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1.
Zhonghua Nei Ke Za Zhi ; 58(11): 796-802, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665853

RESUMO

Objective: To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities, therefore optimizing the treatment strategies. Methods: Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were assessed by multivariate Logistic and Cox regression models in a total of 206 adults (aged 16-65 years) with CBF-AML, including 152 AML patients with t(8;21) and 54 with inv(16). Results: The CR rate of inv(16) patients after first course was 54/54(100%), significantly higher than that of t(8;21) patients [127/147(86.4%), P=0.005]. The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21) patients (P=0.044 and 0.027; respectively). DFS and OS in inv(16) patients tended to be more superior than that in t(8;21) patients (P=0.066 for DFS; P=0.306 for OS; respectively). Multivariate Cox identified negative expression of CD(19) and female gender the independent predictors of inferior DFS in t(8;21) patients (P=0.000 for CD(19); P=0.006 for sex; respectively). Analysis of combining CD(19) with gender indicated that females/CD(1)(9-)subpopulation had significantly poor DFS than did males/CD(19)(+) ones (Bonferroni-P<0.000 01). The number of mutations in each patient, FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS (all P>0.05). Conclusions: Patients with inv(16) have better induction response than those with t(8;21). High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21) patients. Negative CD(19) expression and female gender are independent predictors of inferior DFS in t(8;21) patients.


Assuntos
Fatores de Ligação ao Core , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Indução de Remissão , Adolescente , Adulto , Idoso , China/epidemiologia , Fatores de Ligação ao Core/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
2.
Medicine (Baltimore) ; 98(43): e17314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651837

RESUMO

This study aimed to investigate the prevalence/severity of anxiety and depression, and also their correlations with clinical characteristics and survival profiles in acute myeloid leukemia (AML) patients.In all, 208 AML patients and 200 age and sex-matched healthy controls (HCs) were recruited in this study. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS) in AML patients before initiating therapy and in HCs after being enrolled. Treatment response was assessed, and event-free survival (EFS), and also the overall survival (OS) were calculated.The HADS-anxiety score (P < .001), anxiety prevalence (P < .001), and anxiety severity (P < .001) were increased in AML patients than those in HCs. The HADS-depression score (P < .001), depression prevalence (P < .001), and also depression severity (P < .001) were higher in AML patients compared with HCs. No correlation of anxiety or depression with clinical characteristics was found in AML patients (all P > .05). Moreover, the anxiety (P = .178) and depression (P = .512) rates were similar between complete remission (CR) patients and non-CR patients. Additionally, the EFS was worse in anxiety patients compared with nonanxiety patients (P = .013). The OS was shorter in anxiety patients compared with nonanxiety patients (P = .015) and was also worse in depression patients compared with nondepression patients (P = .007).Anxiety and depression are much more frequent and severe in AML patients compared to HCs, and both of them predict unfavorable survival profiles in AML patients.


Assuntos
Ansiedade/mortalidade , Depressão/mortalidade , Leucemia Mieloide Aguda/mortalidade , Adulto , Antineoplásicos/uso terapêutico , Ansiedade/etiologia , Estudos de Casos e Controles , Depressão/etiologia , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/psicologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Índice de Gravidade de Doença
3.
N Engl J Med ; 381(18): 1728-1740, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31665578

RESUMO

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Pirazinas/uso terapêutico , Terapia de Salvação , Tirosina Quinase 3 Semelhante a fms/genética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Recidiva , Indução de Remissão , Análise de Sobrevida
4.
Ann Hematol ; 98(10): 2319-2328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31396671

