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1.
Medicine (Baltimore) ; 100(6): e24703, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578607

RESUMO

RATIONALE: The abnormal expression of B-cell lymphoma-2 (Bcl-2) family members is often associated with the progression of the disease. Bcl-2 inhibitors (eg, venetoclax) were first reported to inhibit the proliferation of malignant lymphocytes and have a significant effect on patients with chronic lymphoblastic leukemia, but research on myeloid tumors is relatively delayed. Venetoclax was approved in 2018 for the treatment of acute myeloid leukemia (AML) patients who were not suitable for high-dose chemotherapy. The approval of venetoclax is an advance in the treatment of hematological tumors. PATIENT CONCERNS: Here we report a 64-year-old male with an increased white blood cell (WBC) count (39.0 × 109/L) and lymphocyte count (30.6 × 109/L) on physical examination in July 2014. The patients were diagnosed with chronic lymphocytic leukemia (CLL) through bone marrow (BM) smears and immunophenotyping without any cytogenetic or molecular abnormalities. Chlorambucil was prescribed, WBC was stable between 15 × 109/L and 25 × 109/L in the past 6 years. He came to the hospital again in May 2020 and complained of fatigue for 2 weeks. WBC (16.7 × 109/L) and lymphocyte (14.76 × 109/L) counts were increased, hemoglobin (HGB) and platelet (PLT) were decreased in peripheral blood, which indicated the progression of the disease. DIAGNOSES: The patient was diagnosed as secondary AML after CLL based on the clinical and laboratory findings. INTERVENTIONS: He achieved a morphological complete remission in both AML and CLL without any adverse reactions after one course of venetoclax monotherapy. OUTCOMES: He received standard daunorubicin and cytarabine combined with venetoclax as consolidation therapy and is now ready for allogeneic-hematopoietic stem cell transplantation. LESSONS: Our case presents a challenge to traditional treatment. New drugs such as venetoclax have shown outstanding effects in this respect. High expression of Bcl-2 can identify the responders of venetoclax. These findings should be validated in future clinical trials. We fully believe that in the near future, the comprehensive use of targeted drugs with different mechanisms will not only improve the quality of life of patients, but also completely change the prognosis of patients with recurrent and refractory hematological malignancies.


Assuntos
Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Daunorrubicina/administração & dosagem , Daunorrubicina/uso terapêutico , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Resultado do Tratamento
3.
Leukemia ; 34(11): 2914-2924, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32546726

RESUMO

CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m2 on days 1, 3, and 5. Once safety was established, a 100 units/m2 arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m2 arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m2 (19%) compared with 75 units/m2 (38%) and 100 units/m2 (44%) (P = 0.35). The 50 units/m2 arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m2 respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m2 has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m2.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Biomarcadores Tumorais , Citarabina/efeitos adversos , Daunorrubicina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Fatores de Risco , Resultado do Tratamento
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 411-417, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319371

RESUMO

OBJECTIVE: To improve the understanding of the transformation of essential thrombocythemia (ET) into acute myeloid leukemia (AML), and to explore the relationship between JAK2 V617F gene mutation and disease transformation. METHODS: The detection of bone marrow morphology,cytogenetics, JAK2 V617F gene were performed before and after transformation, as well as the immunological tests after transformation was performed in 3 patients with ET into AML. The characteristics, clinical features, diagnosis and treatment of the patients before and after transformation were compared. RESULTS: Case 1 transformed into AML-M2a 5 years after diagnosis of ET. The patient abandoned treatment and was discharged from hospital. Case 2 transformed into AML 6 years after diagnosis of ET. After one course of chemotherapy, bone marrow was partially relieved, and platelets continued to rise up to 702×109/L, presenting as ET bone marrow image. One year later, AML relapsed and no remission was observed after chemotherapy. Case 3 transformed into AML-M6a 7 years after diagnosis of ET. The patient abandoned treatment and was discharged from hospital. The morphological heteromorphism of 3 cases of AML transformed from ET was more obvious than that of patients with newly diagnosed acute leukemia. The AML could not be classified accurately based on morphology simply, but could be classified accurately based on immunological detection. JAK2 V617F gene was positive before and after transformation in case 1 and case 2 of ET, the case 3 showed that JAK2 V617F gene was positive at ET stage and negative after AML transformation. Complex chromosome karyotypes were detected by routine karyotype analysis after ET transformation into AML in case 1, while normal karyotypes were found in case 2 and case 3. CONCLUSION: The morphological abnormality of AML transformed from ET is more significant than that of newly diagnosed acute leukemia, and it needs immunological detection to classify it accurately. The transformation of ET into AML may not involve JAK2 V617F gene mutation, but may be related with the occurrence of abnormal chromosome karyotypes. The condition of AML transformed from ET is dangerous and the effect of chemotherapy is poor.


