Gaiani), and a 100% rate of final agreement wasmaintained.

To performquantitative analysis, data on sensitivity, spec-ificity, PPV, NPV, and main findings were extracted from theeligible studies. If necessary and possible, outcome variableswere calculated by the authors based on the data that wereavailable in individually selected studies. Only on-site (i.e.,real-time) data of CLE imaging analysis were considered.Meta-analyses were performed using MetaDisc (version 5.2;Clinical Biostatistics Unit, Hospital Ramon y Cajal, Madrid,Spain) [19]. Heterogeneity was assessed using 𝐼2 statistics.

3. Results

All database searches were performed without time limituntil January 2015. Overall, the combined search identified662 articles (after removing duplicates); of these, 348 wererejected based upon title and abstract evaluation. Out of theremaining articles, which underwent full-text evaluations,212 were excluded because they either were not pertinent tothe review questions, had nonrelevant study designs, or hadlanguage limitations. A final total of 102 articles were con-sidered to be eligible for the systematic review and wereevaluated by both qualitative and quantitative analyses. Aflowchart of the study’s identification and inclusion/exclusionprocesses is shown in Figure 1.

3.1. Study Characteristics. The studies that were includedwere published between 2004 and 2015. They included 8RCTs, 85 prospective studies, and 9 retrospective studies.Twenty-eight (27.4%) studies were multicentric, with a maxi-mum of 8 centers included. The studies were conducted in 16different countries. The included single-center studies wereconducted in Asia (𝑛 = 33), Europe (𝑛 = 31), USA (𝑛 = 7),andOceania (𝑛 = 3); themulticentric studies were conductedin Europe + USA (𝑛 = 15), Europe + Asia (𝑛 = 2), Europe(𝑛 = 5), and the USA (𝑛 = 6).

Overall, the 102 included studies enrolled a total of 6943patients; the number of patients per study ranged from 4to 1572, with a median sample of 67.4 patients. The medianpatient age was 56.9 years (range: 0.7 to 90 years). All of thepatients that underwent CLE were administered intravenousfluorescein prior to the procedure.

The outcomes produced by CLE technology are hereafterclassified by organ of application, including esophagus, stom-ach, pancreas, biliary tree, and colon.

3.2. Esophagus. The most important application of CLE inthe esophagus is the surveillance and evaluation of suspiciouslesions in patients presenting with Barrett’s esophagus (BE)[20–31]. With regard to the detection of premalignant andmalignant transformations of metaplasia in BE patients, a“per biopsy” meta-analysis of 7 studies [20, 21, 23–26, 30]resulted in a pooled sensitivity of 58% (CI

95%: 52%–63%;𝐼2: 95.2%), a pooled specificity of 90% (CI

95%: 89%–91%;𝐼2: 96.9%), a pooled positive likelihood ratio (LR) of 11.57(CI95%: 5.38–24.89; 𝐼

2: 93.7%), and a pooled negative LR of0.23 (CI

95%: 0.08–0.64; 𝐼2: 98%).The area under the curvewas

0.9758. A “per patient” meta-analysis based on 4 studies [21,24, 30, 31] yielded a pooled sensitivity of 79% (CI

95%: 65%–90%; 𝐼2: 58.5%), a pooled specificity of 90% (CI

95%: 85%–94%;𝐼2: 82.9%), a pooled positive LR of 8.04 (CI

95%: 2.28–28.3; 𝐼2:

83.5%), and a pooled negative LR of 0.24 (CI95%: 0.08–0.69;

𝐼2: 55.4%). The area under the curve was 0.926 (Figure 2 andTable 1). Only anecdotal reports have described using CLEto detect the features of squamous cell carcinoma [32–34],reflux esophagitis [35], and nonerosive reflux disease (NERD)[36].These latter studies were not included in the quantitativeanalysis (Table 1).

3.3. Stomach and Duodenum. Theuse of CLE in patients pre-senting with gastric disease has raised great interest, particu-larly in Asian countries, where these pathologies are highlyprevalent. The primary applications of CLE with respect tothe stomach and duodenum have included the detection ofpolyps and neoplastic lesions and the study of gastritis andmetaplastic lesions [37, 41, 43, 44, 46, 47, 49, 51, 52, 54, 56];the application of CLE has also shown utility in patients withceliac disease [60–62] andHelicobacter pylori-related gastritis[58] (Table 2). The performance of this innovative techniquehas been evaluated both alone and in comparison or in addi-tion to other methods, such as endoscopic ultrasound (EUS)and narrow band imaging (NBI); however, the majority ofthese studies had descriptive aims and focused on the utilityof employing CLE in targeting biopsies [40, 48].With respect


Table1:Summaryof

thes

tudies

applying

CLEfore

soph

ageallesionscreeninganddiagno

sis(“perb

iopsy”

or“per

patie

nt”a

nalysis

).

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Barrett’sesop

hagus

Kiesslich

etal.200

6[20]

Germany

63patie

nts

156biop

sies

58.7

92.9

n/a

98.4

n/a

92.9

n/a

98.4

n/a

97.4

n/a

CLEmay

behelpfulinthem

anagem

ent

ofpatie

ntsw

ithBE

becauseg

astric,

Barrett’sepith

elium

,and

Barrett’s

associated

neop

lasticc

hanges

canbe

diagno

sedwith

high

accuracy.

Pohl

etal.

2008

[21]

Germany

38patie

nts

201b

iopsies

62.1

75 8057.9

94.1

n/a

44.4

91.7

98.8

60.9

93.3

CLEshow

edah

ighNPV

forthe

diagno

sisof

endo

scop

icallyinvisib

leneop

lasia

inBE

.Dun

bare

tal.2009

[22]

USA

39patie

nts

64n/a

n/a

n/a

n/a

n/a

CLEincreasesd

iagn

ostic

yield

for

neop

lasia

andredu

cesthe

numbero

fmucosalbiop

sies.

Wallace

etal.2010

[23]

USA

Germany

France

5patie

nts

20biop

sies

38–86

n/a

88n/a

96n/a

n/a

n/a

n/a

n/a

92

pCLE

hasv

eryhigh

accuracy

and

reliabilityforthe

diagno

sisof

neop

lasia

inBE

.

Bajbou

jet

al.2010

[24]

Germany

68patie

nts

703biop

sies

6060 12

95 9567 18

93 92n/a

n/a

pCLE

canbe

regarded

asno

ninferiorto

endo

scop

icbiop

sybu

t,foritslowPP

Vandsensitivity,m

aycurrently

notreplace

standard

biop

sytechniqu

esforthe

diagno

sisof

BEandassociated

neop

lasia

.

Sharmae

tal.2011

[25]

USA

France

Germany

101p

atients

874biop

sies

65.1

n/a

62.5

n/a

92.7

n/a

57.7

n/a

94.0

n/a

n/a

pCLE

combinedwith

HD-W

LEsig

nificantly

improved

thea

bilityto

detectneop

lasia

inBE

patie

ntsc

ompared

with

HD-W

LE.

Jayasekera

etal.2012

[26]

Austr

alia

50patie

nts

1117

biop

sies

66n/a

75.7

n/a

80.0

n/a

98.1

n/a

19.4

n/a

79.9

Minim

aladditio

nald

iagn

ostic

impactof

CLEaboveH

D-W

LEandNBI

inthe

assessmento

fBE.

Wallace

etal.2012

[27]

USA

France

UK

164patients

67.9

69.6

n/a

n/a

n/a

n/a

n/a

Thea

ddition

ofpC

LEto

high

-definitio

nwhitelight

imagingdo

esno

timprove

diagno

sticaccuracy

norc

linicalou

tcom

esin

patie

ntsu

ndergoingablationor

resectionforB

E.

Nguyenet

al.2012

[28]

USA

18patie

nts

72.6

n/a

n/a

n/a

n/a

n/a

Endo

scop

istsw

ithminim

alexperie

ncein

CLEcaneffectiv

elyusethistechn

olog

yfortargetedbiop

sy,decreasingthen

eed

forintense

tissues

amplingwith

out

loweringthed

iagn

ostic

yieldin

detecting

dysplasia

.


Table1:Con

tinued.

