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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.
Zhonghua Yi Xue Za Zhi ; 99(40): 3145-3151, 2019 Oct 29.
Artigo em Chinês | MEDLINE | ID: mdl-31694105

RESUMO

Objective: To analyze the distribution of gene mutations in newly diagnosed acute myeloid leukemia (AML) patients, based on next generation sequencing technology (NGS) and to evaluate their value in AML risk stratification. Methods: The study analyzed 453 newly diagnosed AML(excluded acute promyelocytic leukemia, APL) patients from seven hospitals in Shanghai, from January 1st 2014 to December 31th 2017. RNA and DNA were extracted from pretreatment bone marrow mononuclear cells and targeted sequencing of AML genes were performed. The data of different groups was compared. Results: A total of 453 newly diagnosed AML patients were enrolled in the study, including 247 males and 206 females with a median age of 49.5 (range,11-85) years. A total of 540 mutations/fusion genes were detected in 289 patients, 29.1% (132/259) of whom with two or more mutations/fusion genes. In all patients, NPM1 was the most common mutation(12.8%), followed by ETO and TET2 mutation (11.92% and 11.04%, respectively) . And WT1 over-expression accounted for 10.6%. Patients over the age of 50 were with a higher frequency of mutations associated with epigenetic modification, 11.93% for ASXL1, 13.99% for DMNT3A, 6.58% for IDH1/IDH2, and 13.17% for TET2. The frequency of DMNT3A mutations was three times higher than that of patients under 50 years of age (P=0.017). In this study, a relatively low proportion of genetic mutations was observed in low-risk karyotype group. In the medium-risk karyotype group, the relatively high mutation frequencies were observed in NPM1, TET2, FLT3-ITD, DNMT3A, ASXL1, and CEBPA genes. In the poor-risk karyotype group, the mutation frequencies of ASXL1, TET2, DNMT3A and PHF6 genes were more than 10%, especially ASXL1 and PHF6 mutation frequencies were significantly higher than other molecular risk stratification groups (P<0.05). Of the 254 patients (56%) with normal karyotype AML (NK-AML), 56 patients were detected to have gene mutations about epigenetic modification. The median OS of this group was worse than that of patients without related mutations, while the median LFS had no significant difference. In patients with NK-AML older than 50 years, the OS and LFS of patients with epigenetic modification related gene mutations was 12 months and 10 months, versus 18 months and 12 months of patients without mutations. Conclusions: The gene mutations frequencies in AML patients with different age and molecular risk stratification groups are different. Epigenetics gene mutation frequencies, such as DNMT3A, ASXL1, IDH1/IDH2 and TET2,are higher in patients older than 50 years. A shorter OS can be observed in older patients(>50 years) with epigenetics gene mutation.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Adulto Jovem
3.
Zhonghua Yi Xue Za Zhi ; 99(40): 3152-3157, 2019 Oct 29.
Artigo em Chinês | MEDLINE | ID: mdl-31694106

