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Contents lists available at ScienceDirect

Leukemia Research

journa l homepage: www.e lsev ier .com/ locate / leukres

hort and long term effects of granulocyte colony-stimulating factor duringnduction therapy in acute myeloid leukemia patients younger than 65:esults of a randomized multicenter phase III trial

eral Beksaca,∗,1, Ridvan Alib,1, Tulay Ozcelikb,1, Muhit Ozcana,1, Osman Ozcebec,1,ahmut Bayikd,1, Semra Paydase,1, Yahya Buyukasikc,1, Osman Ilhana,1,

ahir Ozkalemkasb,1, Gunhan Gurmana,1, Akin Uysala,1, Hamdi Akana,1,nder Akcaglayan Soydana,1, Ahmet Tunalib,1

Department of Hematology and Bone Marrow Transplantation, University of Ankara, Ankara, TurkeyDepartment of Hematology, University of Uludag, Bursa, TurkeyDepartment of Hematology and Bone Marrow Transplantation, University of Hacettepe, Ankara, TurkeyDepartment of Hematology, University of Marmara, Istanbul, TurkeyDepartment of Hematology, University of Cukurova, Adana, Turkey

r t i c l e i n f o

rticle history:eceived 3 May 2010eceived in revised form 3 July 2010

a b s t r a c t

This prospective multicenter phase III clinical trial was designed to assess efficacy and safety of G-CSF asan adjunct to de novo AML remission induction therapy (www.clinicaltrials.gov. NCT00820976). Patients’characteristics were similar in both arms. G-CSF improved severity and duration of leukopenia. Three-

ccepted 4 July 2010vailable online xxx

eywords:ranulocyte colony-stimulating factorcute myeloid leukemia

year OS were similar (25.6 ± 5.1% vs. 31.8 ± 5.6%) in both arms except for patients with myeloblasticfeatures. Significant factors for better survival were the use of G-CSF (p = 0.049), female sex (p = 0.05) andsingle induction cycle (p < 0.001) in multivariate analysis. Female patients performed better than malepatients. Better survival obtained among female AML patients needs to be validated within the contextof cytogenetic analysis.

nductionurvival

. Introduction

Although significant progress has been made in diagnosis andupportive care of acute myeloid leukemia (AML), its treatments still associated with considerable morbidity and mortality [1].he outcome of treatment is dependent particularly on the abil-ty of patients to tolerate myelosuppression [2]. The severity anduration of myelosuppression usually causes infectious morbidityesulting with mortality [3,4]. Myeloid growth factors (myeloid-Fs), such as granulocyte colony-stimulating factors (G-CSF) or

Please cite this article in press as: Beksac M, et al. Short and long tetion therapy in acute myeloid leukemia patients younger than 65: Resdoi:10.1016/j.leukres.2010.07.005

ranulocyte-macrophage colony-stimulating factor (GM-CSF) haveeen shown to shorten the duration of chemotherapy- and bonearrow transplantation-induced neutropenia [3]. Leukemia cells

rom AML patients may express normal granulocyte/progenitor

∗ Corresponding author at: Department of Hematology and Bone Marrow Trans-lantation, University of Ankara, Cebeci Yerleskesi, Dikimevi, 06620 Ankara, Turkey.el.: +90 312 595 74 43; fax: +90 312 319 60 77.

E-mail address: meral.beksac@medicine.ankara.edu.tr (M. Beksac).1 On behalf of the Turkish Leukemia Study Group.