RESUMO

Triple-negative primary myelofibrosis (TN-PMF) and other myeloid neoplasms with associated bone marrow fibrosis such as the myelodysplastic syndromes (MDS-F) or the myelodysplastic/myeloproliferative neoplasms (MDS/MPN-F) are rare entities, often difficult to distinguish from each other. Thirty-four patients previously diagnosed with TN-PMF (n = 14), MDS-F (n = 18), or MDS/MPN-F (n = 2) were included in the present study. After central revision of the bone marrow histology, diagnoses according to the 2016-WHO classification were TN-PMF (n = 6), MDS-F (n = 19), and MDS/MPN-F (n = 9), with TN-PMF genotype representing only 4% of a cohort of 141 molecularly annotated PMF. Genomic classification according to next-generation sequencing and cytogenetic study was performed in 28 cases. Median number of mutations was 4 (range 1-7) in cases with TP53 disruption/aneuploidy or with chromatin-spliceosome mutations versus 1 mutation (range 0-2) in other molecular subgroups (p < 0.0001). The number of mutations and the molecular classification were better than PMF and MDS conventional scoring systems to predict survival and progression to acute leukemia. In conclusion, TN-PMF is an uncommon entity when the 2016 WHO criteria are strictly applied. Genomic classification may help in the prognostic assessment of patients with myeloid neoplasms with bone marrow fibrosis.


Assuntos
Neoplasias Hematológicas , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Mutação , Síndromes Mielodisplásicas , Mielofibrose Primária , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias Hematológicas/classificação , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Mielofibrose Primária/classificação , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Taxa de Sobrevida
5.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
6.
Lancet Haematol ; 6(9): e480-e488, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400961

RESUMO

BACKGROUND: Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. METHODS: This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657. FINDINGS: Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab. INTERPRETATION: Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies. FUNDING: The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Colite/etiologia , Citarabina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Exantema/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Nivolumabe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
7.
Adv Clin Exp Med ; 28(7): 861-869, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31199877

RESUMO

BACKGROUND: Cytostatic treatment induces apoptosis or other types of cell death like autophagy, necrosis, mitotic catastrophe, etc. Autophagy can play a role in the drug resistance of neoplastic cells, allowing the survival of blast cells under stressful conditions, such as the use of cytostatics. Studies on apoptosis and autophagy 12-24 h after the start of treatment have not been conducted until now. OBJECTIVES: The study aimed to investigate the predictive and prognostic significance of autophagy and apoptosis in patients with acute myeloid leukemia (AML). MATERIAL AND METHODS: The study included 38 patients. Blood was collected before and 12-24 h after the start of treatment, since at that time point, the appropriate blast cell count was still available. Autophagy was measured with the expression of the ATG5, MAP1L3, LC3-I, and LC3-II proteins. The percentage of mononuclear cells in early and late apoptosis was evaluated with flow cytometry, using the annexin V and propidium iodide (PI) binding assay. RESULTS: The percentage of apoptotic blast cells before treatment was not associated with the response. However, in the remission group, the overall percentage of apoptotic cells measured 12-24 h after the start of treatment was higher than in non-remission patients, which was statistically significant. In neither group we found any difference in the level of autophagy before and 12-24 h after the start of treatment. Nevertheless, we observed an increasing tendency of the MAP1LC3 protein expression (not statistically significant) in the remission group 12-24 h after the start of treatment. Patients with a higher percentage of blast cells in apoptosis and with a higher expression of MAP1LC3 protein measured 12-24 h after the start of the therapy had longer overall survival (OS). CONCLUSIONS: A higher percentage of apoptotic as well as autophagic blast cells measured 12-24 h after the start of the chemotherapy is an independent factor associated with better outcomes.


Assuntos
Apoptose , Autofagia , Crise Blástica , Leucemia Mieloide Aguda , Proteínas Associadas aos Microtúbulos/metabolismo , Antineoplásicos/uso terapêutico , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Prognóstico , Taxa de Sobrevida
8.
Nat Commun ; 10(1): 2723, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222014

RESUMO

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Transativadores/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Medula Óssea/patologia , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Transativadores/genética , Transativadores/metabolismo , Transcrição Genética/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Ann Hematol ; 98(9): 2073-2080, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201514