RESUMO

Objective: To explore the coexisting mutations in NPM1 mutated elderly patients with acute myeloid leukemia(AML). Methods: The clinical data of 152 elderly adults(aged≥60 years) and 49 young adults(aged 18-45 years) with AML between June 2013 and December 2018 in outpatient and hospitalized patients of Changzhou Second People's Hospital and Wuxi Second People's Hospital were retrospectively analyzed. A total of 51 gene mutations were detected using targeted next-generation sequencing (NGS) and sanger sequencing. The general clinical characteristics, the occurrence of coexistence gene mutations, the correlation between coexistence gene mutations and some clinical parameters, and the initial induction remission rate between elderly and young adult AML patients with NPM1 mutations were analyzed and compared. Results: NPM1 mutations were detected in 46 of 152 elderly AML patients. Thirty eight patients (82.6%) with NPM1 mutations carried other gene mutations at the same time, among whom 8 patients (17.4%) carried NPM1 mutations alone, while 14(30.4%) carried 2, 16 (34.8%) carried 3, and 8 (17.4%) carried ≥ 4 mutations. NPM1 mutations frequently co-occurred with FLT3-ITD15 cases (32.6%) , DNMT3A10 (21.7%) , TET26 (13.4%) and FLT3-TKD5 (10.9%) . Compared with young adults with NPM1 mutations, elderly patients had higher TP53, FLT3-TKD rates, lower incidence of DNMT3A, RAS mutation (all P<0.05) and lower coexistence rate of 4 gene mutations (P=0.002).The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than those in patients with single, double and 3 mutations coexisted in elderly adults AML patients(all P<0.05). With the increase of the amount of mutations, the complete remission(CR) rate decreased gradually after the initial induction. Patients who carried 3 or more mutations showed a lower CR rate than those with single gene mutations (all P<0.05) . Patients who carried>4 genes also showed a significantly lower CR rate than those with double gene mutations (P=0.031). Patients with FLT3-ITD mutations exhibited higher white blood level and lower CR rate than that in nonmutant type group (all P<0.05). The CR rate of patients with DNMT3A mutation was also significantly lower than that with nonmutant type (P=0.033). However, patients with FLT3-TKD mutations showed a higher platelet level than that with nonmutant type (P=0.019). There was no significant difference in CR rate and peripheral blood cell level between TET2 mutated and nonmutant type. Conclusion: NPM1 mutated elderly patients with AML commonly show additional mutations, and the amount and type of coexisting mutations have an influence on the clinical features and CR rate of elderly patients with AML.


Assuntos
Leucemia Mieloide Aguda , Proteínas Nucleares/genética , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms
4.
Rinsho Ketsueki ; 60(9): 1108-1119, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597834

RESUMO

Conventional chemotherapy with cytarabine and anthracycline (often referred to as "7+3") has been used for many years in the treatment of acute myeloid leukemia (AML). Despite meaningful advances in areas of supportive care and transplantation, little progress has been made in developing new chemotherapy options. In 2018, The Food and Drug Administration (FDA) of the US approved several novel agents for AML treatment as follows: ivosidenib, an inhibitor of isocitrate dehydrogenase-1; venetoclax, a potent inhibitor of bcl2; and glasdegib, an inhibitor of hedgehog signaling pathway. Moreover, clinical trials of alvocidib (flavopiridol), an inhibitor of the CDK9, pevonedistat, an inhibitor of NEDD8, and APR-246, a reactivator of mutant p53, are in progress. These agents will either be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents to improve the outcome of AML therapy, and the results will guide the next stage of precision medicine in the treatment of AML.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Benzimidazóis/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclopentanos/farmacologia , Aprovação de Drogas , Flavonoides/farmacologia , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Terapia de Alvo Molecular , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
5.
Rinsho Ketsueki ; 60(9): 1120-1130, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597835

RESUMO

Acute myeloid leukemia is a disease that mainly affects older populations, with a median age at diagnosis of 67 years, and outcomes for these patients are poor. Reduced-intensity regimen improves survival after allogeneic hematopoietic cell transplantation (HCT), but this has not been well studied. To reduce non-relapse mortality (NRM) among the elderly, geriatric assessment, HCT-Comorbidity index, and disease risk must be studied before HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Idoso , Humanos , Transplante Homólogo
6.
Rinsho Ketsueki ; 60(9): 1299-1307, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597856

RESUMO

Down syndrome (DS) is related to constitutional trisomy 21 and is characterized by typical dysmorphic features and various congenital abnormalities. DS is also associated with a broad spectrum of hematological findings, such as transient thrombocytopenia in the neonatal period and acute leukemia. Of those hematological abnormalities, transient abnormal myelopoiesis (TAM) and acute myeloid leukemia (AML) have common genetic abnormalities, i.e., trisomy 21 and GATA1 mutation, and form a continuous spectrum, referred to as myeloid proliferations related to DS. Recent studies have demonstrated interactions between trisomy 21 and GATA1 mutations. Trisomy 21 promotes the expansion of early hematopoietic progenitors and upregulates short form GATA1, resulting in the accelerated production of aberrantly differentiated cells and development of TAM. Following spontaneous remission of TAM, subsequent AML can evolve from a preexisting residual TAM clone through the acquisition of additional mutations involving multiple cohesion components and epigenetic regulators.


