Evaluation of simple blood counts as inflammation markers for brain tumor patients

Original

research

article

Evaluation

of

simple

blood

counts

as

inflammation

markers

for

brain

tumor

patients

Yasar

Dagistan

*

,

Emine

Dagistan

,

Veli

Citisli

a_{AbantIzzetBaysalUniversityHospital,DepartmentofNeurosurgery,Bolu,Turkey}

b_{AbantIzzetBaysalUniversityHospital,DepartmentofRadiology,Bolu,Turkey}

c

PamukkaleUniversityHospital,DepartmentofNeurosurgery,Denizli,Turkey

1.

Introduction

Theinflammatoryresponseplaysacrucialroleinneoplastic

diseasesand closelycorrelateswithtumor progressionand

metastasis[1–3]. Theseverityofinflammationservesasan

importantindicatoroftumorprogressionandsurvivalamong

patients with cancer [2,4,5]. Additionally, inflammatory

molecules have beenshown tobeoverexpressed bytumor

cells[6].

Thehemogramparametersinroutinebloodpanelshave

been proposed as markers of inflammation [7]. The size

variabilityoferythrocyteshasbeenreportedintermsofthe

redcelldistributionwidth(RDW)valueinhemogramassays,

withhigherRDWmeaninghighervariability.TheRDWlevels

areelevatedinirondeficiencyanemia.ElevationinRDWhas

alsobeenassociatedwithinflammatoryconditions[7–10].

Plateletsare thesmallestproductof bonemarrowinthe

blood stream, and they have a crucial role in hemostasis

and inflammation. They are involved in the inflammatory

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Articlehistory:

Received30April2015

Accepted7March2016

Availableonline19March2016

Keywords:

Braintumor

Metastasis

Meanplateletvolume

Redcelldistributionwidth

Inflammation

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Aims: Hemogramparametersinroutinebloodpanelshavebeenproposedasinflammation

markers. Theseparameters,especiallythered celldistributionwidth (RDW)andmean

plateletvolume(MPV),wereevaluatedassurrogateinflammatorymarkersinbraintumor

patients.WeaimedtoobserveRDWandMPVvaluesoftumorpatientsandcomparetothose

inhealthypopulation.

Methods: Werecordedwhitebloodcellcount,neutrophilcount,lymphocytecount,

hemo-globin,hematocrit,RDW,plateletcount,andMPVofthestudygroupatthetimeofdiagnosis

andcomparedtothoseofthecontrolsubjects.

Results:TheRDWwassignificantlyelevatedinstudygroupcomparedtothatofthecontrol

subjects(p=0.001).TheMPVwassignificantlylowerinstudygroupthanthatofthecontrol

group(p=0.01).

Conclusion: DecreasedMPVandincreasedRDWwerebothassociated withbraintumor.

However,prospectivestudieswithlargersamplesizesareneededtosupporttheresultsand

exposeMPVandRDWvariationsbetweenmetastaticandprimarybraintumors.

#2016PolishNeurologicalSociety.PublishedbyElsevierSp.zo.o.Allrightsreserved.

*Correspondingauthorat:AbantIzzetBaysalUniversityHospital,DepartmentofNeurosurgery,14280Bolu,Turkey.Tel.:+903742534656;

fax:+903742534615.

E-mailaddress:dagistanyasar@hotmail.com(Y.Dagistan).

Available

online

at

www.sciencedirect.com

ScienceDirect

journalhomepage:http://www.elsevier.com/locate/pjnns

http://dx.doi.org/10.1016/j.pjnns.2016.03.002

processeswithproinflammatorymoleculestheysecrete[11].

Thesurrogatemarkerofplateletactivationandproductionis

themeanplateletvolume(MPV).Variousstudieshaveshowna

relationship between the MPV and inflammatory diseases

[12–14].Anotherinflammatorymarkerderivedfromaroutine

bloodcounttestistheneutrophiltolymphocyteratio(NLCR).

NLCRhasbeenreportedasapredictivemarkerofoutcomesin

patients treated for various cancers, such as, colorectal

adenocarcinoma[2],renalcancer[4],hepatocellularcarcinoma

(HCC)[15],cancerof esophagogastricjunction[16], andlung

cancer[17].In arecent study, thepreoperativeNLCR

corre-spondedtoglialbraintumorgrading[18].