RESUMO

Patients with primary refractory or early relapsed acute myeloid leukemia (AML) have a dismal prognosis, and the treatment options for these patients are limited. The present study retrospectively examined the efficacy and toxicities of the combination of cladribine 5 mg/m2 per day and intermediate-dose cytarabine 1 g/m2 per day for 5 days and granulocyte colony-stimulating factor (G-CSF) as a salvage treatment in 36 patients with relapsed/refractory AML. Among these, 32 patients had de novo AML, and the remaining 4 patients had secondary AML. The median age for the study cohort was 45.8 years. According to the European LeukemiaNet prognostic index, 5 patients had favorable risk, 18 had intermediate risk, and 11 had poor risk. The complete remission was achieved in 58% of the patients with tolerable toxicities. Fifteen patients underwent stem cell transplantation later. Patients who underwent allogeneic hematopoietic stem cell transplantation had a significantly improved 1-year overall survival compared with those who did not (73% vs. 29%, P < 0.001). The results suggested that, as a salvage regimen, modified cladribine, cytarabine, and G-CSF were effective and well tolerated for patients with relapsed/refractory AML, especially for patients who underwent subsequent stem cell transplantation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Terapia de Salvação , Adulto , Idoso , Aloenxertos , Cladribina/administração & dosagem , Citarabina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Indução de Remissão
10.
Ann Hematol ; 98(9): 2179-2186, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203422

RESUMO

The prognosis of patients with acute myeloid leukemia (AML) is dismal after experiencing multiple relapses. This study retrospectively analyzed outcomes of allogeneic hematopoietic cell transplantation (HCT) for 192 adults with AML in third or subsequent complete remission (CR3+), 300 in second relapse (REL2), and 50 in third or subsequent relapse (REL3+) who were enrolled in a Japanese nationwide transplantation registry. The study population included patients undergoing umbilical cord blood transplantation, but not those undergoing haploidentical HCT. Patients transplanted in CR3+ had better survival than those transplanted in REL2 and REL3+ (48%, 21%, and 12% at 4 years; P < 0.001), and this was due to a reduction in post-transplant relapse (23%, 57%, and 52%; P < 0.001). The corresponding cumulative incidence of non-relapse mortality was 33%, 26%, and 36% (P = 0.022). Multivariate analysis revealed significantly lower relapse and overall mortality for those in CR3+ and significantly lower non-relapse mortality for those in REL2. Hazard ratios (95% confidence intervals) for overall mortality were 2.02 (1.56-2.64) for REL2+ versus CR3+ (P < 0.001) and 2.12 (1.40-3.19) for REL3+ versus CR3+ (P < 0.001). Our analysis demonstrates the curative potential of allogeneic HCT for patients with a history of multiple AML relapses and suggests the potential benefits and risks of reinduction attempt before transplantation, highlighting the need for an individualized approach in determining whether to give reinduction therapy in this setting.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida
11.
Nat Med ; 25(7): 1064-1072, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235963

RESUMO

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.


Assuntos
Genes Codificadores dos Receptores de Linfócitos T , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Proteínas WT1/genética , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Transplante Homólogo
12.
Medicine (Baltimore) ; 98(23): e15948, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169718

RESUMO

CXC chemokine receptor 4 (CXCR4) expression on acute myeloid leukemia (AML) cells correlated with stromal cell derived factor-1α (SDF-1α) and retained hematopoietic progenitors and leukemia cells within the bone marrow microenvironment. Here, we examined CXCR4 expression in 134 de novo AML and 21 controls by flow cytometry, evaluated the relationship between CXCR4 expression and clinical characteristics, and elucidated the prognostic significance of CXCR4 expression in AML prospectively. We found that the CXCR4 expression was significantly higher in AML patients than controls (P = .000). One hundred thirty four cases of de novo AML patients were divided into 2 groups according to the median of CXCR4 relative fluorescence intensity (RFI). CXCR4 high group (RFI >4.23) had markedly shorter overall survival (OS) and disease-free survival (DFS) than CXCR4 low group (RFI ≤4.23) in 106 AML patients who received chemotherapy (P = .002; .026, respectively). Furthermore, in the 87 non-M3 patients who received induction therapy, there was a significant decrease for OS but not for DFS in the CXCR4 high group (P = .047 and .178, respectively). Moreover, high levels of CXCR4 expression independently increased the risk of relapse in both all AML and non-M3 patients who achieved complete remission (CR) after chemotherapy (odds ratio = 1.090, P = .010; odds ratio = 1.068, P = .048, respectively). Collectively, our data suggest that CXCR4 overexpression was an independent prognostic factor for disease relapse and poorer OS in both all AML and non-M3 patients. CXCR4 expression levels can be determined at disease presentation by the flow rapidly and easily. As such, CXCR4 could be used as a potential therapeutic target in AML patients with poor prognosis.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Receptores CXCR4/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Medula Óssea/metabolismo , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Microambiente Tumoral , Adulto Jovem
13.
Ann Hematol ; 98(8): 1927-1932, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187237