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Bertaniet

al.2013

[29]

Italy

100patie

nts

59.7

100

8367

100

n/a

Incident

dysplasia

canbe

morefrequ

ently

detected

bypC

LEthan

byHD-W

LEin

BE.Th

ehigherd

ysplasiadetectionrate

provided

bypC

LEcouldim

provethe

efficacy

ofBE

surveillancep

rogram

s.

Trovatoet

al.2013

[30]

Italy

48patie

nts

422biop

sies

5483.3

93.3

95.2

98.2

71.4

66.6

97.6

99.7

93.7

98.1

CLEcanprovideinvivo

diagno

sisof

Barretttum

or-associatedesop

hagus

leadingto

significantimprovem

entsin

screeningandmon

itorin

gof

invivo

BE.

Cantoet

al.2014

[31]

USA

Germany

192patie

nts

978biop

sies

6295 86

92 9377 65

98 9893 92

Real-timeC

LEandTB

after

HD-W

LEcanim

provethe

diagno

sticyieldand

accuracy

forn

eoplasiaandsig

nificantly

impactin

vivo

decisio

n-makingby

alterin

gthed

iagn

osisandguiding

therapy.

Squamou

scellcarcino

ma

Pech

etal.

2008

[32]

Germany

21patients

64100

87.5

93100

95

CLEisableto

providev

irtualh

istolog

yof

early

squamou

scell

cancersw

ithah

igh

degree

ofaccuracy

andcanfacilitater

apid

diagno

sisdu

ringroutinee

ndoscopy.

Liuetal.

2009

[33]

China

27patie

nts

61.1

n/a

n/a

n/a

n/a

n/a

CLEcanbe

used

todistinguish

cancerou

sfro

mno

rmalepith

elium,w

hich

givesit

potentialvalue

fore

arlydetectionof

esop

hagealcarcinom

a.

Iguchi

etal.2009

[34]

Japan

15patie

nts

65.9

n/a

n/a

n/a

n/a

n/a

Scoringandqu

antifi

catio

nof

CLEim

ages

may

beuseful

forthe

differential

diagno

sisanddeterm

inationof

superficialinvasio

nby

squamou

scell

carcinom

a.Re

fluxesop

hagitis,non

erosiver

eflux

disease(NER

D)

Venk

atesh

etal.2012

[35]

Australia

23patie

nts

7.6 12n/a

n/a

n/a

n/a

n/a

Measuremento

fthe

S-Pdistance

byCL

Ewill

enablereal-timed

iagn

osisof

GER

D-related

esop

hagitis

durin

gon

goingendo

scop

y.

Chuetal.

2012

[36]

China

46patie

nts

48.12

45.23

n/a

n/a

n/a

n/a

n/a

CLErepresentsau

sefuland

potentially

significantimprovem

ento

verstand

ard

endo

scop

yto

exam

inethe

microalteratio

nsof

thee

soph

agus

invivo.


Records identified throughMEDLINE database

Records identified throughScopus database searching

Records identified throughCochrane database

Records identified throughEMBASE database

Additional recordsidentified through other

Articles retained afterfull-text evaluation

348 records excludedbecause of being nonpertinentto the review question or not

eligible study design

212 articles excluded because of(i) being nonpertinent to the review

Studies included inqualitative synthesis

Studies using CLE inthe esophagus

Studies using CLE in thestomach and duodenum

Studies using CLE inthe biliary duct

Studies using CLEin the pancreas

Studies using CLEin the lower GI

(n = 314)

(n = 102)

(n = 17) (n = 26) (n = 44) (n = 10) (n = 5)

n = 12)(iii) language limitations (

(ii) being nonpertinent study designsquestion (n = 20)

Records retained after screening on title and abstract (n = 662)

sources (n = 0)searching (n = 89)searching (n = 0)(n = 27)searching (n = 546)

(n = 180)

Figure 1: Flow chart of the electronic literature search strategy using Medline, Scopus, Embase, and other sources.

to the detection and diagnosis of polyps and neoplasticlesions, a “per patient” meta-analysis was only possible for 3of the included studies [43, 45, 46], and it yielded a pooledsensitivity of 85% (CI

95%: 78%–91%; 𝐼2: 52.3%), a pooled

specificity of 99% (CI95%: 98%-99%; 𝐼

2: 92.9%), a pooledpositive LR of 16.49 (CI

95%: 1.48–183.19; 𝐼2: 96%), and a

pooled negative LR of 0.16 (CI95%: 0.08–0.35; 𝐼

2: 57.4%)(Figure 3).The area under the curve was 0.929.The estimateddiagnostic accuracy of CLE ranged from 85% to 98.8%. Withrespect to the study of gastritis and gastric metaplasia, 6studies [50, 51, 53–56]were included in the “per biopsy”meta-analysis, which resulted in a pooled sensitivity of 94% (CI

95%:92%–96%; 𝐼2: 54.8%), a pooled specificity of 95% (CI

95%:92%–97%; 𝐼2: 55.6%), a positive LR of 17.66 (CI

95%: 9.04–34.51; 𝐼2: 63.8%), and a negative LR of 0.07 (CI

95%: 0.04–0.12;𝐼2: 47.4%). The area under the curve was 0.9832 (Figure 4).

A meta-analysis of two studies regarding HelicobacterPylori-related gastritis [57, 58] yielded a pooled sensitivity of86% (CI

95%: 76%–93%; 𝐼2: 0%), a pooled specificity of 93%

(CI95%: 87%–97%; 𝐼

2: 2.6%), a positive LR of 11.28 (CI95%: 5.4–

23.57; 𝐼2: 15.5%), and a negative LR of 0.16 (CI95%: 0.09–0.27;

𝐼2: 0%) (Figure S1).

The use of CLE in assessing celiac disease, with respect tointraepithelial lymphocytes and villous atrophy, was provento have high sensitivity and specificity. A meta-analysisperformed on 3 studies [60–62] produced a pooled sensitivity

of 84% (CI95%: 72%–92%; 𝐼

2: 71.3%), a pooled specificity of94% (CI

95%: 85%–99%; 𝐼2: 66.4%), a positive LR of 9.9 (CI

95%:2.12–46.35; 𝐼2: 53.9%), and a negative LR of 0.15 (CI

95%: 0.04–0.52; 𝐼2: 45.2%). The area under the curve was 0.9691 (FigureS2).

3.4. Colon. There is a wide range of applications for the useof CLE in patients with colonic diseases. These include thedescription of elementary and pathognomonic lesions in IBD[63–75], the detection of dysplasia/neoplasia in healedmucosa in IBDpatients [76–81], and themicroscopic descrip-tion of colorectal polypoid lesions and neoplasms [82–102].Although they have been less extensively studied, additionalapplications of CLE include obtaining microscopic descrip-tions of mucosa in patients with irritable bowel syndrome(IBS) [105, 106], infectious colitis (i.e., clostridium difficileinfection) [104], and colitis associated with Graft versus HostDisease (GVHD) [103] (Table 3).

A meta-analysis of 4 studies [77, 79–81] that investigateddysplasia and neoplasia in IBD patients produced a pooled“per lesion” sensitivity of 80% (CI

95%: 61%–92%; 𝐼2: 84.5%),

a pooled specificity of 93% (CI95%: 89%–96%; 𝐼

2: 86.3%), apooled positive LR of 8.76 (CI

95%: 1.78–44.23; 𝐼2: 71.7%), and

a pooled negative LR of 0.25 (CI95%: 0.01–7.44; 𝐼

2: 96.2%).Thearea under the curve was 0.9630 (Figure 5). A meta-analysisof 7 studies that investigated colorectal neoplasms and polyps


Table2:Summaryof

thes

tudies

applying

CLEforg

astricanddu

odenallesio

nscreeninganddiagno

sis(“perb

iopsy”

analysisor

“per

patie

nt”a

nalysis

).

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Polyps

andneop

lasticlesions

ofthes

tomach

Kakejiet

al.2006

[37]

Japan

9patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

CLEcouldbe

anew

screeningtoolfor

early

detectionof

malignancy.

Kitabatake

etal.200

6[38]

Japan

27patie

nts

7081.8

97.6

n/a

n/a

97.4

CLEmay

allowvirtualbiopsyin

the

future

with

mores

tableimaging

cond

ition

.

