RESUMO
Hematopoietic stem cell transplantation (HSCT) has benefited an increasing number of patients with hematological disease in the clinic. It is a curative therapy for malignant and nonmalignant hematological diseases. With the advancement and further clinical application of HSCT in recent years, the life expectancy of patients has increased, but complications have become more common. The occurrence of ocular complications is receiving increasing attention because they can seriously affect the quality of life of patients. Ocular complications require increased attention from clinicians because of their negative impact on patients and increasing incidence. Most of recent reports on posttransplant ocular complications involve ocular manifestations of graft-versus-host disease (GVHD), and a few ocular complications that do not originate from GVHD have also been reported. This review summarizes the diagnosis, scoring criteria, pathophysiology, and clinical manifestations of and common therapies for ocular graft-versus-host disease(oGVHD) after HSCT, and includes a description of some rare cases and novel therapies.
RESUMO
Arsenic trioxide (ATO) treatment effectively prolongs the overall survival of patients with acute promyelocytic leukemia (APL). Mutations in the oncogene PML::RARA were found in patients with ATO-resistant and relapsed APL. However, some relapsed patients do not have such mutations. Here, we performed microarray analysis of samples from newly diagnosed and relapsed APL, and found different microRNA (miRNA) expression patterns between these two groups. Among the differentially expressed miRNAs, miR-603 was expressed at the lowest level in relapsed patients. The expression of miR-603 and its predicted target tropomyosin-related kinase B (TrkB) were determined by PCR and Western blot. Proliferation was measured using an MTT assay, while apoptosis, cell cycle and CD11b expression were analyzed using flow cytometry. In APL patients, the expression of miR-603 was negatively correlated with that of TrkB. miR-603 directly targeted TrkB and downregulated TrkB expression in the APL cell line NB4. miR-603 increased cell proliferation by promoting the differentiation and inhibiting the apoptosis of NB4 cells. This study shows that the miR-603/ TrkB axis may be a potent therapeutic target for relapsed APL.
Assuntos
Antineoplásicos , Arsenicais , Leucemia Promielocítica Aguda , MicroRNAs , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Arsenicais/farmacologia , Óxidos/farmacologia , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Apoptose/genética , MicroRNAs/genética , Proliferação de Células , Diferenciação Celular/genética , Antineoplásicos/uso terapêuticoRESUMO
The four and a half LIM domains 1 (FHL1) is considered to play important roles in tumors. This study aims to investigate the role and precise mechanisms of FHL1 in acute myeloid leukemia (AML). Here, we found that FHL1 was highly expressed in AML. CCK8, flow cytometry, and Western blot analysis of cell cycle-related proteins showed that overexpression of FHL1 promoted proliferation and accelerated cell cycle progression in HL-60 cells. Conversely, knockdown of FHL1 inhibited the proliferation and induced cell cycle arrest in KG-1 cells. Furthermore, knockdown of FHL1 promoted cell differentiation, while overexpression of FHL1 restrained all-trans retinoic acid induced cell differentiation in HL-60 cells, revealed by Wright-Giemsa staining and cell surface antigen analysis. Moreover, in vivo experiments revealed that depletion of FHL1 inhibited tumor growth and led to increased levels of CD11b and CD14. Here, we first identify an unexpected and important role of FHL1 that contributes to the AML progression, indicating that FHL1 may be a potential therapeutic target for AML.