Inthepresentretrospectivestudy,thesesimplein

flamma-torymarkerswereevaluatedinpatientswithbraintumorsand

compared with those in the healthy population. These

laboratory parameters were also compared within brain

tumors of either metastatic or primary etiology, as the

radiologicalimagingofbrainmassesusuallycannot

differen-tiatemetastaticorprimarytumors[19–21].

2.

Material

and

methods

2.1. Subjects

Theuseofthedatainthisretrospectivestudywasapprovedby

our hospital. Patients with brain tumor visited outpatient

clinicsofourinstitutionwereenrolledtothestudyasstudy

group.Both primaryand metastaticnewly diagnosedbrain

tumorcasesthatnotreceivedanytreatmentwereincludedto

the study. None of the participants in study group were

receiving medications that may probably affect hemogram

parameters. Hemogram of the tumor patients have been

obtained at the timeof diagnosis before administration of

corticosteroidtherapy.Thecontrolgroupwasselectedfrom

patients who visited the hospital's out patient clinics for

routine checkups. Of the 48 brain tumor patients, 28 had

primarybraintumors,and20hadmetastatictumors.Forthe

28primarytumorpatients,20hadglioblastomamultiforme

(grade4),6hadanaplasticastrocytoma(grade3),and2had

diffuseastrocytoma(grade2).Thecontrolgroupwasselected

frompatientswhovisitedthehospital'soutpatientclinicsfor

routine checkups. None of the subjects in the study and

controlgroupshadahistoryofchronicuseofmaintenance

medicines. The characteristics and laboratory data of the

study population are summarized in Tables 1 and 2. No

significantdifferencewasseenbetweenthestudyandcontrol

groupsintermsofage(p=0.38)orgender(p=0.83).

2.2. Bloodpanel

Thelaboratorydataofthebraintumorpatientswererecorded

before surgeryfrom database of our institution. Thewhite

blood cellcount (WBC),neutrophilcount (neu),lymphocyte

count(lym),hemoglobin(Hb),hematocrit(Htc),RDW,platelet

count(PLT),andMPVoftheparticipantswereobtainedfrom

thehospital'smedicaldatabase.Venousbloodsampleswere

collected in sterile standard tubes containing constant

amountsofethylenediaminetetraaceticacidasan

anticoag-ulant. The laboratory assessment was conducted within

severalminutesafterthebloodsampleswereobtained.The

LH780automaticanalyzer(BeckmanCoulter,Inc.,Brea,CA,

USA)wasusedforcompletebloodcountanalyses.Originalkits

oftheproducerwereusedinthesemeasurements.

2.3. Statisticalanalysis

AlldatarecordedwereassessedwithSPSSsoftware(SPSS15.0;

SPSSInc.,Chicago,IL,USA).Theindependentsamplest-test

was usedfornormallydistributedvariables andtheMann–

WhitneyUtestwasusedfornon-homogeneouslydistributed

parameters.Theprimarybraintumor,metastaticbraintumor,

andcontrolgroupswerecomparedwithanANOVAtest.The

resultsofthestatisticswereexpressedaseithermeanSDor

median(min–max).Statisticalsignificancewassetaspvalue

oflowerthan0.05.

3.

Results

This retrospective study examined 48 patients with brain

tumors (primary and metastatic) and 48 healthy control

Table1–Characteristicsanddataofpatientsinthebraintumorandcontrolgroups.

Braintumorgroup Controlgroup p

Gender Men(n) 27 26 0.83 Women(n) 21 22 Median(Min–Max)a Age(years) 40.5(13–71) 43(32–51) 0.38 Lymphocytecount(k/mm3_{) 2(0.7–3.8) 2.1(1.5–3.7) 0.24} Neutrophil/lymphocyteratio(%) 2.4(1.1–7.5) 2(0.6–3.5) 0.11 Hemoglobin(g/dL) 14.4(10.2–16.4) 14.6(12.3–17.5) 0.30 Hematocrit(%) 43(30–50) 44(36.5–53) 0.77

Meancorpuscularvolume(fL) 86(63–94) 87(73–98) 0.09

Meanplateletvolume(fL) 8.2(6.3–10.5) 8.9(6–10) 0.01

Meanstandarddeviationb

Whitebloodcellcount(k/mm3_{) 7.52 7.11.6 0.30}

Neutrophilcount(k/mm3_{) 4.51.6 4.31.3 0.28}

Redcelldistributionwidth(%) 15.51.7 14.41.2 0.001

Plateletcount(k/mm3_{) 25584 25649 0.95}

a_Mann

–WhitneyUtest.

subjects.Thecharacteristicsandlaboratorydataofthestudy

populationaresummarizedinTables1and2.Nosignificant

differencewasseenbetweenthestudyandcontrolgroupsin

termsofage(p=0.38)orgender(p=0.83).Forthebloodpanel,

nodifferencewasseenbetweenthestudyandcontrolgroups

for the WBC, neu, lym, NLCR, Hb, Htc, mean corpuscular

volume, or PLT (p>0.05for all). However, the mean RDW

valueofthestudygroupwassignificantlyelevatedcompared

tothatofthecontrolsubjects(p=0.001).Inaddition,theMPV

ofthe studygroupwassignificantly lowerthanthat ofthe

controlgroup(p=0.01).