145-2126/$ – see front matter © 2010 Published by Elsevier Ltd.oi:10.1016/j.leukres.2010.07.005

© 2010 Published by Elsevier Ltd.

receptors for hematopoietic growth factors, i.e. G-CSF and GM-CSF[2,3]. Clinical use of myeloid-GFs in AML has been limited mainlydue to concerns about their potential ability to stimulate leukemiacells [2]. This potential has been used in priming of leukemicblasts into chemotherapy-sensitive proliferating cells prior tochemotherapy, to improve antileukemic activity [3,5]. Althougha number of studies with different schedules have demonstratedthe beneficial effect of growth factors on duration of neutrope-nia and infectious morbidity [5–8], it is still controversial whetherthese effects are translated into better therapeutic outcomes or pro-longed survival [3,9]. This prospective multicenter clinical trial wasdesigned to analyze the impact of G-CSF on response and outcomeas well as duration of leukopenia and infection-related parametersin patients with de novo AML, as the primary objective.

2. Materials and methods

rm effects of granulocyte colony-stimulating factor during induc-ults of a randomized multicenter phase III trial. Leuk Res (2010),

The Turkish Leukemia Study Group (TLG) AML trial (95-002) was conducted in14 centers, affiliated with the TLG, between May 1995 and September 1998. Themain objective of this randomized open trial was to assess the impact of G-CSF,given during induction chemotherapy, on response and survival in patients withAML. Patients, aged 16 years or older with newly diagnosed AML classified accordingto French-American-British (FAB) classification, and with a peripheral white blood

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improved with G-CSF use; day 28 WBC count was significantly

Fig. 1. Schematic representation of the trial design.

ell (WBC) count of less than 0.5 × 109/L, and/or marrow leukemic blasts <20% athe 7th day of remission induction treatment, were eligible. Patients with AML-M3ubtype, transformation of myelodysplastic syndromes or blastic crisis of myelo-roliferative disorders, were excluded. Patients with clinical or echocardiographicigns of heart failure or coronary disease, and patients with hepatic or renal failuresere also excluded. The study was approved by the institutional ethics committees

f each participating institution and the central ethical committee, prior to the startf enrollment. All patients gave written informed consents prior to registration. Ran-omization was performed locally by closed envelops distributed prior to the startf the trial. Monitoring and statistical analysis were performed by an independentlinical research organization (OMEGA, Ankara, Turkey). The trial is registered inlinical trials website, as NCT00820976.

Schematic representation of the trial design is depicted in Fig. 1. Patientsere centrally registered after stratification according to age and were random-

zed to receive either cytarabine (ARA-C; 100 mg/m2/d) for 10 days and idarubicine2 mg/m2/d for 3 days (control arm; arm A), or the same induction therapy plus-CSF (Filgrastim, Neupogen® , Roche Ltd., Basel, Switzerland) at a dose of 5 �g/kg

ntravenously over 30 min from day 8 of chemotherapy until the absolute neutrophilount (ANC) exceeded 0.5 × 109/L for 2 consecutive days (G-CSF arm; arm B). Fil-rastim was supplied by Roche. All supportive care, including management of fever,nfection and use of blood components, was given according to the institutionalractice of each center. Bone marrow was examined on the 7th and 21st days of

nduction therapy. When the aspirate demonstrated marrow aplasia with less than0% blasts, patients were randomized to arm A or B.

Second course of induction was given according to guidelines. Patients who didot achieve complete response (CR) after the second course of induction treatmentere considered as refractory. Patients, who achieved CR, were given a consolidation

reatment that consisted ARA-C 1 g/m2/d for 5 days and idarubicin 12 mg/m2/d for 3ays and was followed by stem cell transplantation or second consolidation therapyith ARA-C 6 g/m2/d for days 1, 3 and 5.

Please cite this article in press as: Beksac M, et al. Short and long tetion therapy in acute myeloid leukemia patients younger than 65: Resdoi:10.1016/j.leukres.2010.07.005

Prophylactic antimicrobial therapy was not allowed. Empiric broad-spectrumntibiotics and antifungal agents were used according to guidelines and the local rec-mmendations of each participating institution. Prophylactic platelet transfusionsere administered when the platelet counts decreased to 20 × 109/L. Red blood cells

RBCs) were transfused generally to maintain the hematocrit greater than 30%.