Assuntos
Leucemia Mieloide Aguda , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Células HL-60 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismoRESUMO
WHAT IS KNOWN AND OBJECTIVES: The aim of this study was to investigate the pharmacokinetics (PK) of cefoperazone (CFP) and sulbactam (SUL) in critically ill thrombotic thrombocytopenic purpura (TTP) patients undergoing therapeutic plasma exchange (TPE). METHODS: Critically ill TTP patients receiving a dose of 3 g CFP/SUL (2.0 g/1.0 g) intravenously every 8 h were included in the study. TPE session began 10 min after the end of CFP/SUL infusion. Serial blood samples were collected at 0, 1, 2, 3, 4, 6 and 8 h at the fourth infusion with TPE and the sixth infusion without TPE. Effluent samples were collected at the effluent port of plasma eliminated at the end of TPE. Concentrations of CFP and SUL in plasma and effluent were measured using LC-MS/MS. PK parameters were calculated based on two-compartment open model. RESULTS: Five critically ill TTP patients receiving CFP/SUL monotherapy were enrolled. T1/2α of CFP and SUL with TPE was 0.62 and 1.30 h, respectively. For CFP, T1/2ß with TPE were significantly higher than those without TPE (5.85 ± 3.16 vs. 4.41 ± 2.74, p = 0.016). Vss with TPE were significantly higher than those without TPE (7.23 ± 0.89 vs. 5.24 ± 0.80 L, p = 0.024). AUC0-8 with TPE were significantly lower compared with those without TPE (1380.98 ± 411.99 vs. 1581.61 ± 500.22 mg*h/L, p = 0.011). Relatively, CLt with TPE were significantly higher than those without TPE (1.56 ± 0.46 vs. 1.37 ± 0.44 L/h, p = 0.010). For SUL, Vss and CLt were higher significantly with TPE than those without TPE (28.11 ± 8.42 vs. 18.87 ± 6.45 L, p = 0.002; 10.74 ± 2.01 vs. 8.60 ± 2.10 L/h, p = 0.048). Mean QPE of CFP and SUL were 344.42 ± 55.37 and 34.65 ± 10.09 mg, respectively. Mean fe% of CFP and SUL were 17.22 ± 2.77% and 3.46 ± 1.01%, respectively. WHAT IS NEW AND CONCLUSION: TPE enhances the clearance of CFP and SUL in critically ill TTP patients. CFP is more likely to be removed than SUL due to its a low V and high Pb. TPE is suggested to begin 1-2 h after the end of CFP/SUL infusion. Plasma concentration monitoring is advised when CFP/SUL must be administered during TPE.
Assuntos
Púrpura Trombocitopênica Trombótica , Cefoperazona/uso terapêutico , Cromatografia Líquida , Estado Terminal/terapia , Humanos , Troca Plasmática , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Púrpura Trombocitopênica Trombótica/etiologia , Sulbactam , Espectrometria de Massas em TandemRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy. Understanding of the molecular pathogenesis may lead to novel therapeutic targets. Rapamycin, the mammalian target of rapamycin (mTOR) inhibitor, showed inhibitory effects on T-ALL cells. In this study, we showed that rapamycin significantly reduced MYCN mRNA and protein in a concentration-dependent manner in T-ALL cells. Selective knockdown of MYCN by small interfering RNA had similar effects to rapamycin to inhibit T-ALL proliferation and colony formation and to induce G1-phase cell-cycle arrest and apoptosis. The inhibitory effects of rapamycin and MYCN depletion were also found in a Molt-4 xenograft model. Rapamycin and MYCN inhibition suppressed both Wnt/ß-catenin and mTOR signaling pathways. The results suggest the effects of rapamycin on adult T-ALL is likely mediated by downregulation of MYCN. The findings suggest MYCN a potential target for the treatment of adult T-ALL. Additionally, dual targeting of mTOR and Wnt/ß-catenin pathways may represent a novel strategy in the treatment of adult T-ALL.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Proteína Proto-Oncogênica N-Myc/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/genética , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Proliferação de Células , Humanos , Camundongos , Camundongos Endogâmicos NOD , Sirolimo/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood-brain barrier (BBB) permeability for arsenic. Arsenite (AsIII ), monomethylarsonic acid (MMAV ), dimethylarsinic acid (DMAV ), and arsenate (AsV ) in CSF and plasma were analysed by high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII , DMAV > MMAV > AsV . Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV . Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.
Assuntos
Arsênio , Leucemia Promielocítica Aguda , Trióxido de Arsênio , Cromatografia Líquida de Alta Pressão , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Manitol , Recidiva Local de NeoplasiaRESUMO
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological emergency. Although therapeutic plasma exchange together with corticosteroids achieve successful outcomes, a considerable number of patients remain refractory to this treatment and require early initiation of intensive therapy. However, a method for the early identification of refractory iTTP is not available. To develop and validate a model for predicting the probability of refractory iTTP, a cohort of 265 consecutive iTTP patients from 17 large medical centres was retrospectively identified. The derivation cohort included 94 patients from 11 medical centres. For the validation cohort, we included 40 patients from the other six medical centres using geographical validation. An easy-to-use risk score system was generated, and its performance was assessed using internal and external validation cohorts. In the multivariable logistic analysis of the derivation cohort, three candidate predictors were entered into the final prediction model: age, haemoglobin and creatinine. The prediction model had an area under the curve of 0.886 (95% CI: 0.679-0.974) in the internal validation cohort and 0.862 (95% CI: 0.625-0.999) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. In conclusion, we developed and validated a highly accurate prediction model for the early identification of refractory iTTP. It has the potential to guide tailored therapy and is a step towards more personalized medicine.
