global research on osteosarcoma, 1999–2019: a ...3 osteosarcoma (os) is a primary bone malignancy...
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Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.
GlobalResearchonOsteosarcoma,1999–2019:ABibliometricandVisualAnalysisCURRENTSTATUS:POSTED
HanWuChina-JapanUnionHospitalofJilinUniversity
BaixingWeiChina-JapanUnionHospitalofJilinUniversity
YuanpeiChengChina-JapanUnionHospitalofJilinUniversity
YongboLiChina-JapanUnionHospitalofJilinUniversity
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
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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.