Liuetal.

2008

[39]

China

24patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

CLEob

servations

ofvascular

architecture

may

beassistant

intheidentificatio

nof

early

gastr

oesoph

agealcancer.

Gheorgh

eetal.200

9[40]

Romania

11patie

nts

59.7

n/a

n/a

n/a

n/a

n/a

CLEandendo

scop

icultrasou

ndare

successfu

llyassociated

forh

istological

assessment,diseases

taging

,and

optim

altherapeutic

decisio

n.

Bann

oet

al.2010

[41]

Japan

29patie

nts

68.6

86.4

83.3

n/a

n/a

85

TheC

LEdiagno

sisof

them

ucin

phenotypeingastric

cancersw

aslim

ited

tointestinalandmixed

phenotypes

but

may

beuseful

forthe

diagno

sisof

mucin

phenotypea

nddifferentiald

iagn

osis.

Lietal.

2010

[42]

China

66patie

nts

17–81

n/a

n/a

n/a

n/a

90CL

Edemon

stratesh

ighaccuracy

ofdifferentiatin

ghyperplasticpo

lyps

and

adenom

as.

Lietal.

2010

[43]

China

108patie

nts

5777.8

81.8

n/a

n/a

n/a

CLEisan

acceptableandpo

tentially

useful

techno

logy

forthe

identifi

catio

nandgradingof

gastric

intraepithelial

neop

lasia

invivo.Th

ediagn

ostic

accuracy

needstobe

improved.

Jeon

etal.

2011[44]

Korea

31patie

nts

61.6

n/a

n/a

n/a

n/a

94.2

CLEdemon

stratesa

high

diagno

stic

accuracy

forg

astricepith

elialn

eoplasia.

Theu

seof

CLEcouldpo

ssiblyredu

cethe

numbero

funn

ecessary

biop

siesa

ndmistaken

diagno

sesb

eforee

ndoscopic

subm

ucosaldissectio

n.


Table2:Con

tinued.

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Jietal.

2011[45]

China

24patie

nts

61.2

100

89.5

n/a

n/a

91.7

CELhash

ighaccuracy

forp

redictionof

remnant

tissuea

ftere

ndoscopicm

ucosal

resectionandmay

lead

tosig

nificant

improvem

entsin

clinicalsurveillance

after

endo

scop

icresection.

Lietal.

2011[46]

China

1572

patie

nts

58.1

88.9

99.3

85.3

99.5

98.8

CLEcanbe

used

toidentifygastric

superficialcancer/H

GIN

lesio

nswith

high

valid

ityandreliability.

Lim

etal.

2011[47]

China

36patie

nts

>50

95.2

93.3

n/a

n/a

n/a

Experie

nceinCL

Ewas

associated

with

greatera

ccuracyin

thed

iagn

osisof

gastric

intestinalmetaplasia

.

Wangetal.

2012

[48]

China

59patie

nts

63.1

90.6

84.6

n/a

n/a

88

CLEdemon

stratesh

ighdiagno

stic

accuracy,sensitivity,and

specificityfor

diagno

sticcla

ssificatio

nof

gastric

intraepithelialn

eoplasia.

Boketal.

2013

[49]

Korea

46patie

nts

65.3

n/a

n/a

n/a

n/a

91.7

pCLE

canprovidea

naccuratediagno

sisforsup

erficialgastricneop

lasia

,and

ithas

thep

otentia

ltocompensatefor

the

inherent

limitatio

nsof

acon

ventional

endo

scop

icbiop

sy.

Gastritisa

ndgastric

metaplasia

Guo

etal.

2008

[50]

China

53patie

nts

267biop

sies

51.2

n/a

98.1

n/a

95.3

n/a

96.9

n/a

97.14

n/a

n/a

CLEisau

sefuland

potentially

impo

rtant

metho

dforthe

diagno

sisand

classificatio

nof

gastric

intestinal

metaplasia

invivo.

Jietal.

2011[51]

China

76patie

nts

145biop

sies

48.8

n/a

86.2

n/a

97.4

n/a

89.3

n/a

96.6

n/a

92.8

CLEisuseful

foridentify

inggastric

metaplasia

.Thesefi

ndings

couldhave

potentialapp

licabilityford

uodenal

screeningandsuggesta

possibletargeting

therapyin

functio

nald

yspepsia.

Jietal.

2012

[52]

China

42patie

nts

50.4

n/a

n/a

n/a

n/a

n/a

CLEallowsfun

ctionalimagingof

mucosalbarrierd

efects.

Gastricintestinal

metaplasia

isassociated

with

anim

paire

dparacellu

larb

arrie

rirrespectiveo

fH.

pylorieradication.


Table2:Con

tinued.

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Lim

etal.

2013

[53]

China

20patie

nts

125biop

sies

62.5

n/a

90.9

n/a

84.7

n/a

n/a

n/a

n/a

n/a

88

pCLE

was

superio

rtoautoflu

orescence

imagingandwhite-lightend

oscopy

for

diagno

singgastric


.Off-siter

eviewim

proved

perfo

rmance

ofpC

LE.

Pitta

yano

netal.2013

[54]

Thailand

60patie

nts

120biop

sies

62.8

n/a

96n/a

90n/a

86n/a

97n/a

92

Com

bining

pCLE

with

magnifying

flexibles

pectralimagingcolor

enhancem

ent(ME-FICE

)providesh

igh

sensitivityandNPV

forg

astricintestinal

metaplasia

detection.

Thep

rompt

histo

logy

readingby

thistechniqu

emay

avoidun

necessarybiop

sy.

Lietal.

2014

[55]

China

168patients

492biop

sies

55n/a

91.6

n/a

96.7

n/a

n/a

n/a

n/a

n/a

n/a

CLEwith

targeted

biop

siesissup

eriorto

white-lightend

oscopy

with

standard

biop

siesfor

thed

etectio

nandsurveillance

ofgastric


.The

numbero

fbiopsiesn

eededto

confi

rmgastric


isabou

ton

e-third

ofthatneeded

with

white-light

endo

scop

ywith

stand

ardbiop

sies.

Liuetal.

2015

[56]

China

87patie

nts

130biop

sies

49.7

n/a

91.9

n/a

96.8

n/a

90.4

n/a

97.3

n/a

95.6

CLEisreliablefor

real-timea

ssessm

ento

fatroph

icgastritisandisalso

ableto

differentiatemetaplasticfro

mno

nmetaplasticatroph

y.Helicobacter

pylorirelated

gastritis

Jietal.

2010

[57]

China

103patie

nts

48.4

89.2

95.7

94.3

91.7

92.8

CLEdu

ringendo

scop

ycanaccurately

identifyspecificc

ellulara

ndsubcellular

changeso

fthe

surfa

cegastr

icmucosa

indu

cedby

H.pyloriinfectio

n.

Wangetal.

2010

[58]

China

118patie

nts

49.8

82.9

90.9

n/a

n/a

n/a

CLEcanaccuratelyshow

theh

istological

severityof

H.pyloriinfectio

n-associated

gastritis.


Table2:Con

tinued.

Author

andyear

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Duo

denalinfl

ammatorybo

weldisease

Lim

etal.

2014

[59]

Germany

Japan

UK

25patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

CLEcandetectepith

elialdamagea

ndbarrierlossinthed

uodenu

mof

Croh

n’sDise

asea

ndUlce

rativ

eColitisp

atients

thatisno

tapp

arento

nconventio

nal

endo

scop

yor

histo

logy.

Celiac

disease

Leon

get

al.2008

[60]

Australia

31patie

nts

4194

92n/a

n/a

n/a

CLEcaneffectiv

elydiagno

seandevaluate

celiacd

iseases

everity

invivo

with

potentialtoim

provee

ndoscopy

efficiency.

Gün

ther

etal.2010

[61]

Germany

60patie

nts

5773

100

n/a

n/a

n/a

Thea

ssessm

ento

fduo

denalh

istologyby

CLEin

patientsw

ithceliacd

iseaseis

sensitive

andspecificindeterm

ining

increasednu

mbersof

intraepithelial

lymph

ocytes

andvillo

usatroph

ybu

tinsufficientinrespecto

fcrypt

hyperplasia

.For

routineu

seof

CLEin

patie

ntsw

ithceliacd

isease,thetechn

ique

wou

ldneed

tobe

improved.