Assuntos
Creatinina/sangue , Bases de Dados Factuais , Hemoglobinas/metabolismo , Modelos Biológicos , Púrpura Trombocitopênica Trombótica/sangue , Adulto , Fatores Etários , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
Arsenic-induced side effects limit its application in the treatment of acute promyelocytic leukemia (APL). We recently demonstrated that AS3MT 14215 (rs3740390) genotypes were associated with urinary arsenic metabolites and hematological and biochemical values. To further decipher the role of AS3MT genotypes on arsenic metabolism and toxicity, AS3MT 27215 (rs11191446), 35587 (rs11191453), 35991 (rs10748835), and their interactive effects were examined in fifty APL patients treated with arsenic trioxide (As2O3) for the first time. Urinary arsenic metabolites and methylation capacity indexes were evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), primary methylation index (PMI, MMA/iAs), secondary methylation index (SMI, DMA/MMA), and total methylation index (TMI, [MMA+DMA]/iAs). Results showed 27215 (rs11191446) genotypes had no statistical significance in arsenic metabolism, as only 5 (10%) patients were the non-wild-type genotypes. 35587 (rs11191453) genotypes were significantly associated with MMA%, DMA%, and SMI. 35991 (rs10748835) genotypes were significantly associated with iAs%, DMA%, PMI, TMI, and the level of ALT and AST. Patients with both 35587 (rs11191453) TT and 35991 (rs10748835) AG+GG genotypes were significantly associated with DMA% and SMI. In addition, patients with both 35991 (rs10748835) AA and 35587 (rs11191453) TC+CC genotypes had the highest DMA%, SMI, and TMI, but the lowest iAs%, ALT and AST level, indicating that additive effects exist on arsenic metabolism and liver function. Our data promotes the realization that AS3MT 35587 (rs11191453), 35991 (rs10748835), especially their joint genotypes 35991 (rs10748835) AA / 35587 (rs11191453) TC+CC, is a novel predictive biomarker for the therapeutic efficacy of As2O3 in the treatment of APL.
Assuntos
Antineoplásicos/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Arsênio/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Metiltransferases/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Trióxido de Arsênio/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Criança , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Masculino , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Adulto JovemRESUMO
This study presents outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous haemodialysis (CVVHD). Of 3 acute promyelocytic leukaemia patients receiving CVVHD in management of acute kidney injury, only 1 patient was included. The patient presented disseminated intravascular coagulation and acute kidney injury before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analysed using high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. Plasma concentrations of AsIII , monomethylarsonic acid and dimethylarsinic acid with CVVHD were lower than those without CVVHD. Area under the concentration-time curve from 0 to the last sample with quantifiable concentration of AsIII without CVVHD was significantly higher than that with CVVHD (292.10 ng h/mL vs 195.86 ng h/mL, P = .037), which were not observed for monomethylarsonic acid and dimethylarsinic acid. Dialysate saturation of arsenic species was remarkable, especially for AsIII . Complete remission was achieved and renal function recovered. In this study, ATO can be used safely and effectively to treat acute promyelocytic leukaemia patients undergoing CVVHD without dose adjustment.
