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Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.

GlobalResearchonOsteosarcoma,1999–2019:ABibliometricandVisualAnalysisCURRENTSTATUS:POSTED

HanWuChina-JapanUnionHospitalofJilinUniversity

BaixingWeiChina-JapanUnionHospitalofJilinUniversity

YuanpeiChengChina-JapanUnionHospitalofJilinUniversity

YongboLiChina-JapanUnionHospitalofJilinUniversity

1602307215@qq.comCorrespondingAuthor

DOI:10.21203/rs.3.rs-19452/v1

SUBJECTAREASCancerBiology Oncology

KEYWORDSosteosarcoma,bibliometric,citespace,visualanalysis,co-citation

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AbstractBackground

Osteosarcomaisaprimarymalignantbonetumorthatoccursinchildrenandadolescents.Increasing

numbersofscholarshavestudieditsdevelopmentandtreatment.Tofullyunderstandthecurrent

statusofosteosarcomaresearchandglobaltrendstherein,weperformedabibliometricandvisual

analysisofosteosarcomastudiespublishedbetween1999and2019.

Methods

WesearchedtheWebofSciencedatabaseforpublicationsonosteosarcoma.Thebasiccharacteristics

ofthissampleofpublications,suchasHindices,annualoutputs,languagesofpublication,and

authors,journals,institutions,andcountriesoforigin,weredetermined.Co-citation,collaboration,

andkeywordco-occurrencewereanalyzedusingCiteSpacesoftware.

Results

Thesamplecomprised16,934articles.Thenumberofpublicationsincreasedannually.Hindicesand

totalnumbersofcitationswerefarhigherforarticlesfromtheUnitedStatesthanforthosefromother

countries.Amonginstitutions,thelargestproportionofarticlesoriginatedfromShanghaiJiaotong

University.R.GorlickwastheauthorwiththehighestHindexandtotalnumberofcitations.Oncology

LetterspublishedthelargestnumberofarticlesandCancerResearchwasthemostfrequentlycited

journal.Thefivemostfrequentlyappearingkeywordswere“osteosarcoma,”“cancer,”“expression,”

“apoptosis,”and“metastasis.”Theanalysisgenerated10majorclustersofkeywordsand23clusters

ofco-citedreferences.

Conclusions

Thefindingsofthisstudyhaveguidingsignificanceforresearchersseekingcooperatinginstitutions

andpartnersforosteosarcomaresearch,popularjournalsandimportantliteratureinthefield,an

understandingoftheknowledgebaseforthisresearch,andup-to-dateidentificationofresearch

hotspotsandtrends.

Keywords:osteosarcoma,bibliometric,citespace,visualanalysis,co-citation

1.Background

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Osteosarcoma(OS)isaprimarybonemalignancyencounteredfrequentlyinchildrenandadolescents,

commonlyinthemetaphysesoflongbones(e.g.,distalfemur,proximaltibiaandproximalhumerus)

[1].Inelderlypatients,OSisusuallyconsideredtobeasecondarytumorattributabletothe

sarcomatoustransformationofPaget'sdiseaseorotherbenignbonelesions[2].Distantmetastasis

occursbeforethedefinitivediagnosisofOSinabout15%ofpatients,andmorethan85%ofsuch

metastasesareinthelung[3].Atpresent,theclinicaltreatmentofOSisprimarilysurgical,with

adjunctivechemoradiotherapyandbiotherapy.Inrecentyears,immunotherapy[4,5],molecular

targetedtherapy[6,7],andcancerstemcelltherapy[8,9]havebeenusedincreasinglyforthe

treatmentofthisdisease.Althoughthe5-yearsurvivalrateofpatientswithOShasincreased

significantlywiththeimprovementoftreatmentandclinicalmanagement,therapeuticeffectsremain

unsatisfactoryinpatientswithmetastaticandrecurrentOS[10].Thus,abundantresearchhasbeen

conductedontheoccurrence,development,andtreatmentofOS,andthebodyofliteraturehas

grown.However,nosummaryoranalysisofthestatusofglobalOSresearchorchangesinitsfocus

hasbeenpublished.

Bibliometricsisanobservationalmethodusedtoassessthestatusofresearchandqualityof

publicationsongiventopics;itcanbeusedtostudygrowth,development,andcommunication,and

toidentifythemostinfluentialandpioneeringresearch,inparticularfields.Inthemedicalfield,ithas

beenappliedtoresearchonspinalsurgery,arthroscopy,andsurgicaloncology,aswellasmanyother

topics[11–13].CiteSpaceisawidelyusedbibliometricsandvisualanalysistooldevelopedrecentlyby

Chenetal.[14].Itisbasedmainlyonco-citationanalysisandpathfindingnetworkalgorithms,applied

toexplorekeypathsinbodiesofliteratureandtoidentifypointsofinflectionintheevolutionof

knowledgeonparticulartopics.Itisalsousedtoanalyzeglobalresearchhotspotsingivendisciplines

andexploretrendsinresearchdevelopmentthroughtheapplicationofaseriesofvisualization

techniques[15].

Inthisstudy,weusedtheWebofScienceCoreCollection(WoSCC;http://www.webofknowledge.com)

toolsandCiteSpacesoftwaretoanalyzetheliteratureonOSpublishedbetween1999and2019.The

aimwastofullyunderstandthecurrentsituationandglobaltrendsinOSresearch,toprovidea

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referenceandfoundationfortheorydevelopmentforsubsequentscholars.