Assuntos
Leucemia Mieloide Aguda , Trombocitemia Essencial , Medula Óssea , Humanos , Janus Quinase 2 , Leucemia Mieloide Aguda/etiologia , Mutação , Trombocitemia Essencial/complicações
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 558-566, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319396

RESUMO

OBJECTIVE: To study the high risk factors for the transformation into acute myeloid leukemia(AML) in patients with intermediate and high risk myelodysplastic syndrome(MDS) treated by decitabine-based regimen. METHODS: The clinical characterstics of 60 intermediate and high risk MDS patients and the factors of its transformed into AML were retrospectively analyzed. RESULTS: The overall response rate(ORR) of the patients suffered from intermediate and high risk MDS treated by decitabine-based regimen was 65.0%(39/60), among the 60 cases 17 achieved complete remission(CR), 5 achieved morrow complete remission(mCR), 4 achieved partial remission(PR) and 13 achieved hematologic improvement(HI). Twenty-one cases(35.0%) were transformed into AML among 60 cases of intermediate and high risk MDS treated by decitabine-based regimen. The median time of transformation from intermediate and high risk MDS into AML was 10.0 months(1.6-32.0). χ2 or Fisher's exact test showed that 2016 WHO MDS diagnostic subgrouping, myeloid hyperplasia markedly active, delayed interval of decitabine-based treatment associated with the transformation from intermediate to high risk MDS into AML (χ2=9.878,P=0.031;χ2=4.319,P=0.038;χ2=6406,P=0.011); Univariate analysis of Kaplan-Meier test showed that 2016 WHO MDS diagnostic subgroups, bone marrow blast cell ratio, bone marrow dysplasia coefficients, prolonged interval of decitabine-based treatment associated with the transformation from intermediate and high risk MDS into AML (P=0.015,P=0.008,P=0.012,P=0.032); multivariate analysis showed the bone marrow blast cell ratio and the bone marrow dysplasia coefficients were independent risk factors for the transformation from intermediate to high risk MDS into AML (P=0.022,P=0.018). CONCLUSION: The bone marrow blast cell ratio and the bone marrow dysplasia coefficients are independent risk factors of transformation into AML in the patients with intermediate and high risk MDS treated by decitabine-based regimen. The regular interval of dicitabine treatment is beneficial to maintain the stability of patients conditions.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Azacitidina , Humanos , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/complicações , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
6.
Leukemia ; 34(8): 2206-2216, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32214204

RESUMO

Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -ß, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.


Assuntos
Envelhecimento Saudável , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Leucemia Mieloide Aguda/etiologia , Sirtuínas/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Mutação , Sirtuínas/genética , Células THP-1 , Tirosina Quinase 3 Semelhante a fms/genética
9.
Ann Hematol ; 99(4): 855-866, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036420

RESUMO

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Leucemia Mielomonocítica Crônica/terapia , Ácido Micofenólico/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total , Adulto , Idoso , Soro Antilinfocitário/uso terapêutico , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Masculino , Melfalan/uso terapêutico , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/terapia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Linfócitos T/imunologia , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
10.
Leuk Res ; 90: 106300, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32018118

RESUMO

Salvage therapy regimens for refractory and relapsed AML include mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). We analyzed patients receiving either CLAG-M or MEC as salvage therapy for RR-AML between 09/01/2009-12/31/2017. Of 150 patients with RR-AML, 34 patients received CLAG-M and 116 MEC. CR/CRi rates for CLAG-M and MEC were 61.3 % (19/31) and 55.6 % (60/108). Median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR = 0.88,95 %CI = 0.54-1.41,p = 0.59). 76 patients proceeded to ASCT following salvage therapy. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR = 1.76,95 %CI = 0.87-3.56,p = 0.12). Among those with late relapse and ASCT, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR = 17.6,95 %CI = 1.57-198,p < 0.001). There were no significant differences in outcome between CLAG-M vs. MEC regardless of transplant status. There was a significant improvement in survival in patients with late relapse treated with MEC who proceeded to ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Recidiva , Retratamento , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , Adulto Jovem
11.
Medicine (Baltimore) ; 99(3): e18888, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011516

