RESUMO
In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.
RESUMO
BACKGROUND: Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. METHODS: In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. RESULTS: In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL- 1 in D0 vs. 10.9; 0 to 26.81 pg mL- 1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups (p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls. CONCLUSIONS: We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.
Assuntos
Antineoplásicos/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Interleucina-8/sangue , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Feminino , Humanos , Interleucina-6/sangue , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Halofuginone (HF) is a low-molecular-weight alkaloid that has been demonstrated to interfere with Metalloproteinase-2 (MMP-2) and Tumor Growth Factor-ß (TGF-ß) function and, to present antiangiogenic, antiproliferative and proapoptotic properties in several solid tumor models. Based on the fact that high levels of Vascular Endothelial Growth Factor (VEGF) and increased angiogenesis have been described in acute myeloid leukemia and associated with disease progression, we studied the in vivo effects of HF using an Acute Promyelocytic Leukemia (APL) mouse model. METHODS: NOD/SCID mice were transplanted with leukemic cells from hCG-PML/RARA transgenic mice (TM) and treated with HF 150 µg/kg/day for 21 days. The leukemic infiltration and the percentage of VEGF+ cells were evaluated by morphology and flow cytometry. The effect of HF on the gene expression of several pro- and antiangiogenic factors, phosphorylation of SMAD2 and VEGF secretion was assessed in vitro using NB4 and HUVEC cells. RESULTS: HF treatment resulted in hematological remission with decreased accumulation of immature cell and lower amounts of VEGF in BM of leukemic mice. In vitro, HF modulated gene expression of several pro- and antiangiogenic factors, reduced VEGF secretion and phosphorylation of SMAD2, blocking TGF-ß-signaling. CONCLUSION: Taken together, our results demonstrate that HF inhibits SMAD2 signaling and reduces leukemia growth and angiogenesis.
Assuntos
Leucemia Promielocítica Aguda/metabolismo , Piperidinas/metabolismo , Quinazolinonas/metabolismo , Proteína Smad2/genética , Animais , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Neovascularização Patológica , Fosforilação , Proteína Smad2/metabolismo , Células Tumorais CultivadasRESUMO
Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Criança , DNA de Neoplasias/genética , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Hemoglobinas/análise , Humanos , Idarubicina/administração & dosagem , Estimativa de Kaplan-Meier , América Latina/epidemiologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
We investigated the prevalence of TET2 deletion by using a new FISH probe in a cohort of 362 Brazilian patients with myeloid neoplasms and their association with cytogenetic information (G-banding analysis). Normal karyotype was observed in 45.8 % of MDS (n = 44), 43.8 % of AML (n = 39) and 46.3 % of MPN (n = 82). Abnormalities of 4q24 (deletions, translocations or inversions) were associated with another chromosomal abnormality in four patients by G-banding analysis (2 MDS, 1 AML and 1 MPN). Interphase FISH analysis revealed deletion of TET2 in 21 patients (6 patients with abnormal karyotype and in 15 patients with normal karyotype). arrayCGH analysis revealed a cryptic deletion of the region 4q24 in all eight patients selected with myeloid malignancies (3 MDS, 1 AML and 4 MPN). Considering the significantly high cost of determining the mutational status of TET2 in patient samples by using conventional sequencing methods and sometimes the lack of regular use of SNP/aCGH array methodologies, FISH for the detection of TET2 abnormalities may become a potentially useful clinical tool. The search for alterations in TET2 gene may be important for the prediction of prognosis in normal/altered AML patients' karyotype or in the disease evolution of patients with MNP and MDS.
Assuntos
Proteínas de Ligação a DNA/genética , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Proto-Oncogênicas/genética , Cariótipo Anormal , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Bandeamento Cromossômico , Cromossomos Humanos Par 4 , Estudos de Coortes , Hibridização Genômica Comparativa/métodos , Dioxigenases , Feminino , Deleção de Genes , Neoplasias Hematológicas/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Increased fibrinolysis is an important component of acute promyelocytic leukemia (APL) bleeding diathesis. APL blasts overexpress annexin II (ANXII), a receptor for tissue plasminogen activator (tPA), and plasminogen, thereby increasing plasmin generation. Previous studies suggested that ANXII plays a pivotal role in APL coagulopathy. ANXII binding to tPA can be inhibited by homocysteine and hyperhomocysteinemia can be induced by L-methionine supplementation. In the present study, we used an APL mouse model to study ANXII function and the effects of hyperhomocysteinemia in vivo. Leukemic cells expressed higher ANXII and tPA plasma levels (11.95 ng/mL in leukemic vs 10.74 ng/mL in wild-type; P = .004). In leukemic mice, administration of L-methionine significantly increased homocysteine levels (49.0 µmol/mL and < 6.0 µmol/mL in the treated and nontreated groups, respectively) and reduced tPA levels to baseline concentrations. The latter were also decreased after infusion of the LCKLSL peptide, a competitor for the ANXII tPA-binding site (11.07 ng/mL; P = .001). We also expressed and purified the p36 component of ANXII in Pichia methanolica. The infusion of p36 in wild-type mice increased tPA and thrombin-antithrombin levels, and the latter was reversed by L-methionine administration. The results of the present study demonstrate the relevance of ANXII in vivo and suggest that methionine-induced hyperhomocysteinemia may reverse hyperfibrinolysis in APL.