RESUMO

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neutropenia Febril Induzida por Quimioterapia/mortalidade , Decitabina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo
14.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(1): 50-57, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31102358

RESUMO

OBJECTIVE: To investigate the expression of Wilms'tumor 1 (WT1) gene in patients with acute myeloid leukemia (AML), and to explore its application in predicting prognosis of AML in patients with wild or mutated nucleophosmin 1(NPM1) and Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). METHODS: One hundred and sixty-seven newly diagnosed AML patients(exclued M3 type) were enrolled in this study. The survival of patients were analyzed with Kaplan-Meier method. The clinical data, laboratory findings and the survival of patients were analyzed and compared between patients with high WT1 expression (high-WT1 group) and those with low WT1 expression (low-WT1 group), as well as among the patients with NPM1 or FLT3-ITD wild type and mutants. RESULTS: The overall response rates (ORR) in high-WT1 and low-WT1 groups were 65.9% (83/126) and 95.1% (39/41), respectively (P<0.01). Compared with the low-WT1 group, the high-WT1 group had lower 2-y overall survival (OS) rate (46.1% vs. 75.2%, P<0.05) and 2-y disease free survival (DFS) rate (43.5% vs. 68.5%, P<0.05). After induction chemotherapy, the patients with decreased WT1 gene expression ≥ 1log was associated with higher ORR and 2-y OS rate (all P<0.05), but the advantage of 2-y DFS rate was not shown (P>0.05). In patients with NPM1 wild type, the high-WT1 group had inferior ORR and 2-y OS rate (all P<0.05), while in the patients with FLT3-ITD wild type, the high-WT1 group had inferior ORR, 2-y OS rate and 2-y DFS rate (all P<0.05). In patients with NPM1 or FLT3 -ITD mutations, the WT1 expression had no significantly predicting values in treatment efficacy and survival (all P>0.05). CONCLUSIONS: WT1 gene overexpression indicated poor prognosis of AML patients; the patients with decreased WT1 gene expression ≥ 1 log after the first induction therapy show better prognosis than those with<1 log. The WT1 gene expression level at diagnosis can be used as an unfavorable prognostic factor for AML patients with NPM1 or FLT3-ITD wild types.


Assuntos
Leucemia Mieloide Aguda , Proteínas WT1/genética , Intervalo Livre de Doença , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutação , Proteínas Nucleares/genética , Prognóstico , Tirosina Quinase 3 Semelhante a fms/genética
15.
J Exp Clin Cancer Res ; 38(1): 200, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097000