PRESSarch xxx (2010) xxx–xxx

2.1. Criteria of response and evaluation of outcome

Complete response was defined as a normal marrow with less than 5% blastswith no evidence of extramedullary leukemia, and recovery of peripheral bloodvalues; to platelet counts of at least 100 × 109/L and neutrophils 1.5 × 109/L or more.Failure to respond was defined as treatment resistance with no reduction in theleukemic blast infiltration in the marrow or a reduction that did not meet the criteriaof CR. Relapse was defined as the presence of leukemic blasts after initial CR, asdocumented by cytologic or pathologic evaluation of bone marrow or blood smears,or a pathologic diagnosis of extramedullary leukemia. Cytological, immunologicaland pathological analyses were reviewed by institutional reviewers. The neutrophilrecovery time was defined as the number of days from the start of induction therapyuntil the first day of an ANC higher than or equal to 1.0 × 109/L.

2.2. Statistical methods

Statistical analyses were carried out using SPSS v.15.0 (SPSS Inc., Chicago,IL, USA). Randomization was performed as described above. Descriptive statis-tics included the mean or median ± standard deviation for numeric variables andfrequencies and percentages for categorical variables. CR rates of both treatmentarms were compared by using chi-square test or Fisher’s exact test, as appropri-ate. The medians of skewed distributions were compared by Mann–Whitney testfor continuous data. Group differences in duration of hospitalization, intravenousantibiotics, intravenous antifungals and intravenous antivirals were assessed byusing the Mann–Whitney test. In the multivariate analysis, adjustments were madefor WBC (<5 × 109/L vs. ≥5 × 109/L, <30 × 109/L vs. ≥30 × 109/L), age (<50 vs. ≥50),gender (control arm vs. G-CSF arm) and type of AML (myeloblastic type; control armvs. G-CSF arm, non-myeloblastic type; control arm vs. G-CSF arm). Overall survival(OS) was defined as the time interval from randomization until death. Disease freesurvival (DFS) was defined as the time from CR until the first relapse. For the time-to-events end points (OS; DFS) the actuarial curves were computed using the KaplanMeier technique. Differences between curves were tested for statistical significanceusing the stratified 2-tailed log-rank test. Estimate of the cumulative incidenceof relapse and of death in CR and their corresponding SEs (standard errors) wereobtained using competing risk methods. The Cox proportional hazards model hasbeen used to obtain the estimate and the 95% confidence interval (CI) of the hazardratio (HR) of the instantaneous event rate in one treatment arm vs. the control arm.The significance level was set at p < 0.05.

3. Results

A total of 260 patients were included in the study betweenMay 1995 and September 1998. Median age was 38.5 years (range,16–60); 56.9% were male and 43.1% were female. Patients wererandomized into two arms: G-CSF arm (n = 123) and control arm(n = 137). The arms were balanced with respect to sex, age, andpresence of fever, febrile neutropenia, extramedullary disease andFAB subtypes (Table 1). Majority of patients had M2, M4-5 or M1-2subtypes in both arms. Cytogenetics was informative in only 25%of the patients (data not included). One patient in each group couldnot complete the 10-day chemotherapy, but since intent to treatanalysis was planned, all patients were included in statistical eval-uations.

3.1. Outcome

Effects of G-CSF on induction therapy outcome are summarizedin Table 2. The CR rate, CR rate following single cycle of inductiontherapy, refractoriness, relapse and mortality rates were similar inboth arms. The duration of fever in the G-CSF arm was not dif-ferent from that in the control arm (8.0 days vs. 8.5 days). Theuse of antibacterial, antifungal and antiviral therapies was alsonot affected by the use of G-CSF (Table 2). None of the patientsin the control arm received G-CSF for infectious reasons. Though,the duration of hospitalization was shorter in the G-CSF arm, thedifference was not significant. The effect of G-CSF on WBC recov-ery is also shown in Table 2. Severity and duration of leukopenia

rm effects of granulocyte colony-stimulating factor during induc-ults of a randomized multicenter phase III trial. Leuk Res (2010),

higher in G-CSF arm. The need for RBC or platelet transfusionswas similar between the two arms (Table 2). Number of patientswho received an allogeneic transplant from a sibling donor (n = 13)and autologous peripheral stem cells (n = 14) were statistically bal-

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Table 1Characteristics of the patients enrolled in the study.