Venk

atesh

etal.2010

[62]

UK

19patie

nts

8.35

100

8081

n/a

n/a

CELoff

ersthe

prospectof

diagno

sisof

celiacd

iseased

uringon

goingendo

scop

y.Italso

enablestargetin

gbiop

siesto

abno

rmalmucosaa

ndtherebyincreasin

gthed

iagn

ostic

yield,especiallywhen

villo

usatroph

yispatchy

inthe

duod

enum

.𝑁

stands

forthe

numbero

fpatientse

nrolledin

thestu

dy;n

/a,n

otavailableor

notapp

licable;p

CLE,

prob

e-basedconfocallasere

ndom

icroscop

y;CL

E,confocallasere

ndom

icroscop

y;PP

V,po

sitivepredictiv

evalue;NPV

,negativep

redictivev

alue;and

BE,B

arrett’se

soph

agus.


Table3:Summaryof

thes

tudies

evaluatin

gCL

Ein

lower

gastrointestinaldiseases

creening

anddiagno

sis(“perp

atient”a

nd“per

lesio

n”analysis).

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Inflammatorybo

weldisease

Watanabee

tal.2008[63]

Japan

31patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

Images

obtained

with

CLEprovide

equivalent

inform

ationto

conventio

nal

histo

logy.

Trovatoetal.

2009

[64]

Italy

18patie

nts

253lesio

ns70

n/a

94.1

n/a

100

n/a

n/a

n/a

n/a

n/a

94.4

Endo

microscop

ymay

behelpfulinthe

evaluatio

nof

morph

ologicchangesinileal

pouch.

Lietal.2010

[65]

China

73patie

nts

50.4

n/a

n/a

n/a

n/a

n/a

CLEisreliablefor

real-timea

ssessm

ento

finflammationactiv

ityin

UCby

evaluatio

nof

cryptarchitecture,microvascular

alteratio

ns,and

fluorescein

leakage.

Liuetal.2011

[66]

Canada

USA

57patie

nts

46.6

n/a

n/a

n/a

n/a

n/a

Epith

elialgap

density

visualized

byCL

Eis

significantly

increasedin

patie

ntsw

ithIBD

comparedwith

controls.

Mou

ssatae

tal.2011[67]

France,

Germany,

andUK

21patie

nts

26lesio

nsn/a

n/a

89n/a

100

n/a

100

n/a

80n/a

92.3

CLEisan

ewtoolthatcanim

age

intram

ucosalbacteriain

vivo

inpatie

nts

with

IBD.

Kiesslich

etal.2012[68]

Germany,

France,U

K,andCh

ina

58patie

nts

n/a

62.5

91.2

n/a

n/a

79

Cell

shedding

andbarrierlossd

etectedby

CLEpredictrelapse

ofIBDandhave

potentialasa

diagno

stictoolforthe

managem

ento

fthe

disease.

Kraussetal.

2012

[69]

Germany

146patie

nts

34.9

n/a

n/a

n/a

n/a

n/a

CLEallowsthe

analysisof

thes

ubsurfa

cestr

ucture

oflymph

oidfollicle

s,those

surrou

nded

byar

edrin

gmay

representan

early

markero

fCD.

Neumannet

al.2012[70]

Germany

72patie

nts

39n/a

n/a

n/a

n/a

n/a

CLEhasthe

potentialtosig

nificantly

improved

iagn

osisof

CDcomparedwith

standard

endo

scop

y.

Turcotteetal.

2012

[71]

Canada,U

SA41

patie

nts

41.1

n/a

n/a

n/a

n/a

n/a

Increasedepith

elialgaps

inthes

mall

intestinea

sdetermined

bypC

LEarea

predictorfor

future

hospita

lizationor

surgeryin

IBDpatie

nts.

Musqu

eret

al.2013[72]

France,U

SA16

patie

nts

35.5

n/a

n/a

n/a

n/a

n/a

CLEallowsq

uantitativ

eanalysis

ofcolonic

pitstructure

inhealthyandCD

patie

nts.


Table3:Con

tinued.

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Atreya

etal.

2014

[73]

Germany

25patie

nts

41.6

n/a

n/a

n/a

n/a

n/a

Molecular

imagingwith

fluorescent

antib

odiesh

asthep

otentia

ltopredict

therapeutic

respon

sestobiological

treatmentinCD

andautoim

mun

eor

inflammatorydisorders.

Buda

etal.

2014

[74]

Italy,

Germany,

andUK

38patie

nts

52n/a

n/a

n/a

n/a

n/a

Invivo

intram

ucosalchangesd

etectedby

CLEin

UCremittentp

atientsc

anpredict

diseaser

elapse.

Lietal.2014

[75]

China

43patie

nts

4495.7

85n/a

n/a

90.7

CLEiscomparabletoconventio

nalhistolog

yin

predictin

grelap

sein

patie

ntsw

ithUC.

Dysplasia/neoplasiain

inflammatorybo

weldisease

Hurlston

eet

al.2007[76]

UK

36patie

nts

56n/a

n/a

n/a

n/a

97

Adenom

aLikeM

assesa

ndDisp

lasia

AssociatedLesio

nalM

assesc

anbe

differentiatedby

CLEwith

ahighoverall

accuracy

inpatie

ntsw

ithUlcerativeC

olitis.

Kiesslich

etal.2007[77]

Germany

153patie

nts

134lesio

ns44

n/a

94.7

n/a

98.3

n/a

90n/a

99.1

n/a

97.8

Chromoscopy-guidedendo

microscop

ycan

determ

ineifU

lcerativ

eColitissho

uld

undergobiop

syexam

ination,

increasin

gthe

diagno

sticyieldandredu

cing

then

eedfor

biop

syexam

inations.

Gün

ther

etal.

2011[78]

Germany

150patie

nts

48.3

n/a

n/a

n/a

n/a

n/a

CLEtargeted

biop

siesled

tohigh

erdetectionrateso

fintraepith

elialn

eoplasiain

patie

ntsw

ithlong

-stand

ingUC.

Hlavatyetal.

2011[79]

Slovakia

30patie

nts

68lesio

nsn/a

n/a

100

n/a

98.4

n/a

66.7

n/a

100

n/a

n/a

CLEtargeted

biop

siesa

resuperio

rto

rand

ombiop

siesinthes

creening

ofintraepithelialn

eoplasiain

patie

ntsw

ithinflammatorybo

weldisease.

vanden

Broeketal.

2011[80]

Netherla

nds

22patie

nts

87lesio

ns54

n/a

65n/a

82n/a

n/a

n/a

n/a

n/a 81

pCLE

forU

Csurveillanceisfeasib

lewith

reason

ablediagno

sticaccuracy.

Rispoetal.

2012

[81]

Italy

51patie

nts

14biop

sies

52n/a

100

n/a

90n/a

83n/a

100

n/a

n/a

CLEisan

accuratetoolforthe

detectionof

dysplasia

inlong

-stand

ingUlce

rativ

eColitis,lim

iting

then

eedof

biop

sies.


Table3:Con

tinued.

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Colorectaln

eoplasmsa

ndpo

lyps

Kiesslich

etal.200

4[82]

Germany

42patie

nts

390lesio

ns64

.2n/a

97.4

n/a

99.4

n/a

n/a

n/a

n/a

n/a

99.2

CLEenables

virtualh

istologyof

neop

lastic

changesw

ithhigh

accuracy,optim

izing

diagno

sisdu

ringcolono

scop

y.

Odagietal.

2007

[83]

Japan

45patie

nts

63n/a

n/a

n/a

n/a

n/a

CEM

provides

endo

scop

istsw

ithav

aluable

newdiagno

stictoo

l,foro

bserving

tissuein

situattheh

istop

atho

logicallevel,

allowing

evaluatio

nof

physiologicalfun

ctiondu

ring

endo

scop

icexam

ination.

Wangetal.

2007

[84]

USA

54patie

nts

n/a

9187

n/a

n/a

89CL

Eprovides

invivo

realtim

epatho

logical

interpretatio

nof

tissue.