2.MaterialsAndMethods2.1.DatasourceandretrievalstrategyOn19December2019,wesearchedtheWoSCCforpublicationsrelatedtoOSusingthetopic(TS)

keyword"osteosarcoma*"OR"osteogenicsarcoma*,"filetype"article,”andsearchperiodof1999to

2019.Thesearchgenerated16,934documentrecordsforreview.

2.2.BibliometricsandvisualanalysisFirst,weconductedaWoS-basedanalysistounderstandthebasicfeaturesofthepublicationsinthe

sample,suchastheHindex;annualoutput;allauthors,journals,institutions,andcountries/regionsof

origin;andlanguagesofpublication.TheHindexandtotalnumberofcitationsreflectthequalityand

academicinfluenceofpublicationsattheinstitutionorauthorlevel[16].

Then,weperformedavisualanalysisusingtheCiteSpacesoftware.Thisanalysisgeneratedvisual

knowledgenetworksconsistingofnodes(representing,e.g.,authors,countries,institutions,or

referencescited)connectedbylines(representingcooperation,co-existence,orco-citation),with

representationoftemporalpatternsandthedegreeofnodecentrality,orkeyroleincollaborationand

co-citationnetworks.Networkclusteranalysisofco-citedreferencesandco-occurrencekeywordswas

performed.Theidentificationoffrequentlyusedkeywordsisoftenperformedtodeterminedirections

ofdevelopmentandresearchfociinagivenfield.Theresultsofthisanalysisweremanifestedastwo

indicatorsgeneratedbyCiteSpace–themodule(Q)valueandaveragesilhouette(S)value–which

reflectthenetworkstructureandclusterclarity,respectively.Ingeneral,Qvaluesrangefrom0to1,

withlargervaluesindicatingbetternetworkclustering.Qvalues > 0.3indicateasignificantnetwork

clusterstructure.Svaluesrangefrom− 1to1,andreflectthehomogeneityofnetworkclusters,with

valuescloserto1indicatinggreaterhomogeneity;Svalues > 0.5areconsideredtoreflectreasonable

clusteringresults.

Timelinemapsreflectmainlythehistoricalevolutionandinterrelationshipofclusters,andtimezone

mapsshowtheevolutionofresearchovertime,revealing“hotspots”anddevelopmentaltrends.

Researchhotspotsinfieldswithstrongtemporalcharacteristicscanalsobeidentifiedbyanalyzing

high-frequencykeywords.Weperformedin-depthanalysisofthesemapsandcorrespondingdatato

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explaintheevolutionofOSresearchandidentifyhotspotsemergingatdifferenttimes.

Theknowledgebaseiscomposedofco-citedliterature,andtheresearchfrontiscomposedofthe

literatureinwhichknowledgebasecomponentsarecited.InCiteSpace,weidentifiedclusters,named

accordingtonominaltermsextractedfromthecitingliterature,whichcanbeconsideredtocomprise

theresearchfrontier.Weanalyzedthemostcitedandcentralarticlesineachofthetop10co-citation

clusterstodeterminetheknowledgebaseforeachresearchfrontier.

3.Results3.1.PublicationoutputOfthe16,934articlesincludedinthestudy,about98%(n = 16,583)werewritteninEnglish.Between

1999and2018,thenumberofpublicationsincreasedannually,from459to1559.Thisnumber

decreasedslightlyin2019to1424(Fig.1).

3.2.Country-leveldistributionandcooperationThearticlesoriginatedfrom120countries;the10countriesproducingthemostpublications,withH

indicesandcitationfrequencies,arelistedinTable1.ResearchersinChinapublishedthemost

articles(n = 4783),followedbythoseintheUnitedStates(n = 4533)andJapan(n = 1695).TheUnited

StateshadthehighestHindexvalueandtotalcitationfrequency.Figure2Ashowsthetop10national

cooperationnetworksbyco-occurrencetime.ThetopthreenetworksidentifiedwereChina(n = 4780

),theUnitedStates(n = 4507),andJapan(n = 1685).Intermsofcentrality,thetopthreecountries

wereEngland(0.16),theUnitedStates(0.15),andCanada(0.12;Fig.2B).Extensivecooperationwas

alsoidentifiedamongcountries(Fig.2D).China’simportantresearchpartnersincludedtheUnited

States,Canada,Britain,andAustralia;researchersintheUnitedStatescooperatedwiththosein

Korea,Germany,Russia,Australia,andothercountries;andthoseinJapanestablishedpartnerships

withIndia,Poland,China,andtheUnitedStates,amongothers.Thetopthreecountriesintermsof

periodsofrapidincreasesinthenumberofpublicationswereChina(2015–2019),Japan(1999–2006),

andtheUnitedStates(2000–2002;Fig.2C).