Assuntos
Síndrome de Down/patologia , Leucemia Mieloide Aguda/complicações , Reação Leucemoide/complicações , Células Mieloides/citologia , Proliferação de Células , Síndrome de Down/complicações , Fator de Transcrição GATA1/genética , Humanos , Mutação
7.
Drugs Today (Barc) ; 55(9): 545-562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584572

RESUMO

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.


Assuntos
Benzimidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos Fase II como Assunto , Citarabina , Aprovação de Drogas , Humanos , Quimioterapia de Indução , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug Administration
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1360-1366, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607284

RESUMO

OBJECTIVE: To summarize the clinical characteristics of patients with acute myeloid leukemia-type M2 (AML-M2) and analyze the factors affecting the prognosis. METHODS: One hundred eighty-eight AML-M2 patients were retrospectively analyzed for the following parameters including peripheral blood, immune phenotypes, fusion genes and cytogenetics to explore their significance for the overall survival (OS) and progression-free survival (PFS). The prognostic factors were also analyzed. RESULTS: Among 188 patients with AML-M2, the chromosomal abnormality with t (8;21), normal chromosome and other abnormalities accounted for 37% (70/188), 41% (77/188) and 22% (41/188), respectively. For the immunopheno typing of M2 patients, the hematopoietic progenitor cell differentiation antigen CD117 (96.1%) were mainly expressed, CD34 (81.6%) and HLA-DR (55.9%), and myeloid-associated antigen of CD13 (90.5%) and CD33 (89.4%) were also highly expressed. There were lymphoid-associated antigens expressed in some patients, among which the positive expression rate of CD19 was highest (29.6%), and the next was CD7 (28.5%). The most common accompanied mutations was FLT3 mutation (30.2%). The univariate analysis showed that the patients at age<50 years old, without extramedullary infiltration, with positive expression of CD19, NPM-1 (-), CEBPA double mutation(+), and HSCT were significant superior in OS and PFS (P<0.05); the multivariate analysis showed that the patient at age<50 years old, without extramedullary infiltration, with positive expression of CD19 and CEBPA double mutation (+) were significant superior in OS and PFS (P<0.05). The analysis indicated that the Karytypes affected only OS (P<0.05), while the NPM-1 gene mutation positive affected only PFS (P<0.05). The univarate analysis of factors affecting the survival in 70 AML-M2 patients with t (8;21) abnormatity showed that the C-KIT gene mutation was a poor factor for OS and PFS. CONCLUSION: The clinical characteristics are different between M2 patients with different karyotype, and prognostic analysis shows that the karytypes have an impact on overall survival; age, extramedullary infiltration, CD19 expression and CEBPA double mutation are also the main factors impacting the prognosis of patients.


Assuntos
Leucemia Mieloide Aguda , Antígenos HLA-DR , Humanos , Imunofenotipagem , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1424-1430, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607293