Thepatientsinthestudygroupwerefurtheranalyzed.Of

these patients, 28 had primary brain tumors and 20 had

metastatic lesions. General characteristics and laboratory

parameters of the patients with primary and metastatic

tumorsarepresentedinTable2. Theseparametersshowed

nodifferencebetweenprimaryand metastaticbrain tumor

patients.

4.

Discussion

ThisstudyshowedthattheRDWwashigherandtheMPVwas

lowerinpatientswithbraintumorsthantheywereinhealthy

subjects.Althoughtheliteraturereportedanincreaseinthe

NLCR in neoplasms, the present study lacked such an

association. The possible mechanism for the reduction in

theMPVcouldbethattheinflammatoryburdeninterfereswith

megakaryopoiesisinbonemarrow,resultingintheproduction

of smallerplatelets. Anotherexplanationcould bethatthe

involvementofthelarger,activeplateletsintheinflammatory

microstructureandtheremainingsmaller,inactiveplatelets

causeareductionintheMPV.Similarly,theelevationinthe

RDWcanbeexplainedbytheinflammatorysituationcausing

thebonemarrowtoproduceredbloodcellsofdifferentsize.

Inflammatorymolecules may alterthe use of iron inbone

marrow,consequently,causinganincreaseintheRDW.

ThestudiescomparingMPVinpatientswithmalignancies

had differing results. Karaman et al. found a significant

differenceintheMPVofpatientswithpancreas

adenocarci-nomathanthatofpatientswithpancreaticneuroendocrine

tumor;howevertheageandmeanHblevelswerealsodifferent

betweenthestudygroups[22].Kılınçalpetal.reportedhigher

MPVlevelsinpreoperativegastriccancerpatientscomparedto

healthy subjects [23]. Similarly, a study from South Korea

evaluatedMPVinHCCpatientsandreportedanelevationin

theMPVforthepatientsincomparisontothecontrolsubjects

[24].Ontheotherhand,Aksoyetal.foundtheMPVandPLT

valuesofsolidtumorpatientswithbonemarrowmetastasisto

be significantly decreased compared to the MPV and PLT

values of healthy subjects [25]. The present study found

decreasedMPVvaluesinthebraintumorpatientscomparedto

thecontrols;however,thePLTwasnotstatisticallydifferent

betweenthegroups.

TherecouldbeseveralexplanationsfordecreasedMPVin

braintumorpatients.IL-6hasbeenreportedtobeelevatedin

varioustypesofcancers[26,27]anditisalsoassociatedwith

plateletproductioninbonemarrow[28].Increasedlevelsof

IL-6mayinterferewithplateletproduction,causingthecreation

ofsmallerplateletsand,thus,leadingtoadecreaseinMPV[29].

AnotherspeculationcouldbeconsideredfortheMPVdecrease

inbraintumorpatients.Tumorscauseinflammationbecause

of the various cytokines produced by tumor cells [30] and

activeplatelets,whichtendtobelargerthanrestedplatelets,

areinvolvedininflammatoryprocesses.Theuseofthelarger,

activeplateletsmaycauseareductioninsystemicMPVvalue

because of the remaining smallerplatelets. Fenget al.[31]

demonstratedthatplateletssecreteandaccountfor

circulat-ingCD40ligand,chemokine(C-X-Cmotif)ligand5,chemokine

(C-Cmotif)ligand5,andepidermalgrowthfactorbydetecting

mRNA expression in platelets and megakaryocytes and

measuringcytokinelevelsintheplateletculturesupernatants,

prionprotein-derivedsera,andmurineimmune

thrombocy-topenicpurpuramodel.Theysuggestedthatthemeasurement

ofplatelet-specificcytokineswouldallowinferences

concern-ing physiologyandpathophysiology inquantitative platelet

disorders.