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Table1Top10countriesintermsofthenumberofpublications,Hindex,andtotalcitationfrequency

Rank Publications Country H-index Country Sumoftimescited

Country

1 4783 China 139 UnitedStates 138166 UnitedStates2 4533 UnitedStates 75 Italy 56812 China3 1695 Japan 75 Germany 32931 Japan4 1012 Italy 73 Japan 26433 Italy5 936 Germany 72 China 25797 Germany6 757 England 72 England 20899 England7 615 France 64 Canada 15709 France8 528 Canada 62 France 14607 Canada9 487 SouthKorea 56 Australia 11459 Netherlands10 425 India 53 Netherlands 10846 Australia3.3.Institution-leveldistributionandcooperationArticlesinthesampleoriginatedfrom10,247institutions.Table2liststop10academicinstitutionsin

termsofthenumberofpublications,Hindex,andtotalcitationfrequency.Researchersinthe

UniversityofTexassystempublishedthemostarticles(n = 440),followedbythoseatShanghaiJiao

TongUniversity(n = 379)andthoseintheUniversityofCaliforniasystem(n = 368).IntermsoftheH

indexandtotalcitationfrequency,thetopthreeinstitutionswereHarvardUniversity,theNational

InstitutesofHealth,andtheUniversityofTexassystem.Intermsofco-occurrence,thetopthree

institutionswereShanghaiJiaoTongUniversity(n = 364),ChinaMedicalUniversity(n = 235),andthe

NationalCancerInstitute(n = 205;Fig.3A).Intermsofcentrality,thetopthreeinstitutionswerethe

NationalCancerInstitute(0.22),MassachusettsGeneralHospital(0.2),andHarvardUniversity(0.13;

Fig.3B).Intermsofpublicationintensityincertainperiods,thetopthreeinstitutionswerethe

UniversityofTexassystem(1999–2007),JilinUniversity(2015–2019),andNanjingMedicalUniversity

(2016–2019).Extensivecooperationamonginstitutionswasalsoidentified(Fig.3D).

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Table2Top10institutionsintermsofthenumberofpublications,Hindex,andtotalcitationfrequency

Rank Publications Institution H-index Institution Sumoftimescited

Institution

1 440 UniversityofTexasSystem

66 HarvardUniversity

13641 NationalInstitutesofHealth

2 379 ShanghaiJiaotongUniversity

60 UniversityofTexasSystem

13602 HarvardUniversity

3 368 UniversityofCaliforniaSystem

59 NationalInstitutesofHealth

13474 UniversityofTexasSystem

4 361 HarvardUniversity

56 UniversityofTexasMDAndersonCancerCenter

11008 UniversityofCaliforniaSystem

5 327 UniversityofTexasMDAndersonCancerCenter

56 MemorialSloan-KetteringCancerCenter

10641 MemorialSloan-KetteringCancerCenter

6 305 IstitutoOrtopedicoRizzooli

55 UniversityofCaliforniaSystem

10453 NationalCancerInstitute

7 295 NationalInstitutesofHealth

54 NationalCancerInstitute

9830 IstitutoOrtopedicoRizzooli

8 258 UniversityofLondon

52 IstitutoOrtopedicoRizzooli

9546 MemorialSloan-KetteringCancerCenter

9 246 InstitutNationaldelaSanteetdelaRechercheMedicale,INSERM

49 UniversityofLondon

8778 UniversityofLondon

10 218 NIHNationalCancerInstitute

48 InstitutNationaldelaSanteetdelaRechercheMedicale,INSERM

7645 InstitutNationaldelaSanteetdelaRechercheMedicale,INSERM

3.4.Author-leveldistributionandcooperationIntotal,54,423authorspublishedarticlesrelatedtoOS.Table3liststhetop10authorsintermsof

thenumberofpublications,Hindex,andtotalcitationfrequency.Y.Wangpublishedthemostarticles

(n = 173),followedbyY.Zhang(n = 154)andP.Piccⅰ(n = 153).IntermsoftheHindexandcitation

frequency,thetopthreeauthorswereR.Gorlick,P.Picci,andS.Ferrari.Intermsofco-occurrence,

thetopthreeauthorswereR.Gorlick(n = 94),H.Tsuchiya(n = 88)andP.Picci(n = 77;Fig.4A).In

termsofcentrality,thetopfourauthorswereW.Liu(0.11),P.Picci(0.06),R.M.Hoffman(0.06),and

L.Wang(0.06;Fig.4B).Intermsofpublicationintensity,thetopthreeauthorswereG.Bacci(1999–

2005),P.Picci(1999–2005),andP.F.M.Choong(2007–2011;Fig.4C).Extensivecooperationamong

institutionswasalsoidentified(Fig.4D).

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Table3Top10authorsintermsofthenumberofpublications,Hindex,andtotalcitationfrequency

Rank Publications Author H-index Author Sumoftimescited

Author

1 173 Y.Wang 47 R.Gorlick 6384 R.Gorlick2 154 Y.Zhang 42 P.Picci 5829 P.Picci3 153 P.Picci 38 S.Ferrari 4313 S.Ferrari4 137 Y.Liu 35 G.Bacci 4116 G.Bacci5 129 R.Gorlick 34 PCW.

Hogendoorn3550 PCW.

Hogendoorn6 118 L.Wang 33 M.Serra 3306 Y.Wang7 115 J.Wang 32 Y.Wang 3292 JH.Healey8 114 Y.Li 32 JH.Healey 3142 A.Longhi9 109 H.Tsuchiya 31 A.Longhi 3024 M.Serra10 103 S.Ferrari 29 F.Bertoni 2649 F.Bertoni3.5.Journal-leveldistributionandco-occurrenceIntotal,2338journalspublishedarticlesrelatedtoOS.Table4liststhetop10journalsaccordingto

thenumberofpublications.ThetopthreejournalswereOncologyLetters(n = 303articles),PLoSOne

(n = 288),andClinicalOrthopaedicsandRelatedResearch(n = 269).Thejournalwiththehighest

impactfactor(4.15)amongthetop10journalswasClinicalOrthopaedicsandRelatedResearch.