Assuntos
Anexina A2/metabolismo , Fibrinólise/fisiologia , Hiper-Homocisteinemia/induzido quimicamente , Leucemia Promielocítica Aguda , Metionina/farmacologia , Animais , Anexina A2/farmacologia , Coagulação Sanguínea/fisiologia , Transplante de Medula Óssea , Modelos Animais de Doenças , Fibrinolisina/metabolismo , Homocisteína/sangue , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Ativador de Plasminogênio Tecidual/sangueRESUMO
Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) expression in acute promyelocytic leukemia (APL) impairs transforming growth factor beta (TGFß) signaling, leading to cell growth advantage. Halofuginone (HF), a low-molecular-weight alkaloid that modulates TGFß signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RARα transgenic mice (TG). Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001) and induced apoptosis (Pâ=â0.002) after a 24-hour incubation. Addition of TGFß revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFß target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21) and down-regulation of MYC. Additionally, TGFß protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFß values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFß blockade in APL. Since loss of the TGFß response in leukemic cells may be an important second oncogenic hit, modulation of TGFß signaling may be of therapeutic interest.
Assuntos
Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Contagem de Células Sanguíneas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/genética , Camundongos , Camundongos SCID , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
We analyzed the effect of (+)alpha-tocopheryl succinate (alpha-TOS) alone or associated with arsenic trioxide (ATO) or all-trans retinoid acid (ATRA) in acute promyelocytic leukemia (APL). alpha-TOS-induced apoptosis in APL clinical samples and in ATRA-sensitive (NB4) and ATRA-resistant (NB4-R2) APL cell lines. The effective dose 50% (ED-50) was calculated to be 71 and 58muM, for NB4 and NB4-R2, respectively. alpha-TOS neither induced nor modified ATRA-induced differentiation of APL cells, and did not affect the proliferation and differentiation of normal CD34(+) hematopoietic progenitors in methylcellulose assays. alpha-TOS exerted a moderate antagonistic effect to ATO-induced apoptosis when treatment was done simultaneously but when alpha-TOS was added 24h after ATO, an additive effect was observed. Our results support the concept of alpha-TOS as an anti-leukemic compound which spares normal hematopoiesis.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Óxidos/farmacologia , Tretinoína/farmacologia , alfa-Tocoferol/farmacologia , Antioxidantes/farmacologia , Trióxido de Arsênio , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Inibidores do Crescimento/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Leucemia Promielocítica Aguda/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVES: Differentiation Syndrome (DS) is a treatment complication which can occur in patients treated with acute promyelocytic leukemia (APL) with all transretinoic acid (ATRA) or As(2)O(3), and is characterized by enhanced leukocyte transmigration. As(2)O(3), Phenylbutyrate (PB) and G-CSF are known to potentiate ATRA effects. Our aim was to analyze the changes in expression and function of adhesion molecules induced by ATRA, As(2)O(3), G-CSF and PB, and their association. DESIGN AND METHODS: APL blasts and NB4 cells were treated with ATRA, As(2)O(3), PB, G-CSF or their association and the expression of adhesion molecules was determined by flow cytometry. Cell adhesion was evaluated in vitro using Matrigel and for the in vivo analysis, Balb-c mice were injected with NB4 cells pre-treated with ATRA, As(2)O(3), ATRA+G-CSF or ATRA+As(2)O(3). In addition, CD54 and CD18 knock-out mice were injected with NB4 cells and concomitantly treated with ATRA. In both models, the MPO activity in the lungs was determined 6 hours after the injection of the cells. RESULTS: In NB4 and APL blasts, ATRA and As(2)O(3) increased CD54 expression, but no synergism was detected. CD11b and CD18 were also up-regulated by ATRA in primary cells. PB and G-CSF had no effect, but the latter potentiated ATRA-induced CD18 up-regulation. These changes were accompanied by increased adhesion to Matrigel and to lung microvasculature, and reversed by anti-CD54, anti-CD18 antibodies. In CD54 and CD18 knock-out mice the ATRA effect was canceled. INTERPRETATION AND CONCLUSIONS: The use of As(2)O(3), PB and G-CSF in association with ATRA should not aggravate DS in APL.