Seretis et al. [32] studied RDW levels of breast cancer

patientsandfoundthattheRDWwashigherinthepatients

than it was in the controls. Elevated RDW has also been

associatedwithpoorprognosesinmultiplemyeloma[33]and

lungcancer[34].AstheRDWincreasesininflammatorystatus

[10],andcancerisaninflammatorycondition,onecantheorize

thattheRDWwillelevateinbraintumors.Ourresultsagreed

Table2–Characteristicsanddataofprimaryandmetastaticbraintumorpatients.

Primarybraintumorgroup Metastatictumorgroup p

Gender Men(n) 14 13 0.30

Women(n) 14 7

Meanstandarddeviationa

Age(years) 4216 3816.2 0.38

Whitebloodcellcount(k/mm3_{) 7.52.1 7.42 0.77}

Neutrophilcount(k/mm3_{) 4.61.7 4.61.6 0.89}

Lymphocytecount(k/mm3_{) 20.6 2.10.4 0.71}

Neutrophil/lymphocyteratio(%) 2.41.3 2.20.8 0.56

Hemoglobin(g/dL) 14.11.7 141.8 0.63

Hematocrit(%) 42.75.2 42.25.2 0.72

Meancorpuscularvolume(fL) 83.57.9 856.1 0.47

Redcelldistributionwidth(%) 15.41.5 15.51.9 0.82

Plateletcount(k/mm3_{) 26292 24471 0.48}

Meanplateletvolume(fL) 8.21.2 81 0.49

withthis expectation.Additionally, previous studies [35,36]

haveshownthathighRDWandlowHblevelsaresignificant,

independentpredictorsofpoorsurvivalincancerpatientsand,

therefore, might be relevant prognostic factors in these

patients.Incontrast,Riedl etal.[35]suggestedthatseveral

red blood cell parameters of the hemogram, including Hb

levels,mightnotcontributetoimprovedriskstratificationof

cancer-associatedvenousthromboembolism.

Zadoraetal.[18]foundthatglioblastomapatientshadthe

highestpreoperativevalueofNLCR.Anelevatedpreoperative

NLCR may also result from the peritumoral infiltration of

macrophages,whichassociateswithanincreaseincytokine

levels,suchaslevelsoftumornecrosisfactor-alpha(TNF-a),

interleukin6,andinterleukin8[37].BothGlasgowprognostic

scoreGPSandNLCRareassociatedwithtumorinvasionand

therateofcombinedCBDresection.Wuetal.[1]demonstrated

thatGPShadastrongerassociationwithclinicpathological

factors than NLCR did. As GPS is easy to measure before

startingtreatment,theyproposeditcouldbeausefultoolfor

thestratificationofgallbladdercarcinomapatients.Bambury

etal.[38]suggestedthatinthefuturecreationofprognostic

risk scores for glioblastoma multiforme, NLCR should be

considered an initial candidate variable given its ease of

measurement. Although an association has been seen

betweeninflammationandNLCR[15],thepresentstudyfailed

toshowsuchanassociationinbraintumorpatients.

Allhematologicparameters,includingMPVandRDW,were

similar inpatients witheither primary or metastaticbrain

tumors. This finding suggests that any malign neoplasm

causessimilaramountsofinflammatoryburden.However,our

cohortwithprimaryormetastaticbraintumorwasrelatively

small.Largersamplesizesshouldshowsignificantdifferences

betweenprimaryandmetastaticprocesses.

Theresultsofthepresentstudyweredifficulttointerpret

duetotheretrospectivedesignandsmallsamplesize.Another

limitationwasthesinglecenterdesignofthework.Afourth

limitationcouldbethatwehavenotcomparedpostoperative

hemogramparameterstopreoperativedata.However,tothe

bestofourknowledge,thisstudywasthefirstintheliterature

tostudyMPVandRDWinbraintumorpatients.

5.

Conclusion

The decreased MPV and increased RDW of brain tumor

patients show the usefulness of simple blood panels as

inflammationindicatorsinthesepatients.However,

prospec-tivestudieswithlargersamplesizesareneededtosupportour

results and to expose MPV and RDW variations between

metastaticandprimarybraintumors.

Conflict

of

interest

Nonedeclared.

Acknowledgement

and

financial

support

Nonedeclared.

Ethics

The work described in this article hasbeen carried out in

accordance withThe Code of Ethics of the World Medical

Association(DeclarationofHelsinki)forexperiments

involv-inghumans;UniformRequirementsformanuscripts

submit-tedtoBiomedicaljournals.

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[1] WuXS,ShiLB,LiML,DingQ,WengH,WuWG,etal.