Figure5showsthejournalcitationnetwork.Thetopthreejournalsintermsofcitationfrequencywere

CancerResearch,theJournalofClinicalOncology,andtheJournalofBiologicalChemistry.Intermsof

centrality,thetopthreejournalswereCancerResearch,theJournalofClinicalOncology,and

Oncotarget.

Table4Top10journalsintermsofthenumberofpublications

Rank Publications(%) Journal ImpactFactor1 303(1.789) OncologyLetters 1.8712 288(1.701) PlosOne 2.7763 269(1.589) ClinicalOrthopaedicsAnd

RelatedResearch4.154

4 259(1.529) OncologyReports 3.0415 231(1.364) AnticancerResearch 1.9356 231(1.364) Oncotarget 07 212(1.252) MolecularMedicine

Reports1.851

8 199(1.175) PediatricBlood&Cancer 2.4869 185(1.092) BiochemicalAnd

BiophysicalResearchCommunications

2.705

10 185(1.092) InternationalJournalofOncology

3.571

3.6.Keywordco-occurrenceThefivemostfrequentlyoccurringkeywordswere“osteosarcoma,”“cancer,”“expression,”

“apoptosis,”and“metastasis”(Fig.6A).Tenkeywordclustersweregenerated,withaQvalueof

0.8269andSvalueof0.8009,indicatingasignificantclusterstructureandreasonableclustering

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results,respectively(Fig.6B).Table5showsthemainkeywordsineachcluster.Thethreekeywords

whoseuseincreasedmostrapidlyduringthestudyperiodwere“invasion”(2016–2019),“osteoblast”

(1999–2010),and“migration”(2016–2019;Fig.6C).Figure6Dshowskeywordswhouseexpanded

rapidlyinrecentyears,including“nanoparticletumor,”“supervisor,”and“signalingpathway.”

Table6showsresearchhotspotsaccordingtokeywordtimezones.Figure7showstimelineandtime

zonemapsofkeywordco-occurrence.

Table5Tenmajorkeywordclusters

ClusterNumber ClusterLabel MainKeywords MeanYear0 CellLine Mutation,P53,Nude

mice,Humansarcoma,Transport,Squamouscellcarcinoma

2002

1 Surgery Extremity,Neoadjuvantchemotherapy,Adjuvantchemotherapy,Experience,Preoperativechemotherapy

2002

2 Tumor Osteosarcoma,MRI,Metastasis,Kidney,Galectin-1

20033 Osteosarcoma Differentiation,

Messengerrna,Stemcell,Alkalinephosphatase,Osteogenesis,Celldifferentiation

2002

4 Autophagy Migration,Invasion,Apoptosis,Tumorsuppressor,Mir-100,Wnt/β-catenin

2010

5 Metastasis VEGF,Microrna,Cell,Angiogenesis,Longnoncodingrna,

2008

6 Methotrexate Chemotherapy,Doxorubicin,Model,Survival,Canine,Cisplatin

2003

7 Parathyroidhormone Osteoblast;Proteinkinase;Osteosarcomacell;Calciumchannels;Intracellularstore;Phosphatetransport;Functionalexpression

2000

8 Invitro Nf-kappab;Tumorgrowth;Signalingpathway;Prostatecancer;Nanoparticle;Drugdelivery;Smoothmusclecell;

2006

9 Radiotherapy Reconstruction;Endoprosthesis;Malignanttumor;Survival;Fracture;Humerus;Upperextremity;Management;knee

2003

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Table6Researchhotspotsaccordingtokeywordtimezones

Year Keywoeds1999 osteosarcoma,cancer,expression,apoptosis,chemot

herapy,proliferation,growth,survival,bone,invitro,cell,breastcancer,activation,differentiation,gene,protein,prognosticfactor,prognosis,geneexpression,inhibition,extremity,bonetumor,experience,neoadjuvantchemotherapy,osteosarcomacell,children,invivo,doxorubicin,p53,softtissuesarcoma,cisplatin,osteoblast,identification,receptor,surgery,diagnosis,adjuvantchemotherapy,mutation,messengerrna,induction,highdosemethotrexate,parathyroidhormone,cellline,preoperativechemotherapy,rat,amplification,extracellularmatrix,alkalinephosphatase,boneresorption,proteinkinasec,binding,disease,invitro,multidrugresistance

2000 metastasis,therapy,dog,resection,dna,osteoblastlikecell,fibroblast,cytokine,transgenicmice,

2001 ewingssarcoma,immunohistochemistry,methotrexate,cellcycle

2002 mechanism,angiogenesis,chondrosarcoma,death,amputation,neoplasm,growthfactor,nonmetastaticosteosarcoma,tissue,

2003 limbsalvage,reconstruction,management,softtissue,protocol,

2004 pathway,highgradeosteosarcoma,2005 monoclonalantibody2006 cancercell,phosphorylation,genetherapy2007 nfkappab,breastcancercell,metastase2010 osteoblastdifferentiation,endothelialgrowthfactor

,cytotoxicity,adhesion,2011 invasion,resistance,ewingsarcoma2012 radiotherapy,risk,2013 migration,lungcancer2014 microrna,progression,down

regulation,epidemiology,mesenchymalstemcell,2015 cellproliferation,hepatocellularcarcinoma,gastric

cancer,tumorgrowth2016 colorectalcancer,stemcell,2017 nanoparticle,tumorsuppressor,signaling

pathway,epithelialmesenchymaltransition2018 longnoncodingrna,autophagy,2019 inhibitor3.7.Referenceco-citationTheanalysisrevealedco-citationof579articles.Tables7and8listthetop10mostcitedandmost

centralarticles,respectively.Twenty-threeclustersrepresentingleadingOSresearchtopics,including

“multifocalosteosarcoma,”“survival,”and“osteocalcin,”wereidentified.Thegeneratednetwork

structurehadaQvalueof0.8905andSvalueof0.5184,indicatingasignificantclusterstructureand

reasonableclusteringresults(Fig.8).