Buchnere

tal.

2010

[85]

USA

75patie

nts

119lesio

ns73

n/a

88n/a

76n/a

n/a

n/a

n/a

n/a

n/a

CLEdemon

stratesh

ighersensitivity

than

chromoend

oscopy

with

similarspecificity

indifferentiatin

gcolorectalpo

lyps.

DeP

almae

tal.2010[86]

Italy

20patie

nts

32lesio

ns62.5

n/a

100

n/a

84.6

n/a

90.5

n/a

100

n/a

92.3

pCLE

perm

itshigh

-qualityim

aging

enablin

gpredictio

nof

intraepithelial

neop

lasia

with

high

levelofaccuracy.

Góm

ezetal.

2010

[87]

USA

,Netherla

nds,

andGermany

53patie

nts

75lesio

nsn/a

n/a

76n/a

72n/a

n/a

n/a

n/a

n/a 75

Aninternationalcollabo

ratio

ngrou

phad

mod

eratetogood

interobservera

greement

usingap

CLEsyste

mto

predictn

eoplasia.

Sand

uleanu

etal.2010

[88]

Netherla

nds

72patie

nts

116lesio

ns72

n/a

97.3

n/a

92.8

n/a

n/a

n/a

n/a

n/a

95.7

C-CL

Eaccuratelydiscrim

inates

adenom

atou

sfrom

nonadeno

matou

scolorectalpo

lyps

andenablese

valuationof

degree

ofdysplasia

durin

gon

going

endo

scop

y.

Xiee

tal.2011

[89]

China

115patie

nts

115lesio

ns51.6

n/a

93.9

n/a

95.9

n/a

96.9

n/a

92.2

n/a

n/a

Endo

scop

eintegratedCL

Ewith

fluorescein

staining

may

reliablyassistinther

eal-tim

eidentifi

catio

nof

colonica

deno

mas.

And

réetal.

2012

[90]

USA

,France

71patie

nts

135lesio

ns75

n/a

91.4

n/a

85.7

n/a

n/a

n/a

n/a

n/a

89.6

Thep

ropo

sedsoftw

arefor

automated

classificatio

nof

pCLE

videos

ofcolonic

polyps

achieves

high

perfo

rmance,

comparabletothatof

offlined

iagn

osisof

pCLE

videos

establish

edby

expert

endo

scop

ists.


Table3:Con

tinued.

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Cârţânăe

tal.

2012

[91]

Romania

4patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

Imagingof

bloo

dvessels

with

CLEisfeasible

inno

rmalandtumor

colorectaltissueb

yusingflu

orescentlylabeledantib

odies

targeted

againstanendo

thelialmarker.Th

emetho

dcouldbe

transla

tedinto

thec

linical

setting

form

onito

ringof

antia

ngiogenic

therapy.

Coron

etal.

2012

[92]

France

USA

16patie

nts

13lesio

ns62

n/a

n/a

n/a

n/a

n/a

Standard

colonicb

iopsieso

btaineddu

ring

CLEretain

fluorescein,sho

wexcellent

delin

eatio

nof

mucosalstructures

with

out

additio

nalstaining,allowthee

valuationof

mucosalmicrovasculaturea

ndvascular

perm

eability,andares

uitablefor

immun

ostaining.

Kuiper

etal.

2012

[93]

Netherla

nds

64patie

nts

154lesio

ns59

n/a

57.1

n/a 71

n/a

n/a

n/a

n/a

n/a

66.7

Them

ajority

ofp-CL

Evideos

demon

strated

insufficientq

ualityin

morethanhalfof

the

timer

ecorded.Po

stho

caccuracyof

p-CL

Ewas

significantly

lower

incomparis

onwith

real-timea

ccuracyof

CLEandNBI.

Mascoloetal.

2012

[94]

Italy

22patie

nts

61.6

n/a

n/a

n/a

n/a

n/a

Byp-CL

E,itispo

ssibleto

identifyspecific

cryptarchitecturem

odificatio

nsassociated

with

changesincellu

larinfi

ltrationand

vesselsa

rchitecture,high

lightingag

ood

correspo

ndence

betweenp-CL

Efeatures

andhisto

logy.

Shahid

etal.

2012

[95]

USA

74patie

nts

154lesio

ns69

n/a 81

n/a

76n/a

78n/a

79n/a

79

Real-timea

ndoffl

ineinterpretations

ofp-CL

Eim

ages

arem

oderately

accurate.

Real-timeinterpretationisslightly

less

accuratethan

offlined

iagn

osis.


Table3:Con

tinued.

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Shahid

etal.

2012

[96]

USA

65patie

nts

130lesio

ns69

n/a

86n/a

78n/a

n/a

n/a

n/a

n/a

82

p-CL

Edemon

stratedhigh

ersensitivityin

predictin

ghisto

logy

ofsm

allp

olyps

comparedwith

NBI,w

hereas

NBI

had

high

erspecificity.W

henused

incombinatio

n,thea

ccuracyof

pCLE

andNBI

was

extre

mely

high

,app

roaching

the

accuracy

ofhisto

patholog

y.

Shahid

etal.

2012

[97]

USA

,Netherla

nds

92patie

nts

129lesio

ns70

n/a

97n/a

77n/a 55

n/a

99n/a 81

Con

focalend

omicroscop

yincreasesthe

sensitivityford

etectin

gresid

ualn

eoplasia

after

colorectalEM

Rcomparedwith

endo

scop

yalon

e.In

combinatio

nwith

virtualchrom

oend

oscopy,the

accuracy

isextre

mely

high

,and

sensitivityapproaches

thatof

histo

patholog

y.

Góm

ezetal.

2013

[98]

USA

85patie

nts

127lesio

ns72

n/a

43.4

n/a

70.6

n/a

18.6

n/a

89n/a

n/a

Thea

ttempt

atcreatin

gcla

ssificatio

ncriteria

forp

robe-based

CLEdidno

tcon

sistently

distinguish

advanced

from

nonadvanced

adenom

asand,therefore,isno

tusefulin

applying

a“diagno

se,resect,anddiscard”

strategy.

Liuetal.2013

[99]

China

71patie

nts

166lesio

ns57.6

n/a

97.1

n/a

96.9

n/a

n/a

n/a

n/a

n/a

97.6

CLEhasthe

potentialtoenablean

immediatediagno

sisof

CRCandthed

egree

ofdifferentiatio

nof

CRCdu

ringon

going

endo

scop

yin

vivo.

Liuetal.2013

[100]

China

37patie

nts

37lesio

ns70

n/a

n/a

n/a

n/a

n/a

CLEcouldbe

used

inmolecular

imaging

with

specifictargetin

gof

EGFR

incolorectal

neop

lasia

.


Table3:Con

tinued.

Author

and

year

Cou

ntry

𝑁Meanageo

rrange

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Ciocâlteuet

al.2014[101]

Romania

5patie

nts

n/a

n/a

n/a

n/a

n/a

n/a

Differencesinvesselsm

orph

olog

ywith

CLE

areu

sefulfor

identifying

patie

ntsw

homight

benefit

from

neoadjuvantang

iogenetic

therapy.

Yuan

etal.

2014

[102]

China

39patie

nts

50lesio

ns52

n/a

79n/a

83n/a

n/a

n/a

n/a

n/a 81

Threed

ifferentcon

focallaser

endo

microscop

y(C

LE)d

iagn

ostic

syste

ms

inclu

ding

Maiz,Sand

uleanu

,and

Qilu

for

thep

redictionof

colorectalhyperplastic

polypor

adenom

ahavea

high

accuracy,

sensitivity,and

specificity.

Graftversus

HostD

isease

Bojarskietal.

2009

[103]

Germany

35patie

nts

n/a

74100

n/a

n/a

n/a

CLEprovides

rapiddiagno

sisof

acute

intestinalGVHDwith

high

accuracy

while

perfo

rmingendo

scop

y.Infectious

colitis

Neumannet

al.2013[104]

Germany

10patie

nts

72.5

88.9

97.2

8098.6

96.25

CLEhasthe

potentialfor

invivo

diagno

sisof

CDIa

ssociatedcolitis.