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less understood that the miR-29b/Sp1/FUT4 crosstalk involved in the fucosylation-mediated LSCs malignancy in AML. METHODS: AML cell lines were sorted by magnetic microbeads to obtain the CD34 + CD38- sub-population. The key biomarkers for LSCs were identified by flow cytometry. Fucosyltransferase genes were screened by qRT-PCR, and FUT4 was focused. Effect of FUT4 on LSCs malignancy was determined by CCK8 assay, sphere formation assay, immunofluorescence staining, apoptosis and in vivo xenografts experiments. The linkage of FUT4 promoter and Sp1 was confirmed by dual-luciferase reporter gene assay. ChIP-PCR assay was used to show the directly binding of Sp1 and FUT4 promoter. Activity of Wnt//ß-catenin pathway was determined by western blot. Overall survival curves were diagrammed by Kaplan-Meier analysis. RESULTS: Here, the expressional profiles of 11 fucosyltransferase genes were different comparing LSCs and non-LSCs of KG-1a and MOLM13 cells, whereas CD34 + CD38- cells exhibited higher expression of FUT4. Functionally, alteration of FUT4 in CD34 + CD38- cells modulated LSCs malignant behaviors both in vitro and in vivo. Transcriptional inhibitor actinomycin D (Act D) or translational inhibitor cycloheximide (CHX) prevented LSCs progression, and Sp1 was identified as the efficient regulator of FUT4 transcription. Moreover, miR-29b directly affected the binding of Sp1 and FUT4 promoter region, which further mediated LSCs proliferation, apoptosis and drug-resistance through fucosylated-CD44 via activation of Wnt/ß-catenin pathway. Clinically, Sp1 and FUT4 were up-regulated and positively correlated with poor overall survival of AML patients. CONCLUSION: These data indicated that miR-29b/Sp1/FUT4 axis promoted the malignant behaviors of LSCs by regulating fucosylated CD44 via Wnt/ß-catenin pathway. Identifying LSCs surface markers and targeting LSCs were important for the development of potential therapies in AML.


Assuntos
Fucosiltransferases/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição Sp1/genética , Via de Sinalização Wnt , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Ann Hematol ; 98(7): 1641-1646, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041512

RESUMO

The aim of this study was to explore the clinical features and prognostic significance of CSF3R mutations in AML patients with CEBPA double mutations (CEBPAdm). One hundred one AML patients with CEBPAdm were retrospectively analyzed in this study. Mutation status of CSF3R gene, clinical features, and long-term outcomes were analyzed. The frequency of CSF3R mutations in patients with CEBPAdm was 19.80% (20/101). Patients with CSF3R mutations were associated with a lower platelet (u = 2.728, P = 0.006) and higher leukocytes (u = 3.178, P = 0.001) compared with those with wide-type CSF3R gene. The 5-year relapse-free survival (RFS) was 18.7% in patients with CSF3R mutations, which was significantly lower than those with wide-type CSF3R (31.8%) (P = 0.015). The 5-year overall survival (OS) was also significantly different between patients with and without CSF3R mutations (17.5% versus 57.4%, P = 0.019). The prevalence of CSF3R mutations was high in AML patients with CEBPAdm, which indicated a poor prognosis, and CSF3R mutations may be a new potential candidate for prognostically re-stratifying AML patients with CEBPAdm.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Proteínas de Neoplasias/genética , Receptores de Fator Estimulador de Colônias/genética , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Taxa de Sobrevida
17.
Medicine (Baltimore) ; 98(21): e15804, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124978

RESUMO

Acute myeloid leukemia (AML) is hematopoietic malignancy. This study was designed to develop an individualized prognostic nomogram to predict cancer-specific survival (CSS) and overall survival (OS) of AML.The clinical data of AML patients (n = 58,882) diagnosed from 1973 to 2014 were obtained from the Surveillance, Epidemiology, and End Results database. The patients were divided into training cohort (n = 29,441) and validation cohort (n = 29,441). The prognostic nomograms were designed with clinical variables selected by multivariate Cox regression model in training cohort. The concordance index (C-index), calibration curve, and receiver operating characteristic curve were used to assess the performance of the nomograms.The predictors in nomogram for CSS were AML subtypes, age, sex, region, marital status, and chemotherapy, whereas the predictors for OS were AML subtypes, age, sex, region, race, marital status, and chemotherapy. The C-indexes of the nomograms in internal validation for CSS and OS were 0.712 and 0.703, respectively, whereas the C-indexes in external validation for CSS and OS were 0.712 and 0.705, respectively. The area under the curve of receiver operating characteristic curves for CSS and OS were 0.799 (95% confidence interval: 0.792-0.806) and 0.809 (95% confidence interval: 0.803-0.816), respectively.The individualized prognostic nomogram could perform relatively accurate prediction of outcome in adult patients with AML.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Nomogramas , Idoso , Área Sob a Curva , Estudos de Coortes , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Programa de SEER , Análise de Sobrevida
18.
Nat Commun ; 10(1): 2189, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097698