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Table7Top10citedreferencesintermsofco-citationcounts

Rank Co-citationCounts CitedReference Author Journal1 504 Osteosarcoma

incidenceandsurvivalratesfrom1973to2004:DatafromtheSurveillance,Epidemiology,andEndResultsProgram

L.Mirabello Cancer

2 470 Theepidemiologyofosteosarcoma

G.Ottaviani CancerTreatmentAndResearch

3 429 Osteosarcomatreatment-wheredowestand?Astateoftheartreview.

A.Luetke CancerTreatmentReviews

4 277 Osteosarcoma:CurrentTreatmentandaCollaborativePathwaytoSuccess.

M.S.Isakoff JournalofClinicalOncology

5 254 Prognosticfactorsinhigh-gradeosteosarcomaoftheextremitiesortrunk:Ananalysisof1,702patientstreatedonneoadjuvantcooperativeosteosarcomastudygroupprotocols

S.S.Bielack JournalofClinicalOncology

6 233 Translationalbiologyofosteosarcoma

M.Kansara NatureReviewsCancer

7 188 Osteosarcoma:areviewofdiagnosis,management,andtreatmentstrategies.

D.S.Geller ClinicalAdvancesInHematology&Oncology

8 178 Newmolecularinsightsintoosteosarcomatargetedtherapy

J.L.Yang CurrentOpinionInOncology

9 176 AMeta-AnalysisofOsteosarcomaOutcomesintheModernMedicalEra

D.C.Allison Sarcoma

10 164 Themolecularpathogenesisofosteosarcoma:areview.

M.L.Broadhead Sarcoma

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Table8Top10citedreferencesintermsofcentrality

Rank Centrality CitedReference Author Journal1 0.76 High-resolution

mappingofamplificationsanddeletionsinpediatricosteosarcomabyuseofCGHanalysisofcDNAmicroarrays

J.A.Squire GenesChromosomes&Cancer

2 0.74 Geneamplificationsinosteosarcoma-CGHmicroarrayanalysis

J.Atiye GenesChromosomes&Cancer

3 0.72 GenomicsignaturesofchromosomalinstabilityandosteosarcomaprogressiondetectedbyhighresolutionarrayCGHandinterphaseFISH.

S.Selvarajah CytogeneticAndGenomeResearch

4 0.65 Updatesonthecytogeneticsandmoleculargeneticsofboneandsofttissuetumors:osteosarcomaandrelatedtumors

A.A.Sandberg CancerGeneticsAndCytogenetics

5 0.53 Molecularpathogenesisofosteosarcoma.

M.Kansara DNAAndCellBiology

6 0.47 DNAsequencecopynumberincreaseat8q:Apotentialnewprognosticmarkerinhigh-gradeosteosarcoma

M.Tarkkanen InternationalJournalofCancer

7 0.46 Inhibitionofplatelet-derivedgrowthfactor-mediatedproliferationofosteosarcomacellsbythenoveltyrosinekinaseinhibitorSTI571

E.C.Mcgary ClinicalCancerResearch

8 0.39 Currenttreatmentofosteosarcoma

W.S.Ferguson CancerInvestigation9 0.32 Treatmentof

nonmetastaticosteosarcomaoftheextremitywithpreoperativeandpostoperativechemotherapy:areportfromtheChildren'sCancerGroup

A.J.Provisor JournalofClinicalOncology

10 0.31 GainsandlossesofDNAsequencesinosteosarcomasbycomparativegenomichybridization

M.Tarkkanen CancerResearch

4.Discussion4.1.OSresearchstatusandglobalpublicationquality

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Inthepast20years,thenumberofarticlesonOSpublishedannuallyhasincreasedgradually,

reflectingsteadydevelopmentofresearchinthisfield.Thegrowthratehasacceleratedsince2011,

butthenumberofarticlespublishedannuallydecreasedslightlyin2019,possiblybecausethesearch

periodforthisstudydidnotfullycover2019.

ThenumbersofpublicationsfromresearchersinChinaandtheUnitedStateswerefargreaterthan

thosefromresearchersinothercountries.Hindicesandtotalnumbersofcitationswerefarhigherfor

articlesfromtheUnitedStatesthanforthosefromothercountries;thesemetricswerenot

satisfactoryforChina,indicatingthatthequalityofpublicationsfromresearchersinChinaneedsto

beimproved.Overall,thesefindingsindicatethatthecoreofOSresearchandthegreatest

contributionstoitsdevelopmentaresituatedintheUnitedStates,withadditionalimportant

contributionsoriginatingfromotherdevelopedcountriesinEuropeandNorthAmerica.