Inadditio

n,CL

Eallowed

thed

etectio

nof

intram

ucosal

bacteriain

vivo.

Irritablebo

welsynd

rome

Turcotteetal.

2013

[105]

Canada

34patie

nts

45.1

6289

8373

n/a

Asa

resultof

CLEanalysis,

IBSpatie

ntsh

ave

significantly

moree

pithelialgapsintheir

smallintestin

ecom

paredwith

healthy

controls,

which

may

beac

ause

ofaltered

intestinalperm

eabilityob

served

inIBS.

Fritscher-

Ravens

etal.

2014

[106]

Germany

USA UK

36patie

nts

44.6

n/a

n/a

n/a

n/a

n/a

Basedon

CLEanalysisof

IBSpatie

ntsw

itha

suspectedfood

intolerance,expo

sure

tocand

idatefoo

dantig

ensc

ausedim

mediate

breaks,increased

intervillou

sspaces,and

increasedIELs

intheintestin

almucosa.

CLEsta

ndsfor

confocallasere

ndom

icroscop

y;p-CL

E,prob


ndom

icroscop

y;c-CL

E,colonprob


ndom

icroscop

y;UC,

UlcerativeColitis;IBD,infl

ammatorybo

wel

disease;CD

,Crohn’sdisease;NBI,n

arrowbind

ingim

aging;GVHD,G

raftversus

HostD

isease;PP

V,po

sitivep

redictivev

alue;N

PV,n

egativep

redictivev

alue;and

BE,B

arrett’se

soph

agus.


0 0.2 0.4 0.6 0.8 1

Sensitivity

Pohl et al. 2008Bajbouj et al. 2010Trovato et al. 2013Canto et al. 2014

Sensitivity (95% CI)0.75 (0.19–0.99)0.61 (0.36–0.83)0.83 (0.36–1.00)0.95 (0.75–1.00)

Pooled sensitivity = 0.79 (0.65 to 0.90)𝜒2 = 7.22; df = 3 (p = 0.0651)Inconsistency (I2) = 58.5%

(a)

0 0.2 0.4 0.6 0.8 1

Specificity

Specificity (95% CI)Pohl et al. 2008Bajbouj et al. 2010Trovato et al. 2013Canto et al. 2014

0.58 (0.33–0.80)0.96 (0.86–1.00)0.95 (0.84–0.99)0.92 (0.83–0.97)

Pooled specificity = 0.90 (0.85 to 0.94)𝜒2 = 17.56; df = 3 (p = 0.0005)Inconsistency (I2) = 82.9%

(b)

0.01 1 100.0

Positive LR


Positive LR (95% CI)1.78 (0.82–3.86)14.97 (3.67–61.11)17.50 (4.32–70.90)11.72 (5.41–25.40)

Random effects modelPooled positive LR = 8.04 (2.28 to 28.30)

Inconsistency (I2) = 83.5%𝜏2 = 1.3351

18.18; df = 3 (p = 0.0004)Cochran-Q =

(c)

0.01 1 100.0

Negative LR


Negative LR (95% CI)0.43 (0.08–2.46)0.41 (0.23–0.73)0.18 (0.03–1.05)0.05 (0.01–0.37)

Random effects modelPooled negative LR = 0.24 (0.08 to 0.69)

Inconsistency (I2) = 55.4%𝜏2 = 0.6301

Cochran-Q = 6.73; df = 3 (p = 0.0809)

(d)

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curve

Symmetric SROCAUC = 0.9260SE(AUC) = 0.0576Q∗ = 0.8603SE(Q∗) = 0.0679

(e)

Figure 2: “Per patient” meta-analysis for CLE application in Barrett’s esophagus: (a) pooled sensitivity, (b) pooled specificity, (c) pooledpositive likelihood ratio (LR), (d) pooled negative LR, and (e) summary receiver operatic characteristic (SROC).

produced a pooled “per lesion” sensitivity of 83% (CI95%:

79%–87%; 𝐼2: 88.8%), a pooled specificity of 90% (CI95%:

87%–92%; 𝐼2: 94.8%), a pooled positive LR of 6.65 (CI95%:

2.8–15.8; 𝐼2: 90.3%), and a pooled negative LR of 0.17 (CI95%:

0.07–0.43; 𝐼2: 92%). The area under the curve was 0.9430(Figure 6).

CLE has also been widely applied to describe IBD mor-phologic features, although it was not possible to performa quantitative analysis of this application. In this particularindication, CLE appears to be a safe and feasible diagnostictool for imaging bowelmorphology, assessing disease activity,and predicting therapeutic responses.

3.5. Biliary Duct. In biliary tract and pancreatic cysts, routineforceps are not accurate for sampling and pathology examfails to address diagnosis. CLEwith in situ diagnosis might bea valuable alternative. However, few studies have been care-fully conducted.

CLE has been applied for the diagnosis of common biliaryduct lesions and to distinguish between benign and malig-nant strictures in patients with indeterminate biliary stenosis[2, 107–115] (Table 4). These applications were prospec-tively evaluated in several studies; of these, we performed ameta-analysis of 8 studies [107–109, 111–115], which resultedin a pooled sensitivity of 90% (CI

95%: 86%–94%; 𝐼2: 1.6%),


0 0.2 0.4 0.6 0.8 1

Sensitivity

Sensitivity (95% CI)Li et al. 2010Ji et al. 2011Li et al. 2011

0.78 (0.63–0.89)1.00 (0.48–1.00)0.89 (0.79–0.95)


(a)

0 0.2 0.4 0.6 0.8 1

Specificity

Li et al. 2010Ji et al. 2011Li et al. 2011

0.90 (0.73–0.98)0.79 (0.54–0.94)0.99 (0.99–1.00)


Specificity (95% CI)

(b)

0.01 1 100.0

Positive LR

Positive LR (95% CI)Li et al. 2010Ji et al. 2011Li et al. 2011

7.78 (2.63–23.01)4.07 (1.74–9.52)

133.33 (71.50–248.63)

Random effects model

Cochran-Q = 50.01; df = 2 (p = 0.0000)Inconsistency (I2) = 96.0%𝜏2 = 4.3302

Pooled positive LR = 16.49 (1.48 to 183.19)

(c)

0.01 1 100.0

Negative LR

Negative LR (95% CI)Li et al. 2010Ji et al. 2011Li et al. 2011

0.25 (0.14–0.43)0.11 (0.01–1.54)0.11 (0.06–0.21)

Random effects modelPooled negative LR = 0.16 (0.08 to 0.35)Cochran-Q = 4.70; df = 2 (p = 0.0955)Inconsistency (I2) = 57.4%𝜏2 = 0.2413

(d)

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curveSymmetric SROCAUC = 0.9296SE(AUC) = 0.0606Q∗ = 0.8647SE(Q∗) = 0.0727

(e)

Figure 3: “Per patient” meta-analysis for the application of CLE in detection and diagnosis of neoplastic lesions in the stomach: (a) pooledsensitivity, (b) pooled specificity, (c) pooled positive likelihood ratio (LR), (d) pooled negative LR, and (e) summary receiver operaticcharacteristic (SROC) curve.

a pooled specificity of 72% (CI95%: 65%–79%; 𝐼

2: 0%), apooled positive LR of 3.21 (CI

95%: 2.55–4.11; 𝐼2: 0%), and a

pooled negative LR of 0.15 (CI95%: 0.10–0.23; 𝐼

2: 0%).The areaunder the curve was 0.8578 (Figure 7).

3.6. Pancreas. Currently, in humans, the use of nCLE is exclu-sively applied to pancreatic tissue. The literature concerningthis technique includes a small number of studies that exam-ined the characterization of pancreatic lesions, such as pan-creatic cystic neoplasms [14, 15, 117], indeterminate pancreaticduct strictures [116], and serous cystadenomas [118] (Table 5).A meta-analysis of two studies [14, 117] that applied nCLE for

the diagnosis of pancreatic cyst neoplasms produced a pooledsensitivity of 68% (CI

95%: 55%–80%; 𝐼2: 79.8%), a pooled

specificity of 90% (CI95%: 74%–98%; 𝐼

2: 82.4%), a pooledpositive LR of 6.72 (CI

95%: 0.94–47.89; 𝐼2: 52%), and a pooled

negative LR of 0.30 (CI95%: 0.10–0.84; 𝐼

2: 60.6%) (Figure S3).