Evaluationoftwoinflammation-basedprognosticscoresin patientswithresectablegallbladdercarcinoma.AnnSurg Oncol2014;21:449–57.

[2] MalietzisG,GiacomettiM,KennedyRH,AthanasiouT,Aziz O,JenkinsJT.Theemergingroleofneutrophilto

lymphocyteratioindeterminingcolorectalcancer treatmentoutcomes:asystematicreviewand meta-analysis.AnnSurgOncol2014;21:3938–46.

[3] GrivennikovSI,GretenFR,KarinM.Immunity, inflammation,andcancer.Cell2010;140:883–99.

[4] SteffensS,KöhlerA,RudolphR,EggersH,SeidelC,Janssen M,etal.ValidationofCRPasprognosticmarkerforrenal cellcarcinomainalargeseriesofpatients.BMCCancer 2012;12:399.

[5] MantovaniA,AllavenaP,SicaA,BalkwillF.Cancer-related inflammation.Nature2008;454:436–44.

[6] CandidoJ,HagemannT.Cancer-relatedinflammation.J ClinImmunol2013;33(Suppl.1):S79–84.

[7] AktasG,AlcelikA,TekceBK,SavlıH,UyeturkU,KurtM, etal.Meanplateletvolumeandredcelldistributionwidth inhepatosteatosis.NatlJMedRes2013;3:264–6.

[8] LeeWS,KimTY.Relationbetweenredbloodcell distributionwidthandinflammatorybiomarkersin rheumatoidarthritis.ArchPatholLabMed2010;134:505–6.

[9] BraunE,DomanyE,KenigY,MazorY,MakhoulBF,Azzam ZS.Elevatedredcelldistributionwidthpredictspoor outcomeinyoungpatientswithcommunityacquired pneumonia.CritCare2011;15.

[10] AktasG,SitM,DikbasO,TekceBK,SavliH,TekceH,etal. Couldredcelldistributionwidthbeamarkerin

Hashimoto'sthyroiditis.ExpClinEndocrDiab2014;122: 572–4.

[11] KlingerMHF.Plateletsandinflammation.AnatEmbryol 1997;196:1–11.

[12] JaremoP,Sandberg-GertzenH.Plateletdensityandsizein inflammatoryboweldisease.ThrombHaemost

1996;75:560–1.

[13] GasparyanAY,Stavropoulos-KalinoglouA,TomsTE, DouglasKM,KitasGD.Associationofmeanplateletvolume withhypertensioninrheumatoidarthritis.InflammAllergy DrugTargets2010;9:45–50.

[14] AktasG,CakirogluB,SitM,UyeturkU,AlcelikA,SavliH, etal.Meanplateletvolume:asimpleindicatorofchronic prostatitis.ActaMedMediterr2013;29:551–4.

[15] ZhouSL,DaiZ,ZhouZJ,WangXY,YangGH,WangZ,etal.

OverexpressionofCXCL5mediatesneutrophilinfiltration andindicatespoorprognosisforhepatocellularcarcinoma. Hepatology2012;56:2242–54.

[16] YuanDW,ZhuK,LiK,YanR,JiaY,DangCX.The

preoperativeneutrophil-lymphocyteratiopredicts recurrenceandsurvivalamongpatientsundergoingR0 resectionsofadenocarcinomasoftheesophagogastric junction.JSurgOncol2014;110:333–40.

[17] CedresS,TorrejonD,MartinezA,MartinezP,NavarroA, ZamoraE,etal.Neutrophiltolymphocyteratio(NLR)asan indicatorofpoorprognosisinstageIVnon-smallcelllung cancer.ClinTranslOncol2012;14:864–9.

[18] ZadoraP,DabrowskiW,CzarkoK,SmolenA, Kotlinska-HasiecE,WiorkowskiK,etal.Preoperative neutrophil-lymphocytecountratiohelpspredictthegradeofglial tumor–apilotstudy.NeurolNeurochirPol2015;49:41–4.

[19] HollingworthW,MedinaLS,LenkinskiRE,ShibataDK,Bernal B,ZurakowskiD,etal.Asystematicliteraturereviewof magneticresonancespectroscopyforthecharacterizationof braintumors.AmJNeuroradiol2006;27:1404–11.

[20] FinkKR,FinkJR.Imagingofbrainmetastases.SurgNeurol Int2013;4:S209.