Assuntos
Antígenos CD/biossíntese , Antineoplásicos/farmacologia , Arsenicais/farmacologia , Moléculas de Adesão Celular/biossíntese , Diferenciação Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias/biossíntese , Óxidos/farmacologia , Fenilbutiratos/farmacologia , Tretinoína/farmacologia , Animais , Antígenos CD/genética , Antineoplásicos/agonistas , Trióxido de Arsênio , Arsenicais/agonistas , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Moléculas de Adesão Celular/genética , Diferenciação Celular/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/genética , Fator Estimulador de Colônias de Granulócitos/agonistas , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas de Neoplasias/genética , Óxidos/agonistas , Fenilbutiratos/agonistas , Síndrome , Tretinoína/agonistas , Células Tumorais CultivadasRESUMO
BACKGROUND: Acute Promyelocytic Leukemia (APL) is characterized by its good response to treatment with all trans retinoic acid (ATRA). However, some patients receiving ATRA develop a serious complication called retinoid syndrome (RS). The objective of this study was to compare the hematological and immunophenotypic features of APL patients who developed RS with those who did not. METHODS: We reviewed the medical records, roentgenograms, peripheral blood smears and bone marrow aspirates from 71 APL patients. Immunophenotypic analyses were available in 56 of these cases. Eight cases of RS were detected, whose clinical presentation was characterized by respiratory distress (n = 8), impairment of the renal function (n = 2), fever (n = 5), weight gain (n = 3), edema (n = 3) and/or pleural effusion (n = 5). The following variables were compared in patients with and without RS: hemoglobin levels, leukocyte and platelet counts, frequency of hypergranular and variant morphological subtypes, percentages of CD33+, CD13+, CD117+ blasts in the bone marrow, fluorescence intensity and variation of these markers in the leukemic cells, expressed as the median channel of fluorescence (MCF) and fluorescence coefficient of variation (CV), respectively. RESULTS: RS incidence was 11.26% and the average time for syndrome development was 11.5 days after starting ATRA treatment. All patients presented acute respiratory distress. Other symptoms included fever, weight gain, edema and renal insufficiency. The main radiological findings were ground glass opacities, increased vascular pedicle and peribronchial cuffing. There was no significant correlation between the variables selected and the risk of development of RS, however the Odds Ratios for patients presenting MCF for CD117 > 30 ua and CV for CD33 < 50 were of 7.14 (P = 0.08) and 7.86 (P = 0.06), respectively. CONCLUSIONS: The incidence, as well as the clinical, radiological and laboratory features of RS in this group of Brazilian APL patients were similar to those described in literature. None of the variables studied were significantly correlated to a higher risk of developing RS.
Assuntos
Antineoplásicos/efeitos adversos , Tretinoína/efeitos adversos , Adolescente , Adulto , Distribuição por Idade , Criança , Métodos Epidemiológicos , Feminino , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Distribuição por Sexo , SíndromeRESUMO
OBJETIVO: A leucemia promielocítica aguda (LPA) apresenta uma boa resposta ao tratamento com o ácido all trans retinóico (ATRA). Entretanto, alguns pacientes desenvolvem uma complicação grave chamada síndrome do ácido retinóico (SAR). O objetivo deste estudo foi comparar as características hematológicas e imunofenotípicas de pacientes com LPA que desenvolveram a SAR com as daqueles que não a desenvolveram. MÉTODOS: Foram analisados retrospectivamente os prontuários, exames radiológicos, lâminas de esfregaço de sangue e medula óssea de 71 pacientes com LPA, dos quais a análise imunofenotípica havia sido realizada em 56 casos. Foram identificados oito casos de SAR que, do ponto de vista clínico, caracterizaram-se por insuficiência respiratória (n=8), insuficiência renal (n=2), febre (n=5), ganho ponderal (n=3), edema periférico (n=3) e derrame pleural (n=5). As seguintes variáveis foram comparadas entre pacientes com e sem SAR: dosagem de hemoglobina, contagens de leucócitos e plaquetas no sangue periférico, distribuição dos subtipos hipergranular e variante, percentagens de blastos CD33+, CD13+, CD117+ na medula óssea, intensidade e variação dos valores de fluorescência destes antígenos nas células leucêmicas, expressas através dos canais medianos (CMFs) e dos coeficientes de variação (CVs) de fluorescência, respectivamente. RESULTADOS: A incidência da SAR foi de 11,26 por cento e o tempo médio para seu desenvolvimento 11,5 dias do início do tratamento. Todos os pacientes apresentaram desconforto respiratório agudo, por vezes associado à febre, ganho de peso, edema e insuficiência renal. Os achados radiológicos mais comuns foram: opacidades em vidro fosco, derrame pleural, espessamento peribrônquico e aumento da trama vascular pulmonar. Nenhuma das variáveis laboratoriais analisadas correlacionou-se significativamente ao risco de desenvolvimento da SAR, entretanto as Odd Ratios para CMF para o CD117 > 30 ua e CV para o CD33 < 50 foram de 7,14 (P=0,08) e de 7,86 (P=0,06), respectivamente. CONCLUSAO: A incidência e as características da SAR neste grupo de pacientes brasileiros foi semelhante à descrita na literatura. Nenhum dos parâmetros estudados correlacionou-se significativamente a um maior risco de desenvolvimento desta complicação.