3.7. Study Quality Assessment. Based on the GRADE system,the overall quality of the evidence included in our analysiswas judged as low (10 studies had a very low level of quality; 59were low; 31 were moderate; and 2 were high).The risk of biasin the comparative randomized and nonrandomized studieswas evaluated by two independent reviewers (Alessandro


0 0.2 0.4 0.6 0.8 1

Sensitivity

Sensitivity (95% CI)Guo et al. 2008Ji et al. 2011Lim et al. 2013Pittayanon et al. 2013Li et al. 2014Liu et al. 2014

0.98 (0.95–1.00)0.86 (0.68–0.96)0.91 (0.81–0.97)0.96 (0.86–1.00)0.93 (0.87–0.97)0.91 (0.81–0.97)


(a)

0 0.2 0.4 0.6 0.8 1

Specificity

Specificity (95% CI)Guo et al. 2008Ji et al. 2011Lim et al. 2013Pittayanon et al. 2013Li et al. 2014Liu et al. 2014

0.95 (0.89–0.98)0.97 (0.93–0.99)0.85 (0.73–0.93)0.94 (0.86–0.98)0.97 (0.88–1.00)0.97 (0.89–1.00)


(b)

0.01 1 100.0

Positive LR

Positive LR (95% CI)Guo et al. 2008Ji et al. 2011Lim et al. 2013Pittayanon et al. 2013Li et al. 2014Liu et al. 2014

21.00 (8.92–49.43)33.33 (10.81–102.81)

17.03 (6.56–44.19)27.41 (7.01–107.14)28.74 (7.33–112.65)

Random effects modelPooled positive LR = 17.66 (9.04 to 34.51)Cochran-Q = 13.83; df = 5 (p = 0.0167)Inconsistency (I2) = 63.8%𝜏2 = 0.4262

5.96 (3.25–10.93)

(c)

0.01 1 100.0

Negative LR

Negative LR (95% CI)Guo et al. 2008Ji et al. 2011Lim et al. 2013Pittayanon et al. 2013Li et al. 2014Liu et al. 2014

0.02 (0.01–0.06)0.14 (0.06–0.35)0.11 (0.05–0.23)0.04 (0.01–0.17)0.07 (0.04–0.14)0.09 (0.04–0.21)


(d)

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curveSymmetric SROCAUC = 0.9832SE(AUC) = 0.0069Q∗ = 0.9435

SE(Q∗) = 0.0138

(e)

Figure 4: “Per biopsy”meta-analysis for the application of CLE in gastritis and gastricmetaplasia: (a) pooled sensitivity, (b) pooled specificity,(c) pooled positive likelihood ratio (LR), (d) pooled negative LR, and (e) summary receiver operatic characteristic (SROC) curve.

Fugazza, Federica Gaiani) based on Cochrane and NOS cri-teria. Specifically, two RCTs [55, 77] were classified as havinga low risk of bias, and 6 RCTs had a high risk of bias [22, 25,27, 28, 31, 54] (Table S2). Based onNOS criteria, 5 studies [29,52, 62, 70, 74] were classified as having a low risk of bias, and17 [36, 39, 48, 59–61, 63, 66–69, 71, 72, 78, 94, 106, 112] had ahigh risk of bias (Table S3).

4. Discussion

To the best of our knowledge, this is the first systematic reviewto analyze the diagnostic accuracy of CLE across all of theapplications for which it has been used.

A crucial differencebetweenCLE andalternative endosco-pic techniques is that CLE does not merely identify a lesion,


Kiesslich et al. 2007Hlavaty et al. 2011van den Broek et al. 2011Rispo et al. 2012

0.95 (0.74–1.00)0.00 (0.00–0.60)0.50 (0.01–0.99)1.00 (0.48–1.00)


0 0.2 0.4 0.6 0.8 1

Sensitivity

Sensitivity (95% CI)

(a)


0.98 (0.94–1.00)0.98 (0.92–1.00)0.82 (0.73–0.90)0.89 (0.52–1.00)


0 0.2 0.4 0.6 0.8 1

Specificity


(b)


54.47 (13.72–216.07)4.33 (0.20–93.22)2.83 (0.66–12.20)6.11 (1.37–27.25)


0.01 1 100.0

Positive LR

Positive LR (95% CI)

(c)


0.05 (0.01–0.36)0.92 (0.69–1.24)0.61 (0.15–2.44)0.10 (0.01–1.41)


0.01 1 100.0

Negative LR

Negative LR (95% CI)

(d)


1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curve

(e)

Figure 5: “Per lesion” meta-analysis for the application of CLE in the detection of dysplasia and neoplasia in inflammatory bowel diseasepatients: (a) pooled sensitivity, (b) pooled specificity, (c) pooled positive likelihood ratio (LR), (d) pooled negative LR, and (e) summaryreceiver operatic characteristic (SROC) curve.

but it also enables the discrimination of benign or malignantfeatures via direct and immediate microscopic investigation,which can be performed simultaneously with endoscopicexamination [119]. Despite this, CLE is still viewed as anexpensive tool that requires standardized criteria for the diag-nosis of select pathologies and needs specific training tointerpret CLE images before it can be implemented as a rou-tine diagnostic tool.

4.1. CLE in the Esophagus. Several studies have validatedthe diagnostic and therapeutic role of CLE with respect topremalignant lesions and cancers of the upper GI tract. In

a feasibility study, the use of pCLE demonstrated an up to92% accuracy rate in detecting malignant and premalignantmodifications of GI mucosa compared to conventional histo-pathology [120]. However, the primary application of CLE inesophageal tissue has been for the detection of high-gradedysplasia and cost-effective treatment strategies of BE. Inparticular, CLE has been used for follow-up of BE patientspresenting with HG dysplasia and to define the lateral extentof neoplasias prior to therapy.

It has been demonstrated that when using endomicros-copy for the surveillance of BE, the number of required biop-sies can be significantly decreased by up to 87% [22], as this


Table4:Summaryof

thes

tudies

evaluatin

gCL

Ein

biliary

diseases

creening

anddiagno

sis(all“per

patie

nt”a

nalysis

).

Author

and

year

Cou

ntry

𝑁Meanage(yr)

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Meining

etal.

2008

[107]

Germany

14patie

nts

61.3

8388

//

86p-CL

Econsiderablyincreasessensitivity

forthe

detectionof

biliary

neop

lasia

andtherefore

representsap

romising

diagno

sticapproach.

Giovann

iniet

al.2011[108]

France

37patie

nts

62.3

8375

n/a

n/a

86IntrabiliarypC

LEisfeasible.

Meining

etal.

2011[109]

Germany

USA

89patie

nts

62.8

9867

7197

81

p-CL

Eprovides

reliablem

icroscop

icexam

ination

andhase

xcellent

sensitivityandNPV

with

significantly

high

eraccuracy

ofER

CPandpC

LEcomparedwith

ERCP

with

tissuea

cquisition.

Meining

etal.

2012

[110]

Germany

USA

47and42

patie

nts

63.2 63

9733

8080

n/a

TheM

iamiC

lassificatio

nenablesa

structured,

unifo

rm,and

reprod

ucibledescrip

tionof

pancreaticob

iliarypC

LE.

Shiehetal.

2012

[2]

USA

10patie

nts

56.9

n/a

n/a

n/a

n/a

n/a

pCLE

oftheC

BDviathe

Gastro

Flex

UHD

miniprobe

isfeasibleandmay

offer

improved

imageq

ualityover

thes

tand

ardCh

olangioF

lex

prob

e.

Cailloletal.

2013

[111]

France

USA

60patie

nts

62.2

96.3

75.7

76.5

96.2

85Th

eParisClassifi

catio

nim

provethe

accuracy

ofpC

LEford

iagn

osingbenign

inflammatory

stric

tures.

Cailloletal.

2013

[112]

France

54patie

nts

6688

83n/a

n/a

87Inflammationfro

mprestentingprocedures

interfe

resw

ithpC

LEdiagno

sisof

theb

iledu

ctlesio

ns.