RESUMO

OBJECTIVE: To investigate the relationship of miR-140 expression level with the therapeutic effect of decitabine, and to explore whether the molecular mechanism is dependent on the regulation of TLR4 expression. METHODS: Forty-seven patients with acute myeloid leukaemia (AML) were enrolled in our study and divided into decitabine combination treatment group (22 cases) and traditional treatment group (25 cases). The clinical efficacy was compared between these two groups. Real-time PCR was used to determine the plasma level of miR-140 in AML patients. Decitabine, miR-140 mimic and miR140 inhibitor were used to treat AML HL-60 cells in vitro, the real-time PCR and Western blot were used to detect the expressions of miR-140, TLR4 and NF-κB at both mRNA and protein levels. RESULTS: Compared with traditional treatment group, decitabine combination treatment group showed more significant clinical efficacy. Plasma miR-140 level in both 2 treatment groups both decreased, but the plasma miR-140 level was higher in decitabine combination treatment group as compared with traditional treatment group. Experiment in vitro showed that 0.3 µmol/L decitabine significantly inhibited the HL-60 cell proliferation accompanied by up-regulation of miR-140 expression and down-regulation of expression of TLR4 and NF-κB. These effects induced by decitabine were partly reversed by pretreating the cells with 200 nmol/L miR-140 inhibitor. CONCLUSION: Decitabine-induced up-regulation of miR-140 expression may be related with its chemotherapeutic effects, and miR-140/TLR4/NF-κB pathway may partly mediate the pharmacologic action of decitabine.


Assuntos
Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Regulação para Baixo , Células HL-60 , Humanos , MicroRNAs , NF-kappa B
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1431-1435, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607294

RESUMO

OBJECTIVE: To investigate the efficacy and safety of decitabine combined with half-course pre-excitation for the treatment of elderly patients with acute myeloid leukemia (AML). METHODS: 44 cases of newly diagnosed elderly AML admitted in our hospital from January 2016 to December 2017 were selected for the retrospective analysis. The patients were randomly divided into 2 groups: pre-excitation therapy group as control and combined therapy group. The 22 patients in pre-excitation therapy group reccived the routine complete course pre-excitation treatment, 22 patients in combined therapy group received the desitabine combined the half course pre-excitation treatment. The therapentic efficacy and adverse reactions during treatment were compared between 2 groups. All patients were followed-up and the survival rate at 6,12 and 24 months was compared between 2 groups. RESULTS: The remission rate(RR) in the combined therapy group was 72.73%, and that in the control group was 50.00%, with significant statistically difference (P<0.05). The median survival time in combined therapy group (17.82±4.19 months) and control group (12.43±3.71 months) was statistically significant (P<0.05). The rate of adverse reactions of digestive tract in combined therapy group was 40.91%, which was higher than that in control group (18.18%), and the difference of two groups was statistically significant (P<0.05). The incidence of adverse reactions in blood system and bone marrow suppression in combined therapy group was 9.09% and 68.18%, which were lower than those in control group (27.27% and 95.45%), with statistically significant differences (P<0.05). There was no statistically significant difference in the incidence of liver dysfunction, cardiac insufficiency and hair loss between the two groups (P>0.05). The incidence of pulmonary infection, intestinal infection and other complications in combined therapy group was 13.64%, which was lower than that in control group 31.82%, and the difference of two groups was statistically significant (P<0.05). No serious complications such as arteriovenous thrombosis occurred in either group, and no patients died during chemotherapy. CONCLUSION: Combination of disitamine and half-course prestimulation treatmentis is a safe and effective and elderly patients with AML shown a good tolerance.


Assuntos
Decitabina/uso terapêutico , Leucemia Mieloide Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1440-1448, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607296

RESUMO

OBJECTIVE: To explore the coexisting mutations in IDH-mutated acute myeloid leukemia(AML) and its relation with partial clinical parametrs. METHODS: The exon 4 mutation of IDH1/2 gene was screened by using genome DNA-PCR combined with sanger sequencing, 51 targeted gene mutations in the patients with IDH1/2 mutation were detected by using high throughput DNA sequencing combined with sanger sequencing. RESULTS: Among 358 patients, the IDH1/2 mutation was found in 46 cases including IDH1 mutation in 35 cases and IDH2 mutation in 11 cases, 97.87%(45/46) patients with IDH1/2 mutation simultaneously carried other gene mutations including 8(17.8%) cases with mutation of double gene, 17(37.8%) cases with mutation of 3 genes and 20(44.4%) cases with mutation of ≥ 4 genes. The mutation frequency of each patient averaged 3.52 times. In mutation of accompanied genes, the common genes were NPM1(n=29, 63.0%), next DNMT3A(n=25, 54.3%), FLT3-ITD(n=7, 15.2%), TET2(n=5, 10.9%) and NRAS(n=5, 10.9%). The average WBC level of patients with NPM1 mutation in IDH1 mutation group was higher than that of patients in wild type group(P<0.05). The complete remission (CR) rate of patients with DNMT3A mutation was significant lower than that of patients with wild type (30% vs 80%, P<0.01). The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than that in the patients with double mutations(P<0.05). CONCLUSION: More than 95% AML patients with IDH1/2 mutation commonly show additional mutations. The number and the type of IDH coexisting mutations have certain effect on the clinical features and CR rate.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Éxons , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Indução de Remissão
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1449-1454, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607297