Assuntos
Injúria Renal Aguda/terapia , Antineoplásicos/farmacocinética , Trióxido de Arsênio/farmacocinética , Terapia de Substituição Renal Contínua , Leucemia Promielocítica Aguda/tratamento farmacológico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Idoso , Antineoplásicos/administração & dosagem , Área Sob a Curva , Trióxido de Arsênio/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Leucemia Promielocítica Aguda/sangue , Masculino , Estudos Prospectivos , Indução de Remissão/métodos , Estudos de Caso Único como Assunto , Resultado do TratamentoRESUMO
Dickkopf-3 (DKK3) is frequently down-regulated by promoter hypermethylation and is closely associated with a poor prognosis in many cancers. Our previous studies have shown that miR-708 down-regulates DKK3 at the post-transcriptional level in B-ALL. However, whether transcriptional mechanisms lead to DKK3 silencing remains unclear. Here, we analysed the promoter regions of DKK3 by bioinformatics and found binding sites for MYCN. A dual-luciferase reporter gene assay and ChIP experiments revealed that MYCN negatively regulates DKK3 at the transcriptional level in B-ALL cell lines, and using bisulphite sequencing PCR, we affirmed that MYCN has no effect on the methylation of the DKK3 promoter. MYCN silencing in B-ALL cells resulted in reduced cell proliferation, increased apoptosis and G1 phase arrest. Treatment with MYCN siRNA or 5-aza-2'-deoxycytidine (5-AdC), a demethylating agent, significantly increased the levels of DKK3 mRNA and protein and decreased the protein levels of p-GSK3ß and nuclear ß-catenin, which indicates inhibition of the Wnt/ß-catenin pathway in vitro. MYCN knockdown significantly decreased the tumorigenic capacity of Nalm6 cells, which restored DKK3 levels and inhibited the Wnt/ß-catenin pathway in vivo. Our study provides an increased understanding of adult B-ALL pathogenesis, which may be beneficial to the development of effective prognostic markers or therapeutic targets.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína Proto-Oncogênica N-Myc/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/genética , Sítios de Ligação , Linhagem Celular Tumoral , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Humanos , Camundongos SCID , Proteína Proto-Oncogênica N-Myc/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Regiões Promotoras Genéticas , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genéticaRESUMO
This study was conducted to identify the characteristics and risk factors for early death in critically ill acute promyelocytic leukaemia (APL) patients in the Hemato-oncology ICU (HICU). A total of 44 APL patients from 2017 to 2023 were included. The mortality among APL patients in the HICU was high (27/44, 61.36%). Compared with patients who survived, nonsurvivors had a longer prothrombin time (P = 0.002), lower fibrinogen (P = 0.022), higher white blood cell count (P = 0.004) and higher creatinine (P = 0.037) on hosipital admission. Severe bleeding was the most frequent complication (34 cases, 77.27%), which occurred either preinduction or on Day 5 (IQR 3-7.5 days) of induction. Cerebral bleeding associated with consciousness disturbance was the main reason for HICU admission (18 cases, 40.9%). The leading cause of death was fatal haemorrhage (18/34, 52.94%), which occurred either preinduction or on Day 4 (IQR 3-7 days) of induction. Another common cause of death was sepsis (8/18, 44.44%), which occurred on Day 12 (IQR 9.5-24.75 days) during induction. In conclusion, the main cause of death in APL patients treated in the HICU was primary being attributed to fatal bleeding, followed by sepsis.
Assuntos
Estado Terminal , Unidades de Terapia Intensiva , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/complicações , Feminino , Masculino , Estado Terminal/mortalidade , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Idoso , Hemorragia/mortalidade , Mortalidade Hospitalar , Estudos Retrospectivos , Sepse/mortalidade , Sepse/complicaçõesRESUMO
BACKGROUND: The prognosis of acute promyelocytic leukemia (APL) in the elderly is poorer than that of younger patients after treatment with all-trans retinoic acid plus chemotherapy, which is the current standard therapy for APL. A significantly higher mortality during consolidation therapy was found, which is mainly due to deaths from sepsis following chemotherapy-induced myelosuppression. METHODS: A total of 33 patients aged 60 years or older with de novo APL were treated with single-agent arsenic trioxide (ATO) for remission induction and postremission therapy. The postremission therapy continued for up to 4 years. RESULTS: Twenty-nine patients (87.9%) achieved a hematologic complete remission, and the most common adverse event during remission induction was leukocytosis (63.6%). Definite differentiation syndrome was observed in 5 patients. Nonhematologic adverse events were all manageable and reversible. Twenty-eight patients proceeded to postremission therapy. Adverse effects during postremission therapy were mild, transient, and no treatment was required. No patients died from ATO-related toxicities. With a median follow-up of 99 months, the 10-year cumulative incidence of relapse, overall survival, disease-free survival, and cause-specific survival were 10.3%, 69.3%, 64.8%, and 84.8%, respectively, which are comparable with those in the younger APL partners. No significant risks for development of chronic arsenicosis or second malignancy were observed during the follow-up period. CONCLUSIONS: The results indicate that the single-agent ATO regimen is safe and effective with long-term durable remission, and could be used as first-line treatment for elderly patients with de novo APL.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Trióxido de Arsênio , Arsenicais/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Óxidos/efeitos adversos , Prognóstico , RecidivaRESUMO
SET-CAN/NUP214 fusion is a recurrent event commonly observed in adult male patients diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and has occasionally been reported in other diseases such as acute myeloid leukemia (AML), myeloid sarcoma (MS), acute undifferentiated leukemia (AUL), chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). This fusion gene is derived from chromosome del(9)(q34.11;q34.13) or t(9;9)(q34;q34) and may have an inhibitory effect on primitive progenitor differentiation. The prognosis of the reported patients is varied, with these patients often show resistance to chemotherapy regimens that include high doses of glucocorticoids. The optional treatment has not been determined, more cases need to be accumulated and evaluated. The scope of this review is to summarize the general features and prognostic significance in leukemia associated with the SET-CAN/NUP214 fusion gene and to discuss the methods of detection and treatment, aiming at providing some useful references for relevant researchers in the field of blood tumor.