[21] BulakbasiN,KocaogluM,OrsF,TayfunC,UcozT. Combinationofsingle-voxelprotonMRspectroscopyand apparentdiffusioncoefficientcalculationintheevaluation ofcommonbraintumors.AmJNeuroradiol2003;24:225–33.

[22] KaramanK,BostanciEB,AksoyE,KurtM,CelepB,UlasM, etal.Thepredictivevalueofmeanplateletvolumein differentialdiagnosisofnon-functionalpancreatic neuroendocrinetumorsfrompancreaticadenocarcinomas. EurJInternMed2011;22:E95–8.

[23] KilincalpS,EkizF,BasarO,AyteMR,CobanS,YilmazB, etal.Meanplateletvolumecouldbepossiblebiomarkerin earlydiagnosisandmonitoringofgastriccancer.Platelets 2014;25:592–4.

[24] ChoSY,YangJJ,YouE,KimBH,ShimJ,LeeHJ,etal.Mean

plateletvolume/plateletcountratioinhepatocellular carcinoma.Platelets2013;24:375–7.

[25] HarputluogluH,DizdarO,AksoyS,KilickapS,DedeDS, OzisikY,etal.Characteristicsofbreastcancerpatientswith centralnervoussystemmetastases:asingle-center experience.JNatlMedAssoc2008;100:521–6.

[26] TrikhaM,CorringhamR,KleinB,RossiJ-F.Targeted anti-interleukin-6monoclonalantibodytherapyforcancer:a reviewoftherationaleandclinicalevidence.ClinCancer Res2003;9:4653–65.

[27] BergerFG.Theinterleukin-6gene:asusceptibilityfactor thatmaycontributetoracialandethnicdisparitiesin breastcancermortality.BreastCancerResTreat 2004;88:281–5.

[28] BaatoutS.Interleukin-6andmegakaryocytopoiesis:an update.AnnHematol1996;73:157–62.

[29] Talar-WojnarowskaR,GasiorowskaA,SmolarzB, Romanowicz-MakowskaH,KuligA,Malecka-PanasE. Clinicalsignificanceofinterleukin-6(Il-6)gene polymorphismandIl-6serumlevelinpancreatic adenocarcinomaandchronicpancreatitis.DigDisSci 2009;54:683–9.

[30] CoussensLM,WerbZ.Inflammationandcancer.Nature 2002;420:860–7.

[31] FengX,ScheinbergP,SamselL,RiosO,ChenJ,McCoyJP, etal.Decreasedplasmacytokinesareassociatedwithlow plateletcountsinaplasticanemiaandimmune

thrombocytopenicpurpura.JThrombHaemost 2012;10:1616–23.

[32] SeretisC,SeretisF,LagoudianakisE,GemenetzisG,Salemis NS.Isredcelldistributionwidthanovelbiomarkerof breastcanceractivity?Datafromapilotstudy. JClinMed Res2013;5:121.

[33] LeeH,KongSY,SohnJY,ShimH,YounHS,LeeS,etal.

Elevatedredbloodcelldistributionwidthasasimple prognosticfactorinpatientswithsymptomaticmultiple myeloma.BiomedResInt2014.

[34] KomaY,OnishiA,MatsuokaH,OdaN,YokotaN, MatsumotoY,etal.Increasedredbloodcelldistribution widthassociateswithcancerstageandprognosisin patientswithlungcancer.PLOSONE2013;8.

[35] RiedlJ,PoschF,KonigsbruggeO,LotschF,ReitterEM, EigenbauerE,etal.Redcelldistributionwidthandotherred bloodcellparametersinpatientswithcancer:association withriskofvenousthromboembolismandmortality.PLOS ONE2014;9.

[36] PatelKVSR,FerrucciL,NewmanAB,FriedLP,WallaceRB, BandinelliS,etal.Redcelldistributionwidthandmortality inolderadults:ameta-analysis.JGerontolA:BiolSciMed Sci2010;65:258–65.

[37] KatakiASV,MemosN,NikolopoulouM,OikonomouV, AndroulisA,KonstadoulakisMM,etal.Similarimmunity profilesinpatientswithmeningiomaandgliomatumors despitedifferencesintheapoptosisandnecrosisof circulatinglymphocyteandmonocytepopulations.J NeurosurgSci2014;58:9–15.

[38] BamburyRMTM,PowerDG,YusufA,MurrayS,BattleyJE, DrakeC,etal.Theassociationofpre-treatmentneutrophil tolymphocyteratiowithoverallsurvivalinpatientswith glioblastomamultiforme.JNeurooncol2013;114:149–54.