RESUMO

OBJECTIVE: To analyze and investigate the expression levels of HES1, C-MYC and NF-kB in peripheral blood of patients with T cell acute lymphoblastic leukemia (T-ALL) and their significance. METHODS: Sixty patients with T-ALL and 60 patients with acute myelogenous leukemia (AML) diagnosed in our hospital from June 2012 to March 2015 were enrolled in T-ALL group and AML group, respectively. Another 30 healthy people were enrolled in the control group. Peripheral blood was collected to detect the expression levels of HES1, C-MYC and NF-kB by RT-PCR. The general data and the expression of HES1, C-MYC and NF-kB in peripheral blood were compared among the patients with different type of leukemia, cytogenetical types and different prognosis. RESULTS: There was no significant difference in baseline data, such as age and sex among the 3 groups (P>0.05). The Hb level, WBC and Plt count, BM blast cell ratio in T-ALL and AML groups all were significantly higher than those in control group (P<0.01), but there were no statistical difference in above-mentioned indicators between T-ALL and AML groups (P>0.05). The expression levels of HES1, C-MYC and NF-kB in peripheral blood among 3 groups were significantly differenct (P<0.01), the expressions levels of HES1, C-MYC and NF-kB in T-ALL and AML groups were significantly higher than those in control were significantly group (P<0.01), moreover, the expression levels of above-mentional indicators in T-ALL groups were significantly higher than than those in AML group (P<0.01). The expression levels of HES1, C-MYC and NF-kB iin T-ALL patients with poor prognosis were significantly higher than those in T-ALL patients with favorable prognosis (P<0.01); the expression levels of HES1, C-MYC and NF-kB in peripheral blood of patients with different theraptic efficacy were follow: complete remission group<partial remission group<no remission group (P<0.01). CONCLUSION: The HES1, C-MYC and NF-kB are highly expressed in peripheral blood of the patients with T-ALL, moreover, the expression levels maybe different, because of the cytogenetic, and theraptic efficacy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia Mieloide Aguda , NF-kappa B , Indução de Remissão , Linfócitos T , Fatores de Transcrição HES-1
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1678-1681, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607331

RESUMO

OBJECTIVE: To analyze the diagnostic value of (1, 3) -ß-D-glucan and galactomannan (GM) tests in the patients with acute leukemia complicated by invasive fungal disease, and explore the application of serological detection (G/GM) and lung CT for early diagnosis of invasive fungal disease (IFD). METHODS: A total of 493 patients with acute leukemia complicated by high risk invasive fungal infection, also receival G and GM tests, in Department of hematology of our hospital from June 2016 to December 2016 were selected and were divided into IFD-confirmed group (62 cases) including confirmed and clinical diagnesed IFD, and IFD-unconfirmed group (431 cases) including suspected IFD and non-IFD according to the diagnostic criteria of IFD. The results of G and GM tests in patients of 2 groups were analyzed, then the diagnostic efficacy of G and GM done and combination evaluated. In addition, 26 patients whose lung CT negative at hospitalization, moreover, presentation of changes in lung by CT during hospitalization and serological G and GM test positive were selected, and the difference of time between serological that postive and presentation of changes in lung by CT were compared for the estimation of early diagnotic value. RESULTS: The positive rate of (1, 3) -ß-D-glucan in IFD-confirmed group and IFD-unconfirmed group was 56.5% and 10.4%, respectively. Meanwhile, that of galactomannan test was 41.9% and 9.0%, respectively. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of (1, 3) -ß-D-glucan was 56%, 90%, 44% and 92%, and that of galactomannan was 42%、91%、40% and 93%, respectively. Moreover, the combination of (1, 3) -ß-D-glucan and galactomannan could raise the sensitivity to 69% and specificity to 98%. The positive results of serological detection (G/GM) come earlier about five days than CT changes. CONCLUSION: Both (1, 3) -ß-D-glucan and galactomannan test have high sensitivity and specificity, and the combination of them can improve the diagnostic efficacy, and make the clinical antifungal therapy more precisely. In the early clinical diagnosis of IFD, the positive results of serological detection coming earlier than lung CT.