RESUMO
Purpose: The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however, few studies have been published on the efficacy and safety of VEN combined with both hypomethylating agents (HMAs) and low-dose chemotherapy for patients with unfit or R/R AML. Methods: This study retrospectively analyzed the clinical characteristics, treatment details, safety profile and clinical outcomes of patients with unfit or R/R AML treated with VEN+ HMAs+ half-dose CAG (LDAC, aclarubicin and granulocyte colony-stimulating factor). Results: A total of 24 AML patients were involved in the study, of whom 13 (54.2%) were in the unfit group, and 11 (45.8%) were in the R/R group. FLT3 and IDH (8/24, 33.3%) were the most common gene aberrations. Patients in the R/R group were found to be more likely to carry KIT (5/11, 45.5%) compared with the unfit group (0/13, 0%) (P = 0.006). The ORR observed during the study was 83.3% (20/24; 14 CR, 2CRi, 4PR). In the unfit group, 11/13 (84.6%) patients achieved cCR (10 CR and 1 CRi); while 5/11 (45.5%) R/R patients achieved response (4 CR and 1 CRi). CR was observed in all AML patients with TP53 (5/5), GATA2 (3/3), CEBPA (3/3) and ASXL1 (3/3). The most common adverse events (AEs) during VEN+ HMAs+ half-dose CAG therapy were persistent cytopenias and infections. Conclusion: The results of this study confirm that VEN+ HMAs+ half-dose CAG is associated with promising efficacy (even high-risk molecular patterns) and tolerable safety profile in patients with unfit or R/R AML. Yet, the study involves only a small sample size, which should not be overlooked. As such, further studies on the efficacy of VEN combined with HMAs and half-dose CAG regimen in AML patients are essential.
RESUMO
Objective: This study aimed to derive and validate a prognostic scoring system to identify patients with hematological malignancies (HMs) and sepsis who have a high mortality rate. Methods: Cohorts for derivation and validation were created from all data. Using univariate and multivariate analysis, the independent variables connected to 28-day mortality in the derivation cohort were found. A receiver operating characteristic (ROC) curve was used to compare the predictive power and determine their cutoff points. These risk variables were given a score weighted by risk prediction function, and a new scoring system was also developed. The area under the ROC curve (AUROC) and sensitivity and specificity for mortality of the risk category of the new scoring system were compared with Sequential Organ Failure Assessment (SOFA) score. Results: 90 (45.22%) of the 199 patients passed away within 28 days. Ninety-nine patients made up the derivation cohort, with 47 (47.47%) fatalities. Ages in the non-survival group were higher (61.47 ± 14.53 vs 55.13 ± 15.66) than in the survival group. As independent predictors of death, multivariable analysis identified SOFA score (OR 1.442, 95% CI 1.035, 2.009), age (OR 1.242, 95% CI 1.026, 1.503), and prothrombin time (PT) (OR 1.213, 95% CI 1.030, 1.430). The AUROC with 95% CI of the new scoring system and its sensitivity and specificity to mortality were virtually all superior to SOFA score in both derivation and validation cohorts: AUROC (0.757 vs 0.716), Sensitivity (75 vs 67.3%), and Specificity (68.1% vs 63.8%) are the Derivation cohort; Validation cohort: Sensitivity (91.2% vs 84.2%), AUROC (0.792 vs 0.733), and Specificity (58.1% vs 58.1%). The model was correctly calibrated, according to the Hosmer-Lemeshow test. Conclusion: The new scoring system was more accurate in predicting 28-day mortality among patients with HMs and sepsis than the SOFA score.