RESUMO

RATIONALE: The success of tyrosine kinase inhibitor (TKI) therapy has greatly prolonged the survival time of patients with chronic myeloid leukemia (CML), harboring the characteristic Philadelphia (Ph) chromosome. However, a fraction of patients, achieving complete cytogenetic response after TKI therapy, develop a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with additional clonal chromosomal abnormalities in Philadelphia-negative cells (CCA/Ph-). PATIENT CONCERNS: A 56-year-old woman with AML, developing from Philadelphia-negative CML after TKI therapy. She showed 6 kinds of somatic variants-CEBPA, ATRX, WT1, CSMD1, IKZF1, and LRP1B mutation after diagnosed as AML. DIAGNOSIS: The patient was diagnosed with chronic phase CML that developed to AML after achieving durable complete cytogenetic response (CCR) and major molecular response (MMR). INTERVENTIONS: The patient was treated with TKI therapy at the period of CML. When diagnosed with AML, she received induction chemotherapy regimens, consolidation therapy, and allogeneic hematopoietic stem cell transplantation subsequently. OUTCOMES: The patient has been CCR and MMR for nearly 4 years, and has achieved complete remission after intervention related to AML. She is now preparing for allogeneic hematopoietic stem cell transplantation. LESSONS: These rare occurrences highlight the importance of exploring the relevant pathogenesis of AML developing from CML after TKI therapy. In addition to monitoring molecular changes in the course of CML, cytogenetic analysis, or next-generation sequencing of CML patients should be performed.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mieloide Aguda/etiologia , Antineoplásicos/uso terapêutico , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Análise Citogenética , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Translocação Genética
12.
Nat Rev Cancer ; 20(3): 158-173, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31907378

RESUMO

For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles' heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores Tumorais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , História do Século XX , História do Século XXI , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Pesquisa/história , Pesquisa/tendências
13.
Cancer Epidemiol ; 65: 101667, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31955038

RESUMO

BACKGROUND: Parental occupational exposures are suggested as contributing causes of childhood cancer. METHODS: Children age< = 19, born in Denmark and diagnosed with leukemia, central nervous system (CNS) cancers and likely prenatally initiated cancers [hepatoblastoma, medulloblastoma, Wilms tumor (nephroblastoma), neuroblastoma, retinoblastoma and acute lymphoid leukemia] n = 4268 were identified using Danish registries. We randomly selected twenty-five controls per case matched on birth year and sex. Parents and their employment histories were extracted from nationwide registries. We examined occupational dust exposures perinatally and postnatally in both parents. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were estimated using conditional logistic regression. RESULTS: Maternal wood dust exposure from birth to diagnosis was associated with increased risks of leukemia (OR 1.44, 95 % CI 1.08-1.94) and acute myeloid leukemia (OR 2.14, 95 % CI 1.13-4.03); exposure to paper dust was associated with CNS cancer (OR 2.28, 95 % CI 1.22-4.2).. Paternal exposure to wood dust was associated with astrocytoma in both periods (OR 1.43, 95 % CI 1.05-1.96 and 1.42, 1.09-1.86, respectively) and CNS cancer (OR 1.24, 95 % CI 1.00-1.53) in the perinatal period. The increased risk observed for potentially prenatally-initiated cancers in relation to wood was driven by ORs for neuroblastoma (1.54, 95 % CI 1.03-2.29) and hepatoblastoma (2.41, 95 % CI 0.99-5.88). An OR of 2.58 (95 % CI 1.10-6.05) for CNS cancer was associated with both parents working in textile industries postnatally. CONCLUSION: The study suggests that parental exposure to wood dust may increase risk of specific childhood cancers.


Assuntos
Poeira , Neoplasias/epidemiologia , Neoplasias/etiologia , Exposição Ocupacional/efeitos adversos , Exposição Paterna/efeitos adversos , Sistema de Registros , Adolescente , Adulto , Estudos de Casos e Controles , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/etiologia , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Masculino , Neuroblastoma/epidemiologia , Neuroblastoma/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Gravidez , Risco , Tumor de Wilms/epidemiologia , Tumor de Wilms/etiologia , Adulto Jovem
14.
Ann Hematol ; 99(2): 385-388, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773213

Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Terapia de Alvo Molecular , Segunda Neoplasia Primária/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Aloenxertos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/etiologia , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Masculino , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protoporfiria Eritropoética/terapia , Recidiva , Indução de Remissão , Ativação Viral , Adulto Jovem
15.
Cell Biol Int ; 44(2): 456-466, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31617641

RESUMO

Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl2 can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Fatores de Transcrição/genética , Células Tumorais Cultivadas
16.
Arch Pathol Lab Med ; 144(4): 466-472, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31429606

RESUMO

CONTEXT.­: Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. OBJECTIVE.­: To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. DESIGN.­: Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, GATA1 mutation status, cytogenetics, and minimal residual disease results. RESULTS.­: Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. CONCLUSIONS.­: Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.