Assuntos
Infecções Fúngicas Invasivas , Leucemia Mieloide Aguda , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/etiologia , Leucemia Mieloide Aguda/complicações , Mananas
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 420-424, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631611

RESUMO

Objective: To investigate the expression of cystic fibrosis transmembrane conductance regulator (CFTR) protein in patients with acute leukemia and its relationship to clinical features and prognosis of acute leukemia. Methods: A total of115 patients with acute leukemia were enrolled in the experimental group and 20 healthy individuals were used as control. Peripheral blood or bone marrow samples were collected, and mononuclear cells were isolated. The expression of CFTR protein was detected by Western blot. The relationships of CFTR protein expression to clinical features and prognosis was analyzed. Results: The expression of CFTR protein was not detected in peripheral blood mononuclear cells of normal control, while it was positive in more than half of acute leukemias including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but negative in the patients with acute promyelocytic leukemia (M3). In the patients with AML, there was no difference in peripheral white blood cells (WBC), peripheral blast cells, platelet and hemoglobin (HGB) between CFTR-positive and CFTR-negative patients. There was no relationship between the expression of CFTR protein and gene mutations such as NPM1, CEBPA, FLT3-ITD, and C-Kit. Complete remission (CR) rate after two course in CFTR-negative patients was slightly higher than that in positive patients. The survival time of CFTR-negative patients was little longer than that of positive patients, but the difference was not statistically significant. Conclusions: The expression of CFTR protein seems not associated with clinical features, treatment response and prognosis in the patients with acute leukemia.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Leucemia Mieloide Aguda/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucócitos Mononucleares , Mutação , Prognóstico
15.
Zhonghua Xue Ye Xue Za Zhi ; 40(9): 755-758, 2019 Sep 14.
Artigo em Chinês | MEDLINE | ID: mdl-31648478

RESUMO

Objective: To investigate the expression characteristics of Tim-3 on natural killer (NK) cells of peripheral blood in patients with acute myeloid leukemia (AML) and its clinical significance. Methods: Peripheral blood was obtained from 39 patients with newly diagnosed AML before intervention, with peripheral blood from 28 cases of healthy volunteers collected as normal control. Using CD3, CD56 and Tim-3 as markers, expression levels of Tim-3 on the peripheral blood NK cells were detected by immune fluorescence labeling and flow cytometry. Results: The ratio of the peripheral blood CD3(-)CD56(+) NK cells in newly diagnosed AML patients (5.74±5.31) %decreased significantly, compared with the normal control (12.55±6.33) % (t=4.596, P<0.001) . Tim-3 expression on the peripheral blood NK cells in newly diagnosed AML patients (42.67±19.08) % decreased significantly, compared with the normal control group (60.99±20.69) % (t=3.781, P<0.001) . CD3(-)CD56(+)NK cell ratio of peripheral blood in AML patients was significantly correlated with Chromosome karyotype (t=2.915, P<0.005) . Expression level of Tim-3 on NK cells in the peripheral blood of AML patients had significant correlation with ratio of CR and NCCN high risk group (P<0.05) . Conclusion: The rate of NK cells in peripheral blood and the expression level of Tim-3 on NK cells in AML patients decreased significantly.The lower expression level of Tim-3 on NK cells correlate with prognosis of AML.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Células Matadoras Naturais , Leucemia Mieloide Aguda , Citometria de Fluxo , Humanos , Prognóstico
16.
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
17.
Medicine (Baltimore) ; 98(40): e17406, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577751