Theleading10of10,247institutionsatwhichOSresearchisconductedaccountfor12.9%of

publicationsinoursample,and90%oftheseinstitutionsareinEuropeandtheUnitedStates.Thus,

OSresearchisconductedatmanyinstitutionsworldwide,butmostresearchresultsaredisseminated

byinstitutionsindevelopedcountries.ThesixinstitutionswiththehighestHindices,andsevenofthe

top10institutionsintermsofthetotalnumberofcitations,areintheUnitedStates,againreflecting

thequalityandinfluenceofresearchinstitutionsinthiscountry.

Amongauthors,China'sY.WangandY.Zhangledintermsofthenumberofpublications,andthe

UnitedStates’R.GorlickledintermsoftheHindexandtotalnumberofcitations.Theanalysis

identifiednosingleleadresearcherorteaminthisfield.Giventhesignificantimpactsofthetop10

authors,intermsoftheHindexandtotalnumberofcitations,inOSresearch,interestedscholars

shouldpaycloseattentiontoresearchtrendsandprogressinthisgroup.

Theco-occurrenceanalysisrevealedbroadcooperationamongcountries,primarilybyresearchersin

ChinaandtheUnitedStates.AlthoughChina'scurrentacademicinfluenceisrelativelysmall,Chinese

scholarsfocusoncommunicationandcooperationwithothercountries.AsChinashowedthemost

rapidgrowthinpublicationsinthisfield,theacademicstandardsandinfluenceofresearchersin

Chinawilllikelyimproveinthenextfewyears.TheUnitedKingdomhadthemostintermediate

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centrality,indicatingthatBritishresearchersplaykeyrolesininternationalcooperation.Insummary,

weidentifiedbroadandcloserelationshipsamongcountries,institutions,andauthors.Suchacademic

exchangepromotesthedevelopmentofOSresearch.

4.2.ResearchhotspotsandtrendsTheanalysisofhigh-frequencykeywordsidentified10clusters.Usefulinformationcanbeextracted

viain-depthinterpretationofthedatapresentedinTable5.Forexample,thep53mutationorp53-

mediatedphasepathwayaffectstheproliferationandmetastasisofOScells.Theeffectof

neoadjuvantchemotherapycombinedwithsurgicaltreatmentofOShasbeeninvestigated.Micro-

RNA-100ortheWnt/β-actinsignalingpathwayaffectstheinvasionandmigrationofOScells.Micro-

RNAandlongnon-codingRNAaffecttheapoptosis,autophagy,anddevelopmentofOScells.Other

topicsofstudycontainedwithinresearchhotspotsincludetheexpressionofnuclearfactor–kappaBin

OS,nanoparticlesasantitumordrugcarriersforOStreatment,andprosthesis-basedreconstruction

afterOSresection.

HotspotsofOSresearchpublishedin1999–2006formed10clustersencompassingresearchon

diversetopicswithrichcontent.Fewerhotspotswereidentifiedfor2007–2010,andtopicsofresearch

shiftedinthisperiodtonuclearfactor–kappaBandosteoblastdifferentiation,amongothers.During

2011–2019,thenumberofhotspotsdecreasedfurtherwiththemainfocibeingradiotherapy,micro-

RNA,nanoparticles,tumorsuppressors,signalingpathways,andlongnoncodingRNA.Ingeneral,the

pathogenesisofOS,factorsinfluencingitsproliferationandmetastasis,thecurativeeffectsofvarious

treatments,andtheanalysisofprognosiswereconsistentlyresearchfocithroughoutthestudy

period,withresearchonnanoparticlesandsignalingpathwaysemergingrecently.Theserecent

hotspotsreflectongoingprogressinOStreatmentandpointtofuturetrendsinnano-medicineand

targetedtherapy.

4.3.ResearchfrontiersandknowledgebaseTheco-citationanalysisyielded23clustersrepresentingtheOSresearchfrontiers.Themostcited

andcentralarticlesinthetop10co-citationclustersaredescribedheretocharacterizethe

knowledgebasefortheseresearchfrontiers.

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NonmetastaticOS

A1997study[17]describedgoodhistologicalresponsestopreoperativechemotherapyamong

patientswithnonmetastaticOS,withan8-yearpostoperativeevent-freesurvival(EFS)rateof81%

andoverallsurvivalrateof87%;thosewithpoorhistologicalresponseshadan8-yearpostoperative

EFSrateof46%andoverallsurvivalrateof52%.TheauthorsconcludedthatEFSandsurvivalwere

relateddirectlytothehistologicalresponsetoneoadjuvantchemotherapyinthesepatients[17].

Baccietal.[18]reportedthatage,theserumalkalinephosphataselevel,tumorvolume,surgical

margins,andhistologicalresponseareofindependentprognosticvaluefornonmetastaticOSofthe

extremities.

Survival

Bielacketal.[1]foundthattumorsiteandsize,primarymetastasis,responsetochemotherapy,and

surgicalremissionhadindependentprognosticvalueforsurvivalin1702consecutivepatientswith

newlydiagnosedhigh-gradeOSofthetrunkorlimbs.Meyersetal.[19]showedthattheadditionof

ifosfamidetostandardchemotherapy(cisplatin,doxorubicin,andhigh-dosemethotrexate)didnot

enhanceEFS,butthattheadditionofmuramyltripeptidetochemotherapymightimproveEFS,in

patientswithnewlydiagnosedOS.Goorinandcolleagues[20]reportednoadvantageofpreoperative

chemotherapyintermsoftheEFSofpatientswithOS.