Assuntos
Síndrome de Down/complicações , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia
17.
Int J Cancer ; 146(4): 943-952, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31054169

RESUMO

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Exposição Materna/efeitos adversos , Exposição Ocupacional/efeitos adversos , Exposição Paterna/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Adulto , Animais , Animais Domésticos , Austrália/epidemiologia , Neoplasias do Sistema Nervoso Central/etiologia , Criança , Pré-Escolar , Dinamarca/epidemiologia , Poeira , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Israel/epidemiologia , Leucemia Mieloide Aguda/etiologia , Masculino , Noruega/epidemiologia , Praguicidas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
18.
Pan Afr Med J ; 37: 300, 2020.
Artigo em Francês | MEDLINE | ID: mdl-33654519

RESUMO

We conducted a retrospective descriptive analytical study in the Department of Clinical Haematology at the Mohammed V Military Training Hospital in Rabat over a period of 10 years. This study included 76 patients diagnosed with myelodysplastic syndrome (MDS) between 2008 and 2018. The average number of cases per year was 7.6. Out of 76 patients, 57% were men and 43% were women. The average age of our study population was 65.75 ± 12.55. The average age was 66.88 ± 13.10. No cases of profession exposed to disease was reported. Ninety-seven point three percent of patients had primary myelodysplastic syndrome and only 2 or 2.7% had myelodysplastic syndrome secondary to chemotherapy. The average time between the first visit and the diagnosis of myelodysplastic syndrome was, on average, 33.6 days ± 51, with a median of 19 days. The IPSS prognostic score was: low risk in 37.4% of cases, intermediate risk 1 in 46.6% of cases, intermediate risk in 12% of cases and high risk in 4% of cases. Thus, 84% of patients had low-risk MDS and 16% had high-risk MDS. Regular monitoring of patients showed many complications such as bleeding in 13% of patients, infections in 8% of cases, secondary hemochromatosis as a result of iterative transfusions in 6.6% of patients and transformation to acute myeloid leukemia in 2.7% of patients. In our study, abstention was the therapeutic choice in 42.1% of patients, transfusion was recommended in 35.5% of patients: red cells in 70% of cases, platelet concentrates in 40% of cases, iron chelators in 25% of transfused patients and EPO in 27% of patients. azacitidine was prescribed in 18% of patients, 50% had low-risk MDS and 50% had high-risk MDS. Bone marrow transplant was the only curative treatment for MDS. It was performed in a single patient with high risk MDS.


Assuntos
Transfusão de Sangue/estatística & dados numéricos , Transplante de Medula Óssea/estatística & dados numéricos , Leucemia Mieloide Aguda/epidemiologia , Síndromes Mielodisplásicas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Marrocos , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/etiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
19.
Cells ; 8(12)2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817547

RESUMO

: Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), CD157 proved not to be restricted to the myeloid compartment and to have a diversified functional repertoire ranging from immunity to cancer and metabolism. Despite being a NAD+-metabolizing ectoenzyme anchored to the cell surface through a glycosylphosphatidylinositol moiety, the functional significance of human CD157 as an enzyme remains unclear, while its receptor role emerged from its discovery and has been clearly delineated with the identification of its high affinity binding to fibronectin. The aim of this review is to provide an overview of the immunoregulatory functions of human CD157/BST-1 in physiological and pathological conditions. We then focus on CD157 expression in hematological tumors highlighting its emerging role in the interaction between acute myeloid leukemia and extracellular matrix proteins and its potential utility for monoclonal antibody targeted therapy in this disease.


Assuntos
ADP-Ribosil Ciclase/metabolismo , Antígenos CD/metabolismo , Células Mieloides/citologia , Células Mieloides/metabolismo , ADP-Ribosil Ciclase/antagonistas & inibidores , ADP-Ribosil Ciclase/química , Imunidade Adaptativa , Antígenos CD/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Suscetibilidade a Doenças , Ativação Enzimática , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunidade Inata , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Terapia de Alvo Molecular , Células Mieloides/efeitos dos fármacos , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Distribuição Tecidual
20.
Blood Adv ; 3(23): 3962-3967, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31805192

RESUMO

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/etiologia , Mieloma Múltiplo/complicações , Segunda Neoplasia Primária/etiologia , Humanos , Leucemia Mieloide Aguda/patologia , Mieloma Múltiplo/patologia , Mutação , Segunda Neoplasia Primária/patologia
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