RESUMO

Serum ferritin (SF) has been identified as a potential prognostic factor for patients undergoing stem cell transplantation, but the prognostic value of SF in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients and the impact of iron chelation therapy (ICT) on MDS patients are controversial. The present meta-analysis aimed to better elucidate these relationships.Three electronic databases were searched systematically to identify reports on the prognostic role of SF in MDS and AML patients, and those investigating the impact of ICT on prognosis of MDS patients. The hazard ratios (HRs) and its 95% confidence interval (95%CI) were extracted from the identified studies using Cox proportional hazard regression model for overall survival (OS) and progression of MDS to AML.Twenty reports including 1066 AML patients and 4054 MDS patients were included in present study. The overall pooled HRs for OS of AML and MDS patients with elevated SF prior to transplantation was 1.73 (1.40-2.14), subgroup analyses stratified by the cut-off value of SF ≥1400/1000 ng/mL showed that the pooled HRs were 1.45 (0.98-2.15) and 1.65 (1.30-2.10), respectively. The pooled HRs for ICT in MDS patients was 0.30 (0.23-0.40). For ICT, the pooled HRs for the progression of MDS to AML was 0.84 (0.61-1.61).SF has a negative impact on the OS of AML and MDS patients when it is higher than 1000 ng/mL. ICT can improve the OS of MDS patients with iron overload but it is not associated with the progression of MDS to AML.


Assuntos
Terapia por Quelação/métodos , Ferritinas/sangue , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Leucemia Mieloide Aguda/complicações , Síndromes Mielodisplásicas/complicações , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/fisiopatologia , Estudos Observacionais como Assunto , Prognóstico , Modelos de Riscos Proporcionais , Projetos de Pesquisa , Transplante de Células-Tronco/métodos , Análise de Sobrevida
18.
Expert Opin Investig Drugs ; 28(11): 989-1001, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31612739

RESUMO

Introduction: Despite advancements over the last 2 years, outcomes for acute myeloid leukemia (AML) are poor; however, a greater comprehension of disease mechanisms has driven the investigation of new targeted treatments. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, transcription and DNA repair, and are aberrantly expressed in AML. Targeting the CDK pathway is an emerging promising therapeutic strategy in AML.Areas covered: We describe the rationale for targeting CDK9 and CDK4/6, the ongoing preclinical and clinical trials and the potential of these inhibitors in AML. Our analysis included an extensive literature search via the Pubmed database and clinicaltrials.gov (March to August, 2019).Expert opinion: While CDK4/6 inhibitors are early in development for AML, CDK9 inhibition with alvocidib has encouraging clinical activity in newly diagnosed and relapsed/refractory AML. Preclinical data suggests that leukemic MCL-1 dependence may predict response to alvocidib. Moreover, MCL-1 plays a key role in resistance to BCL-2 inhibition with venetoclax. Investigational strategies of concomitant BCL-2 and CDK9 inhibition represent a promising therapeutic platform for AML. Furthermore, preclinical data suggests that CDK4/6 inhibition has selective activity in patients with KMT2A-rearrangements and FLT3 mutations. Incorporation of CDK9 and 4/6 inhibitors into the existing therapeutic armamentarium may improve outcomes in AML.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Desenvolvimento de Medicamentos , Humanos , Leucemia Mieloide Aguda/patologia
19.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(5): 885-892, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31631640

RESUMO

Mouse animal models are the most commonly used experimental tools in scientific research, which have been widely favored by researchers. The animal model of mouse leukemia appeared in the 1930s. During the past 90 years, researchers have developed various types of mouse leukemia models to simulate the development and treatment of human leukemia in order to promote effectively the elucidation of the molecular mechanism of leukemia' development and progression, as well as the development of targeted drugs for the treatment of leukemia. Considering that to myeloid leukemia, especially acute myeloid leukemia, there currently is no good clinical treatment, it is urgent to clarify its new molecular mechanism and develop new therapeutic targets. This review focuses on the various types of mouse models about myeloid leukemia used commonly in recent years, including mouse strains, myeloid leukemia cell types, and modeling methods, which are expected to provide a reference for relevant researchers to select animal models during myeloid leukemia research.