RESUMO

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Inibidores de Janus Quinases/farmacologia , Leucemia Experimental/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Linhagem Celular Tumoral , Criança , Pré-Escolar , Citarabina/farmacologia , Citarabina/uso terapêutico , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Lactente , Inibidores de Janus Quinases/uso terapêutico , Leucemia Experimental/etiologia , Leucemia Experimental/mortalidade , Leucemia Experimental/patologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Taxoides/farmacologia , Taxoides/uso terapêutico , Irradiação Corporal Total/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
19.
BMC Cancer ; 19(1): 358, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30991992

RESUMO

BACKGROUND: Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML). METHODS: Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity ( Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy. RESULTS: The 65 patients (median age = 51 years, male:female = 34:31) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1-68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable: liver function abnormality (Grade 2, n = 1; Grade 3, n = 1) and allergic reaction (Grade 2, n = 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety. CONCLUSIONS: Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML. TRIAL REGISTRATION: Clinicaltrials.gov NCT02440178, registered May 12th 2015.


Assuntos
Antifúngicos/uso terapêutico , Quimioterapia de Indução/efeitos adversos , Leucemia Mieloide Aguda/complicações , Micafungina/uso terapêutico , Micoses/etiologia , Micoses/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Quimioterapia de Indução/métodos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Micoses/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Resultado do Tratamento , Adulto Jovem
20.
Ann Hematol ; 98(7): 1765-1773, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993416

RESUMO

To investigate the effect of chronic graft-versus-host disease (cGVHD) on the outcomes of acute myeloid leukemia (AML) patients who relapsed after allogenic hematopoietic cell transplantation, we performed a retrospective analysis on 218 patients with a median follow-up of 21.4 (3.4-179.6) months. A total of 103 patients developed cGVHD, with a 2-year cumulative incidence of 48.9% (95% CI 42.1-55.7%). The estimated 3-year overall survival was 85.7% (95% CI 75.7-95.7%), 48.8% (95% CI 31.7-66.0%), and 54.1% (95% CI 44.3-63.8%) for patients with limited cGVHD, extensive cGVHD, and without cGVHD (P < 0.001). The 3-year event-free survival were 75.5% (95% CI 63.7-87.4%), 46.0% (95% CI 28.8-63.2%), and 45.0% (95% CI 35.6-54.4%) (P < 0.001), while the 3-year cumulative relapse rates were 22.8% (95% CI 11.0-34.6%), 11.6% (95% CI 5.3-22.6%), and 40.3% (95% CI 31.0-49.6%), respectively (P < 0.001). At the last evaluation, 62 patients relapsed with 17 patients having active cGVHD and 45 without. Compared to patients relapsing without cGVHD, patients who relapsed with cGVHD had a longer duration of remission and a better 2-year post-relapse survival [10.9 months (3.7-42.2) versus 4.4 months (2.2-28.3); P < 0.001]; [32.8% (95% CI 8.2-57.4%) versus 4.5% (95% CI 0-12.8%); P = 0.043]. For patients who relapsed with cGVHD, the remission rates were both 60% after salvage chemotherapy with or without donor lymphocyte infusion (P = 1.000). In conclusion, cGVHD may exert a stronger graft-versus-leukemia effect, which may decrease the post-transplantation relapse rate and may also benefit those patients who eventually relapsed after transplantation in terms of prolong post-relapse survival.


Assuntos
Doença Enxerto-Hospedeiro , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Adolescente , Adulto , Doença Crônica , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Humanos , Incidência , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida
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