Arm A (n = 137) Arm B (n = 123) p

SexMale 74 (54%) 74 (60.2%) 0.32Female 63 (46%) 49 (39.8%)Age 38.3 ± 14.0 38.9 ± 13.5 0.72

Symptoms at diagnosis (%)Fever 36.8 42.5 0.36Febrile neutropenia 35.1 34.7 0.95Gingival hypertrophy 13.5 12.0 0.71Granulocytic sarcoma − 0.9 0.47Lymphadenomegaly 26.3 30.3 0.49Hepatomegaly 34.6 23.3 0.04Splenomegaly 30.8 25.0 0.30CNS involvement 2.3 1.7 0.73Skin involvement 27.8 26.9 0.87Lung involvement 11.5 10.8 0.88Other 9.8 7.6 0.52

FAB (%)M0 4.4 2.4M1 1.5 1.6M1-2 16.8 14.6M2 21.9 30.9M4 1.5 1.6M4-5 27.7 29.3M5 11.7 6.5M6 5.8 4.1

F

a2(afFb(iiautof

Fig. 2. Overall survival of all patients in the G-CSF arm and control arm.

Table 3Overall survival according to gender.

OS-days [median (SE)] p

Male Female

All patients 152 (35) 437 (150) 0.006Control arm 136 (44) 407 (122) 0.063G-CSF arm 152 (60) 649 (NA*) 0.037

G-CSF: granulocyte colony-stimulating factor; SE: standard errors; OS: overall sur-vival; NA: not applicable (*the last uncensored patient defines the median, SE cannot

TE

CM

M7 0.0 0.8Unclassified 8.8 8.1

AB: French-American-British.

nced among arms A and B. Median survival in the G-CSF arm was39 days compared with 184 days in the control arm (p = 0.38)Fig. 2). Three-year survival rates were similar between arms And B (25.6 ± 5.1% vs. 31.8 ± 5.6%). Kaplan Meier analysis was per-ormed to determine the factors affecting OS; i.e. age, WBC counts,AB subtype, and G-CSF use. Univariate survival analysis revealedetter outcomes in FAB subtype M2 (p = 0.013), one induction cyclep < 0.0001) and female sex (p = 0.006) (Tables 3 and 4). After adjust-ng these factors according to G-CSF use, FAB subtype M2, onenduction cycle and gender continued to be significant. Multivari-

Please cite this article in press as: Beksac M, et al. Short and long tetion therapy in acute myeloid leukemia patients younger than 65: Resdoi:10.1016/j.leukres.2010.07.005

te Cox regression analysis (backward analysis) showed that, G-CSFse (p = 0.049), female sex (p = 0.050) and application of one induc-ion cycle (p < 0.001), were statistically significant. When the effectf female sex in arms A and B were analyzed, survival advantage ofemale sex was seen in both arms but was significant only in the

able 2ffects of G-CSF on response following induction therapy.

Arm A

CR (%) 64.6CR with 1 cycle 86.0CR with 2 cycles 14.0

Rate of refractoriness (%) 20.3Rate of relapse (%) 36.6Rate of mortality (%) 43.0Duration of OS, days (median ± SD) 184 ±Fever, days [median (min–max)] 8.5 (0.Antibacterial therapy (%) 92.4Antifungal therapy (%) 61.8Antiviral therapy (%) 5.3Erythrocyte transfusion, unit [median (min–max)] 6.0 (0.Platelet transfusion, unit [median (min–max)] 7.5 (0.Duration of hospitalization, days [median (min–max)] 35.0 (3Day 7 WBC, ×109/L [median (min–max)] 0.7 (0–Day 14 WBC, ×109/L [median (min–max)] 0.4 (0–Day 21 WBC, ×109/L [median (min–max)] 0.5 (0.Day 28 WBC, ×109/L [median (min–max)] 1.8 (0.