Osteocalcin

Ducyetal.[21]identifiedanosteoblast-specificcis-actingelement,termedOSE2,intheosteocalcin

promoterandclonedthecDNAencodingOsf2/Cbfa1,theproteinthatbindstoOSE2.They

demonstratedthatOsf2/Cbfa1isanosteoblast-specifictranscriptionfactorandregulatorofosteoblast

differentiation[21].UsingaCbfa1-mutatedmousemodel,Komorietal.[22]showedthatCbfa1is

essentialforosteoblastsandboneformation,andmayregulateavarietyofgenes,includingthose

relatedtoosteocalcinandosteopontin.

Systemsbiology

Atiyeetal.[23]identifiedOS-relatedampliconsandreportedthat12Qampliconsseemtooccurmuch

morefrequentlythanpreviouslyassumed.Thesedataarevaluableforfurtherelectrophoresis

16

research.Usinghigh-resolutionarraycomparativegenomichybridizationcombinedwithinterphase

fluorescencein-situhybridization,Selvarajahandcolleagues[24]characterizedthegenomic

imbalanceandchromosomalinstabilityassociatedwithOS,providingimportantinsightintothe

mechanismsthatproducecomplexgenomesinpatientswiththisdisease.

Zoledronicacid

A2005studydemonstratedthatthecombineduseofzoledronicacidandifosfamidepromotedtumor

regressionandtissuerepairinratswithOS,providinganewdirectionforcombinedOStreatment

[25].Oryetal.showedthatzoledronicacidsignificantlyreducedOS-inducedlungmetastasisand

prolongedthesurvivalofmicewithOS[26].Inamolecular-levelstudy,thesameresearchgroup

demonstratedthatzoledronicacidactivatesthes-phasecheckpointandmitochondrialpathwaysof

DNAdamagethroughapoptosis-inducingfactorandendonucleo-gtranslocation,bypassingthese

potentialmutationstoinhibitOScellproliferationandinducingcelldeath[27].

Ezrin

Khannaetal.[28]showedthatezrin,amemberoftheezrin/radixin/moesinfamily,wasnecessaryfor

metastasisinamousemodelofOS,thatearlymetastasisdependedonmitogen-activatedprotein

kinaseactivation,andthathighezrinexpressioncorrelatedsignificantlywithpoorprognosisin

patientswithOS.Otherresearchersfoundthatezrin-mediatedmetastasisisrelatedtothe

mTOR/S6KI/4E-BP1pathway,andthatblockadeofthispathwaywithrapamycinsignificantlyinhibited

lungmetastasisinmicewithOS[29].TheseresultsprovideasuitabletargetforthetreatmentofOS

metastasis.

Chemotherapy

A2006reviewfocusedonthemechanismsofdrugresistanceandwaystoovercomesuchresistance

inthecourseofchemotherapyforOS,whichhashelpedresearchersandcliniciansunderstand

bottlenecksinthischemotherapyandidentifycopingstrategies[30].AEuropeanstudyrevealedno

differenceinthesurvivalofpatientswithoperablenon-metastaticcarcinomareceivingthetwo-drug

(doxorubicinandcisplatin)regimenandtheT10multidrugregimen;theauthorsrecommendedthat

thetwo-drugregimenbethefirst-choicetherapybecauseofitsshortcourseandgoodtolerance[31].

17

Amputation

Researchhasfocusedontheidentificationoftreatmentplansforpatientswithhigh-gradeOSofthe

extremitiesthatavoidamputationandimprovelong-termsurvival.Preoperativechemotherapycan

shrinkthetumorvolume,whichisconducivetolimbsalvage.Bacciandcolleagues[32]showedthat

thepostoperativelocalrecurrenceratewasrelatedcloselytothequalityofthesurgicalresection

marginsandchemotherapyresponsein540patientswithnon-metastaticOSoftheextremities.They

reportedthatlimb-salvagesurgeryissuccessfulonlywhensufficientsurgicalmarginsareobtained;

otherwise,immediateamputationshouldbeconsidered,especiallyincasesofpoorhistological

responsetopreoperativechemotherapy.

P-glycoprotein

Baldinietal.[33]foundthathighP-glycoproteinlevelssignificantlyincreasedtheriskofadverse

events,andthattheP-glycoproteinlevelwasnotrelatedtothedegreeofnecrosisafterpreoperative

chemotherapy,inpatientswithhigh-gradeOS.

Pigmentepithelium–derivedfactor

A2007studydemonstratedthemulti-targetrolesofpigmentepithelium–derivedfactor(PEDF)in

inhibitingtumorgrowth,angiogenesis,andmetastasisintwoin-situOSmodels(ratUMR-106-01and

humanSAOS-2)[34].Takenakaetal.showedthatPEDFcaninducetumorcellapoptosisandinhibit

theexpressionofvascularendothelialgrowthfactor(VEGF)inhumanOSMG63cells,preventing

angiogenesis[35].ThesestudieshavedemonstratedthebroadpotentialofPEDFuseinOStreatment.

4.4.StudylimitationsThisstudyhascertainlimitations.First,theresultsofouranalysismaybebiasedbyourrelianceon

theWoSdatabase,asotherdatabasesmaycontaindifferentbodiesofliterature.Second,differences

mayexistbetweentheresultsofthebibliometricanalysisandrealresearchconditions.Forexample,

theanalysismaynothaveproperlycapturedtheimpactsofsomerecentlypublishedhigh-quality

papersbecauseofthelowfrequencyofcitations.Thus,futureresearchshouldnotbebasedasingle

database,andshouldfocusonrecentlypublishedarticles.