Heifetal.

2013

[113]

USA

15patie

nts

54100

61.1

22.2

100

n/a

pCLE

may

have

ahighsensitivityandnegativ

epredictiv

evalue

toexclu

deneop

lasia

inpatie

nts

with

PSCandDS.

Cailloletal.

2015

[114]

France

61patie

nts

6788

7992

6985

Thea

ddition

ofap

CLEprocedureinthe

diagno

stichisto

logice

xaminationof

abiliary

stric

ture

perm

itsas

ignificantincreasein

diagno

sticreliabilityandallowsfor

aVPN

of100%

.

Slivka

etal.

2015

[115]

USA Italy

France

112patie

nts

64.5

8971

9382

88pC

LEprovided

amorea

ccuratea

ndsensitive

diagno

sisof

cholangiocarcino

mac

omparedwith

tissues

amplingalon

e.𝑁

stands

forthe

numbero

fpatientse

nrolledin

thes

tudy

;pCL

E,prob


ndom

icroscop

y;CL

E,confocallasere

ndom

icroscop

y;PP

V,po

sitivep

redictivev

alue;N

PV,n

egativep

redictivev

alue;

PSC,

prim

arysclerosin

gcholangitis;D

S,do

minantb

iliarystr

icture;and

CBD,com

mon

biledu

ct.


Table5:Summaryof

thes

tudies

evaluatin

gCL

Ein

pancreaticdiseases

creening

anddiagno

sis(all“per

patie

nt”a

nalysis

).

Authorsa

ndyear

Cou

ntry

𝑁Meanage(yr)

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Accuracy

(%)

Mainfin

ding

s

Kond

aetal.2011

[15]

USA

18patie

nts

57.9

n/a

n/a

n/a

n/a

n/a

nCLE

isthep

ancreasistechn

icallyfeasible.

Kond

aetal.

2013

[14]

USA

Germany

France

66patie

nts

63.1

59100

100

5071

nCLE

hasa

high

specificityin

thed

etectio

nof

PCNbu

titm

aybe

limitedby

alow

sensitivity.

Kahaleh

etal.

2015

[116]

USA

France

18patie

nts

58.3

n/a

n/a

n/a

n/a

94CL

Eiseffectiv

einassistin

gwith

diagno

sisof

indeterm

inatep

ancreatic

ductstr

icturesp

riorto

surgery.

Nakaietal.2015

[117]

USA

30patie

nts

7287

77100

100

77Th

ecom

binatio

nof

cysto

scop

yandnC

LEof

pancreaticcysts

appearstohave

stron

gconcordancew

iththec

linicaldiagno

sisof

PCN.

Napoléonetal.

2015

[118]

France

31patie

nts

5769

100

100

8287

Then

ewlydevelopednC

LEcriterio

nseem

stobe

high

lyspecificfor

thed

iagn

osisof

serous

cystadenom

a.𝑁

stands

forthe

numbero

fpatientse

nrolledin

thes

tudy

;nCL

E,needle-based

confocallasere

ndom

icroscop

y;CL

E,confocallasere

ndom

icroscop

y;PP

V,po

sitivep

redictivev

alue;N

PV,negativep

redictivev

alue;

andPC

N,pancreatic

cysticn

eoplasms.


0 0.2 0.4 0.6 0.8 1

Sensitivity

Sensitivity (95% CI)Kiesslich et al. 2004

Gomez et al. 2010Shahid et al. 2012aShahid et al. 2012bGomez et al. 2013Liu et al. 2013


0.97 (0.86–1.00)1.00 (0.84–1.00)0.76 (0.62–0.87)0.71 (0.60–0.81)0.86 (0.75–0.94)0.41 (0.18–0.67)0.97 (0.90–1.00)

De Palma et al. 2010

(a)

0 0.2 0.4 0.6 0.8 1

Specificity

Specificity (95% CI)Kiesslich et al. 2004


0.99 (0.98–1.00)0.82 (0.48–0.98)0.72 (0.51–0.88)0.82 (0.72–0.90)0.78 (0.66–0.87)0.71 (0.61–0.79)0.97 (0.91–0.99)



(b)

0.01 1 100.0

Positive LR

Positive LR (95% CI)Kiesslich et al. 2004De Palma et al. 2010Gomez et al. 2010Shahid et al. 2012aShahid et al. 2012bGomez et al. 2013Liu et al. 2013

171.37 (42.99–683.19)4.69 (1.55–14.16)2.71 (1.42–5.19)4.06 (2.43–6.77)3.88 (2.49–6.05)1.42 (0.75–2.68)

31.40 (10.30–95.72)


(c)

0.01 1 100.0

Negative LR

Negative LR (95% CI)Kiesslich et al. 2004


0.03 (0.00–0.18)0.03 (0.00–0.45)0.33 (0.19–0.58)0.35 (0.24–0.50)0.18 (0.09–0.34)0.83 (0.55–1.26)0.03 (0.01–0.12)



(d)

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curveSymmetric SROCAUC = 0.9430SE(AUC) = 0.0487Q∗ = 0.8812SE(Q∗) = 0.0628

(e)

Figure 6: “Per lesion” meta-analysis for the application of CLE in colorectal neoplasms and malignant foci in polypoid lesions: (a) pooledsensitivity, (b) pooled specificity, (c) pooled positive likelihood ratio (LR), (d) pooled negative LR, and (e) summary receiver operaticcharacteristic (SROC) curve.

technique produces a higher diagnostic yield for the detectionof neoplasia compared to randombiopsy.This improved yielddirectly results from the need to sample only the suspiciousareas that have been identified byCLE [22, 31]. However, whatthe optimal surveillance biopsy procedure is in BE patientsremains unclear. Current surveillance programs, such as the

four-quadrant Seattle biopsy protocol, are relatively expen-sive and time-consuming [29]. The Preservation and Incor-poration of Valuable Endoscopic Innovation (PIVI) initiativethat was recently implemented by the American Societyof Gastrointestinal Endoscopy (ASGE) [121] recommendsthat, before replacing the current Seattle protocol, a targeted


Meining et al. 2008Meining et al. 2011Giovannini et al. 2011Caillol et al. 2013aCaillol et al. 2013bHeif et al. 2013Caillol et al. 2014Slivka et al. 2015

0.83 (0.36–1.00)0.98 (0.87–1.00)0.83 (0.61–0.95)0.96 (0.81–1.00)0.88 (0.72–0.97)1.00 (0.03–1.00)0.88 (0.74–0.96)0.89 (0.79–0.95)


0 0.2 0.4 0.6 0.8 1

Sensitivity

Sensitivity (95% CI)

(a)


0.88 (0.47–1.00)0.67 (0.52–0.80)0.71 (0.29–0.96)0.76 (0.58–0.89)0.83 (0.36–1.00)0.64 (0.35–0.87)0.79 (0.49–0.95)0.71 (0.54–0.84)


0 0.2 0.4 0.6 0.8 1

Specificity


(b)


6.67 (1.03–43.17)2.99 (1.99–4.48)2.89 (0.88–9.47)

5.27 (0.88–31.70)2.05 (0.72–5.79)4.10 (1.49–11.24)3.03 (1.87–4.91)


0.01 1 100.0

Positive LR

Positive LR (95% CI)

3.97 (2.16–7.29)

(c)


0.19 (0.03–1.16)0.04 (0.01–0.26)0.24 (0.09–0.67)0.05 (0.01–0.34)0.15 (0.05–0.39)0.39 (0.03–4.49)0.16 (0.07–0.37)0.16 (0.08–0.32)


0.01 1 100.0

Negative LR

Negative LR (95% CI)

(d)


1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Sens

itivi

ty

0 0.2 0.4 0.6 0.8 1

1 − specificity

SROC curve

(e)

Figure 7: “Per patient” meta-analysis for biliary duct application of CLE: (a) pooled sensitivity, (b) pooled specificity, (c) pooled positivelikelihood ratio (LR), (d) pooled ne

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Review Article Confocal Laser Endomicroscopy in ...downloads.hindawi.com/journals/bmri/2016/4638683.pdfCancer Research Lab. ECM, Universit ´eParis-Est,ValdeMarneUPEC, C r ´eteil,