R: complete response; OS: overall survival; WBC: white blood cell; SD: standard deviatiean and median survival times were calculated using Kaplan Meier survival analysis an

be calculated).Median survival times were calculated using Kaplan Meier survival analysis andwere compared using the log-rank test.

control arm (Table 3). Relative risk ratios for the variables identifiedto be significant by the Cox regression was summarized in Table 5.

3.2. Adverse events

rm effects of granulocyte colony-stimulating factor during induc-ults of a randomized multicenter phase III trial. Leuk Res (2010),

The nature and incidence of adverse events and causes of deathreported were similar in both arms. The most frequently reportedadverse events were rash, musculoskeletal pain and fever. Capillaryleakage syndrome and Sweet’s syndrome were not reported.

(n = 137) Arm B (n = 123) p

62.5 0.7293.3 0.106.725.3 0.4029.8 0.3647.9 0.42

65 239 ± 81 0.380–28) 8.0 (1.0–27) 0.96

91.6 0.8263.0 0.858.4 0.34

0–23) 6.0 (1.0–29) 0.970–96) 8.0 (1.0–72) 0.79.0–80.0) 31.0 (9.0–72.0) 0.1825) 0.7 (0.1–98) 0.3310) 0.5 (0–24) 0.12

1–9.6) 0.6 (0.1–37) 0.081–9.3) 3.2 (0.1–55.9) 0.003

on.d were compared using the log-rank test.

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Table 5Relative risk ratios of the variables in Table 4.

Relative risk (95% CI)

Arm A vs. arm B 1.5 (1.0–2.1)No remission vs. CR after 1st cycle 11.1 (7.3–17.0)No remission vs. CR after 2nd cycle 4.0 (2.0–7.9)Male vs. female 1.5 (1.0–2.1)

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. Discussion

Filgrastim (recombinant methionyl human granulocyte colony-timulating factor [r-metHuG-CSF]) is a growth factor thattimulates the survival, proliferation, differentiation, and functionf progenitor and mature cells of the granulocytic lineage [10]. Initro studies have shown that exposure to myeloid-GFs, increasehe susceptibility of leukemic cells to cell cycle-specific chemother-peutic agents. It was hypothesized that administration of G-CSFight improve the outcome of chemotherapy for AML [1,5]. The

se of myeloid-GFs may also slightly shorten the duration of neu-ropenia and hospitalization, but do not necessarily modify CR ratend survival when given during induction chemotherapy [11–28].ased on these evidences, this prospective randomized multicen-er trial was initiated to assess the efficacy and safety of G-CSFFilgrastim) as an adjunct to remission induction therapy in deovo AML patients. The primary objective of this study was to

nvestigate the impact of G-CSF on response as well as severitynd duration of leukopenia, duration of hospitalization and use ofntimicrobials. This study showed no benefit arising from use of-CSF on CR (62.5% vs. 64.6%, p = 0.72), refractoriness (25.3% vs.0.3%, p = 0.40), relapse (29.8% vs. 36.6%, p = 0.36) and mortalityates (47.9% vs. 43%, p = 0.42). However G-CSF use had a border-ine impact on duration of survival (RR: 1.5) (p = 0.049) but not onhree-year OS rates. Univariate analysis revealed better outcomesn some subgroups; patients with AML-M2 (p = 0.013), patients whochieved CR with a single induction cycle (p < 0.0001) and femaleender (p = 0.006). Multivariate analysis confirmed the significantole of gender (p = 0.05) and number of induction cycles (p < 0.001).ccording to our results, G-CSF as applied in this protocol does notppear to affect the antileukemic activity of current chemotherapy.ur data, in accordance with previously published reports, indicate

hat the administration of G-CSF does not worsen the outcome ofe novo AML, and its use during induction therapy of de novo AMLs safe with minor survival effects [1,2,11,13,15].