5.Conclusions

18

ThisstudyprovidesacomprehensiveviewofthestatusofOSresearchinthepast20years.The

volumeofglobalpublicationshasincreasedannually,andmanyacademicexchangesamong

researchersandinstitutionshaveoccurred.Webelievethatthisresearchhasimportantguiding

significanceforresearchersseekingcooperatinginstitutionsandpartnersforOSresearch,popular

journalsandimportantliteratureinthefield,anunderstandingoftheknowledgebaseforthis

research,andup-to-dateidentificationofresearchhotspotsandtrends.

AbbreviationsOS

Osteosarcoma;

WOSCC

TheWebofScienceCoreCollection;

TS

Topic;

WOS

TheWebofScience;

EFS

Event-freesurvival;

OSE2

Osteoblast-specificcis-actingelement-2;

PEDF

Pigmentepithelium-derivedfactor;

VEGF

Vascularendothelialgrowthfactor;

DeclarationsAcknowledgements

Notapplicable

Authors’contributions

YBLdesignedthestudy;YPCperformeddatacollection;BXWanalyzedthedataandperformedthe

statisticalanalysis.YBLdraftedtheinitialmanuscript.HWcriticallyreviewedandrevisedthe

manuscript.AllauthorsreadandapprovedthefinalManuscript

Funding

19

Notapplicable

Availabilityofdataandmaterials

Notapplicable

Ethicsapprovalandconsenttoparticipate

Notapplicable

Consentforpublication

Notapplicable

Competinginterests

Theauthorsdeclarethattheyhavenocompetinginterests.

Authordetails

1DepartmentofOrthopedics,China-JapanUnionHospital,JilinUniversity,Changchun130000,China

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Figures

23

Figure1

Annualnumberofpublicationsonosteosarcoma,1999–201

Figure1

Annualnumberofpublicationsonosteosarcoma,1999–201

24

Figure2

Country-levelco-occurrencefindings.A.Top10countriesintermsofco-occurrencecounts.

B.Top10countriesintermsofcentrality.C.Countriesshowingthestrongestburstsin

publication.D.Collaborationnetwork.Forallvisualanalysisgraphics,thesizeofeachpoint

reflectsthefrequencyofoccurrenceorreference.Colorsinthenodesandlinesrepresent

differentyears.Thenodewiththemostcentralityandconsideredtobeakeypointinthe

networkisindicatedinpurple.

25

Figure2

Country-levelco-occurrencefindings.A.Top10countriesintermsofco-occurrencecounts.

B.Top10countriesintermsofcentrality.C.Countriesshowingthestrongestburstsin

publication.D.Collaborationnetwork.Forallvisualanalysisgraphics,thesizeofeachpoint

reflectsthefrequencyofoccurrenceorreference.Colorsinthenodesandlinesrepresent

differentyears.Thenodewiththemostcentralityandconsideredtobeakeypointinthe

networkisindicatedinpurple.

26

Figure3

Institution-levelco-occurrencefindings.A.Top10institutionsintermsofco-occurrence

counts.B.Top10institutionsintermsofcentrality.C.Institutionsshowingthestrongest

burstsinpublication.D.Cooperationnetwork.

27

Figure3

Institution-levelco-occurrencefindings.A.Top10institutionsintermsofco-occurrence

counts.B.Top10institutionsintermsofcentrality.C.Institutionsshowingthestrongest

burstsinpublication.D.Cooperationnetwork.

28

Figure4

Author-levelco-occurrencefindings.A.Top10authorsintermsofco-occurrencecounts.B.

Top10authorsintermsofcentrality.C.Authorsshowingthestrongestburstsinpublication.

D.Cooperationnetwork.

29

Figure4

Author-levelco-occurrencefindings.A.Top10authorsintermsofco-occurrencecounts.B.

Top10authorsintermsofcentrality.C.Authorsshowingthestrongestburstsinpublication.

D.Cooperationnetwork.

30

Figure5

Journal-levelco-occurrencefindings.A.Top10journalsintermsofco-occurrencecounts.B.

Top10journalsintermsofcentrality.

31

Figure5

Journal-levelco-occurrencefindings.A.Top10journalsintermsofco-occurrencecounts.B.

Top10journalsintermsofcentrality.

32

Figure6

Keywordco-occurrencefindings.A.Topkeywordsintermsofco-occurrencecounts.B.

Clustermapofkeywordco-occurrence.C.Keywordsshowingthestrongestburstsinusage.

D.Keywordsshowingthestrongestburstsinusageinrecentyears.

33

Figure6

Keywordco-occurrencefindings.A.Topkeywordsintermsofco-occurrencecounts.B.

Clustermapofkeywordco-occurrence.C.Keywordsshowingthestrongestburstsinusage.

D.Keywordsshowingthestrongestburstsinusageinrecentyears.

34

Figure7

A.Co-occurrencetimelineatlasofkeywords.B.Co-occurrencetimezonemapofkeywords.

35

Figure7

A.Co-occurrencetimelineatlasofkeywords.B.Co-occurrencetimezonemapofkeywords.

36

Figure8

Co-citationofreferences.A.Top10referencesintermsofco-citationcounts.B.Clustermap

ofreferenceco-citation.C.Top20referencesshowingthestrongestburstsinco-citation.

37

Figure8

Co-citationofreferences.A.Top10referencesintermsofco-citationcounts.B.Clustermap

ofreferenceco-citation.C.Top20referencesshowingthestrongestburstsinco-citation.