RESUMO
HLA-C*15:02:58 differs from HLA-C*15:02:01:01 by one nucleotide in exon 1.
Assuntos
População do Leste Asiático , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Sequência de Bases , NucleotídeosRESUMO
OBJECTIVE: Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/ß-catenin signaling pathway in leukemia cell lines. METHODS: Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed. RESULTS: Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments. CONCLUSIONS: This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML.
Assuntos
Antimetabólitos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Inibidores de Histona Desacetilases , Leucemia Mieloide Aguda , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Citarabina/uso terapêutico , Decitabina/efeitos adversos , Inibidores de Histona Desacetilases/efeitos adversos , Leucemia Mieloide Aguda/metabolismo , Estudos Retrospectivos , Antimetabólitos Antineoplásicos/efeitos adversosRESUMO
The aim of this study was to determine the efficacy and safety of treatment of pediatric acute promyelocytic leukemia (APL) with single-agent arsenic trioxide (ATO). A total of 19 children (< or = 15 years of age) with newly diagnosed APL were treated with single-agent ATO for remission induction and postremission therapy. Seventeen of the children (89.5%) achieved complete hematologic remission, and 2 early deaths occurred from intracranial hemorrhage. ATO-induced leukocytosis was observed in 13 (68.4%) patients. Other ATO-related toxicities were minimal and transient. Postremission ATO therapy continued for 3 years; the most common side effect was ATO-induced neutropenia. With a median follow-up of 53 months (range, 23-76 months), the calculated 5-year overall survival and event-free survival were 83.9% and 72.7%, respectively, which are comparable with results achieved by the use of ATRA plus chemotherapy, which is the standard therapy for APL. No chronic arsenic toxicity or second malignancies were found during the follow-up period, and arsenic retention was not significant in patients off treatment more than 24 months. ATO resistance was observed in only 1 patient with a complex karyotype. The results indicate the high efficacy and safety of single-agent ATO regimens in the treatment of children with de novo APL.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Adolescente , Antineoplásicos/efeitos adversos , Trióxido de Arsênio , Arsenicais/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Cariotipagem , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Masculino , Neutropenia/induzido quimicamente , Óxidos/efeitos adversos , Indução de Remissão , Fatores de TempoRESUMO
Mismatched human leukocyte antigen (HLA) loss is an essential mechanism involved in immune escape and recurrence in acute leukemia after haploidentical transplantation. Patients relapsing after transplantation with HLA loss have a poor prognosis, and are less likely to benefit from donor lymphocyte infusion (DLI) from the original donor. Here, we report a patient with high-risk acute myeloid leukemia who relapsed within six months after haploidentical peripheral blood stem cell transplantation (PBSCT) combined with unrelated umbilical cord blood (UCB) with a session of prophylactic DLI. This patient achieved transient remission after subsequent Interferon-α-1b treatment for two weeks but experienced a second relapse within one month. Genomic analysis by real-time PCR assay revealed that this patient had a loss of an entire mismatched HLA haplotype that was derived from her haploidentical donor. Haploidentical peripheral blood stem cell transplantation with prophylactic DLI might be a triggering event for HLA loss relapse after haploidentical transplantation combined with UCB. HLA loss should be considered in patients with post-HSCT relapse, especially in haploidentical transplantation.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante de Células-Tronco de Sangue Periférico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Feminino , Sangue Fetal , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antígenos de Histocompatibilidade , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe II , Humanos , Interferon-alfa , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Recidiva , Estudos RetrospectivosRESUMO
Long non-coding RNAs (LncRNAs) exert important regulatory roles in chronic myeloid leukemia (CML). In this study, we aimed to investigate the potential role and molecular mechanism of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in CML. We found that the expression of ADORA2A-AS1 was upregulated in CML. Further, knockdown of ADORA2A-AS1 inhibited the proliferation, induced apoptosis, arrested cell cycle, and enhanced imatinib sensitivity in CML cells. Besides, ADORA2A-AS1 promoted the expression of transforming growth factor-beta receptor 1 (TGFBR1) and ATP binding cassette subfamily C member 2 (ABCC2) via sponging miR-665, thereby exerting a tumor-promoting activity. Collectively, our results confirmed the oncogenic effect of ADORA2A-AS1 in CML, indicating that ADORA2A-AS1 is a promosing therapeutic target for CML.