Neutropenia associated with sepsis remains a major cause of

Please cite this article in press as: Beksac M, et al. Short and long tetion therapy in acute myeloid leukemia patients younger than 65: Resdoi:10.1016/j.leukres.2010.07.005

orbidity and mortality, and causes high health care costs. Theajority of deaths occur early, within the first 28 days of induction

reatment [2]. Therefore, reduction in the duration of neutropenias essential not only for reducing infection-related morbidity and

able 4esults of univariate survival analysis.

Parameter p-valueunivariatea

p-value adjustedfor G-CSF useb

Age (<50 vs. ≥50) 0.10 0.11WBC (<5 × 109/L vs.≥5 × 109/L)

0.088 0.092

WBC (<30 × 109/Lvs. ≥30 × 109/L)

0.14 0.17

M0 0.07 0.090M1 0.89 0.86M2 0.013 0.015M4 0.62 0.62M5 0.29 0.26M6 0.28 0.38Induction cycle CRwas achieved

<0.0001 <0.0001

Gender 0.006 0.005G-CSF 0.38 −Extramedullaryinvolvement

0.40 0.39

Fever 0.27 0.29Hepatosplenomegaly 0.35 0.50

BC: white blood cell; CR: complete response; G-CSF: granulocyte colony-timulating factor.

a Log-rank-test.b Log-rank test (p-values controlled for G-CSF use).

CR: complete response and CI: confidence interval.

mortality but also has the potential to improve quality of life, rateof remission, OS, and to reduce the overall cost of supportive care.When given after chemotherapy for solid tumors, G-CSF was shownto shorten the duration of severe neutropenia, with no influence oninfection-related mortality duration of hospitalization or need forantimicrobial therapy [29]. Recently a systematic review in solidtumors emphasized the role of G-CSF as a prophylactic agent toreduce the risk of febrile neutropenia and early deaths, includinginfection-related mortality. However the authors also concludedthat current data is insufficient to assess the impact of G-CSF onDFS and OS in such patients [30]. A number of controlled stud-ies have been undertaken to evaluate the use of myeloid-GFs inpatients with AML [2,4,8,12–27,31,32]. A correlation between res-olution of fever, neutrophil recovery and benefits expected to beassociated with shorter neutropenia; i.e. frequencies of infections,days of fever, use of antibiotics and duration of hospitalization werenot observed in these studies. In our study, severity and duration ofleukopenia were improved with G-CSF; days 21 and 28 leukocytecounts were higher in G-CSF arm (0.5 vs. 0.6, p = 0.08; 1.8 vs. 3.2,p = 0.003). Despite the faster leukocyte recovery, no reduction in theresolution of fever or frequency of febrile neutropenia was observedin the G-CSF arm. Also RBC or platelet transfusion need was notinfluenced. Although, the median duration of hospitalization wasshorter in the G-CSF arm, this did not confer to a significant reduc-tion in the need for antibacterial, antifungal and antiviral agents,which contradict with some but not most of the previous reports[2]. Thus in accordance with published reports, we may concludethat, G-CSF administration has a potential to protect some patientsfrom infection but is not effective on the duration of fever [7,31–34].Since G-CSF does not influence the risk of infectious complicationsin patients undergoing induction therapy for AML, the routine useof G-CSF in these patients is not advocated [35,36]. Within our expe-rience, use of G-CSF starting on day 8 until neutrophil recoveryprolonged median duration of survival in female patients and thosewith myeloblastic features. Such an effect is a borderline advantagewhich prevents routine use of G-CSF in AML. However our currentresults is in favor of a possibility for an advantage among patientswith certain features.