Assuntos
Modelos Animais de Doenças , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos
20.
Zhonghua Zhong Liu Za Zhi ; 41(10): 753-759, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648497

RESUMO

Objective: To investigate the effects of miR-23a-3p on proliferation, migration and apoptosis on human acute myeloid leukemia (AML) cells by targeting SMC1A. Methods: Microarray analysis was used to screen differentially expressed microRNAs and mRNAs in human AML cells. Real-time fluorescence quantitative PCR (RT-qRCR) was used to detect the expressions of miR-23a-3p and SMCA in human AML cell line U937. TargetScan database was used to analyze the correlation between miR-23a-3p and SMC1A. Double luciferase reporter gene was used to detect the interaction between miR-23a-3p and SMC1A. The effect of miR-23a-3p expression on the proliferation of U937 cells was detected by clonal assay. The migration, apoptosis, cell cycle and caspase-3 activity of U937 cells regulated by miR-23a-3p were detected by cell scratch assay and flow cytometry, respectively. Western blot was used to detect the expressions of Bax and Bcl-2 in U937 cells. Results: Compared with human normal monocyte SC group (1.00), the expression of miR-23a-3p in U937 cells was up-regulated (2.56±0.78) (P<0.01), while the expression of SMC1A was down-regulated (0.48±0.56, P<0.01). miR-23a-3p specifically bond to SMC1A 3'UTR and regulated the expression activity of SMC1A. Overexpression of miR-23a-3p promoted the proliferation and migration of U937 cells and inhibited the apoptosis of U937 cells, while up-regulation of SMC1A inhibited the proliferation and migration of U937 cells and promoted the apoptosis of U937 cells. The percentages of G(0)/G1 phase, G(2)/M phase and S phase cells in the negative control group were (37.48±0.21)%, (16.78±0.18)% and (45.74±0.15)% respectively, and those in the miR-23a-3p mimics group were (19.96±0.11)%, (41.69±0.24)% and (38.24±0.34)%, respectively. The difference was statistically significant (all P<0.05). The proportions of G(0)/G(1) phase, G(2)/M phase and S phase cells in the group of miR-23a-3p mimics+ pcDNA3.1-SMC1A were (36.88±0.21)%, (30.44±0.33)% and (32.88±0.16)%, respectively, without significant difference when compared with those of the miR-23a-3p mimics group (P>0.05). The relative expression levels of Bax and Bcl-2 protein in the negative control group were 0.55±0.45 and 0.31±0.54, respectively. Overexpression of miR-23a-3p inhibited the expression of Bax protein in U937 cells (0.23±0.13, P<0.001), promoted the expression of Bcl-2 protein (0.50±0.23, P<0.01), while SMC1A increased the expression of Bax protein in U937 cells (0.40±0.11, P<0.01), and inhibited the expression of Bcl-2 protein (0.37±0.15). In the negative control group, caspase-3 activity was (25.82±0.89)%. Overexpression of miR-23a-3p inhibited caspase-3 activity in U937 cells (3.64±0.56)%, P<0.01, while up-regulation of SMC1A promoted caspase-3 activity in U937 cells (15.29±0.85)%, P<0.01. Conclusion: miR-23a-3p can inhibit the proliferation and migration and promote apoptosis of human AML cells by targeting SMC1A.


Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , Biomarcadores/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona , Humanos , Leucemia Mieloide Aguda/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
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