The negative impact of male sex in acute leukemia is known fora long time. Although etiology is less clear, genetic susceptibilityfactors for the development of leukemia are more apparent amongmale subjects. To our knowledge, the role of gender as a prognosticfactor in AML has been addressed in only two publications [37,38].The association between the good prognostic NMP1 mutations andthe female sex is the closest finding to our results [39]. G-CSF usewas not included in any of these studies. Similarly none of the stud-ies on GF use in AML included sex as a prognostic factor. In ourstudy the better outcome in a subgroup of patients with AML-M2and female sex are findings that have not been reported previ-ously. Also the benefits of G-CSF use were more evident amongfemale patients. Since this is the first report showing an advantageof female sex and G-CSF use, it needs to be confirmed in future.

rm effects of granulocyte colony-stimulating factor during induc-ults of a randomized multicenter phase III trial. Leuk Res (2010),

However we are aware of the fact that, it is essential to analyze theimpact of gender in the presence of cytogenetic analysis, the mostsignificant prognostic risk assessment tool.

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In conclusion, this study has shown that Filgrastim does notorsen the outcome of the disease in patients with de novo AML;

s the CR rate, rate of refractoriness, rate of relapse, rate of deathnd duration of survival are similar between arms A and B. Theesults suggest that G-CSF, administered during induction therapyan decrease the time to neutrophil recovery, duration of hospital-zation without adversely affecting toxicity or mortality. The betterurvival in patients with AML-M2 and/or female gender need to beonfirmed by other groups.

onflict of Interest

There are none.

cknowledgements

The authors are indebted to the efforts of all the institutionsho participated in the trial and their data management teams.lso the authors would like to thank to all physicians including Dr.emra Dundar, who died in 2005, and their patients for this col-aborative effort. Filgrastim was supplied by Roche, This study wasartially supported by the Turkish Academy of Sciences. Monitoringnd statistical analysis were performed by an independent clini-al research organization (OMEGA, Ankara, Turkey). And a specialhank you to the following hospitals and investigators that partic-pated in this trial: Akdeniz University, Antalya, Turkey (L. Undar);nkara University, Ankara, Turkey (M.B., M.O., O. l., G.G., A.U., H.A.,.A.); Cukurova University, Adana, Turkey (S.P.); Dokuz Eylul Uni-ersity, Izmir, Turkey (B. Undar); Ege University, Izmir, Turkey (S.agirgan); Erciyes University, Kayseri, Turkey (A. Unal, M. Cetin);ulhane Military University, Ankara, Turkey (A. U. Ural, C. Beyan);acettepe University, Ankara, Turkey (S. Dundar, O.O., Y.B.); Inonuniversity, Malatya, Turkey (I. Aydogdu); Istanbul University oferrahpasa, Istanbul, Turkey (B. Ferhanoglu); Istanbul Universityf Istanbul, Istanbul, Turkey (D. Sargin, Sevgi Kalayoglu-Besisik);armara University, Istanbul, Turkey (M.B.); Osmangazi Univer-

ity, Eskisehir, Turkey (Z. Gulbas); Uludag University, Bursa, TurkeyA.T., R.A., F.O., T.O.).

Contributions: M.B. provided the conception and design of thetudy, or acquisition of data, or analysis and interpretation of data;rafting the article or revising it critically for important intellectualontent and final approval of the version to be submitted; M.O.,.A.S. and A.T. provided the conception and design of the study, orcquisition of data, or analysis and interpretation of data and finalpproval of the version to be submitted; R.A. and T.O. provided therafting the article or revising it critically for important intellec-ual content and final approval of the version to be submitted and.O, M.B., S.P., Y.B., O.I., F.O., G.G., A.U. and H.A. provided the finalpproval of the version to be submitted.

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