RESUMEN
Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.
RESUMEN
Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante Haploidéntico/efectos adversos , Estudios Retrospectivos , Inducción de Remisión , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Recurrencia , Albúmina Sérica , Esteroides/uso terapéutico , Acondicionamiento PretrasplanteRESUMEN
In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II-IV (36.8% vs 38.8%), III-IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Humanos , Estudios Retrospectivos , Trasplante Haploidéntico/efectos adversos , Tasa de Supervivencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5 mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8 µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8 µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Suero Antilinfocítico , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
OBJECTIVES: To determine the impact of the use of hydroxyethyl starch (HES) in granulocyte apheresis using Spectra Optia. BACKGROUND: Granulocyte transfusion (GT) is a therapeutic option for neutropenic patients with severe bacterial or fungal infections. Recent studies in emergency medicine have shown the potential risk of using HES, which is routinely used in granulocyte apheresis to increase yield by sedimenting red blood cells. We hypothesized that the use of a newer device (Spectra Optia) would spare the need for HES. METHODS: We retrospectively compared granulocyte apheresis with HES (HES group, n = 89) and without HES (non-HES group, n = 36) using Spectra Optia. RESULTS: The granulocyte yield was significantly higher in the HES group (7.3 × 1010 vs. 2.0 × 10, p < 0.01) and was attributed to the difference in collection efficiency (36% vs. 7.7%, p < 0.01). The absolute neutrophil count on the following morning of GT was significantly higher in the HES group than in the non-HES group (2460/µl vs. 505/µl, p < 0.01). There were no significant differences in the occurrence of adverse events between the HES and non-HES groups. The renal function was unchanged in both groups after apheresis. CONCLUSIONS: We demonstrated that the advantage of using HES remained unchanged in granulocyte apheresis using Spectra Optia.
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Eliminación de Componentes Sanguíneos , Granulocitos , Humanos , Transfusión de Leucocitos , Estudios Retrospectivos , AlmidónRESUMEN
Letermovir is used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. Although this agent decreases voriconazole exposure in healthy individuals, the effect of coadministration of letermovir and voriconazole in HSCT recipients is unknown. This retrospective, observational, single-center study was conducted between January 2016 and July 2019 to examine the voriconazole concentration-to-dose ratio over three periods: (A) (days -7 to -1 [day 0: day of HCST]), (B) (days 4-10), and (C) (days 11-17). Forty-two HSCT recipients administered voriconazole were divided into the following two groups based on letermovir coadministration: letermovir (n = 15) and control (n = 27). The percent change (-33.2%, p < 0.05) in the voriconazole concentration-to-dose ratio from periods A to C in the letermovir group was significantly lower than that in the control group. Therefore, frequent therapeutic drug monitoring of voriconazole concentrations and subsequent dose adjustments should be performed regularly in HSCT recipients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Acetatos , Antivirales , Humanos , Quinazolinas , Estudios Retrospectivos , VoriconazolRESUMEN
HLA haploidentical hematopoietic stem cell transplantation (HSCT), i.e., HSCT from a 1-HLA-haplotype-mismatched family donor, has been successfully performed even as a second transplantation for posttransplant relapse. Is the haploidentical the limit of HLA mismatches in HSCT? In order to explore the possibility of HLA-mismatched HSCT from family donors beyond haploidentical relatives, we conducted a prospective phase I/II study of 2-HLA-haplotype-mismatched HSCT (2-haplo-mismatch HSCT). We enrolled 30 patients with posttransplant relapse (acute myeloid leukemia: 18, acute lymphoblastic leukemia: 11, non-Hodgkin lymphoma: 1). 2-haplo-mismatch HSCT was performed as the second to sixth transplantations. The donors were siblings (n = 12), cousins (n = 16), and second cousins (n = 2). The conditioning regimen consisted of fludarabine, cytarabine, melphalan, low-dose anti-thymocyte globulin, and 3 Gy of total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. All patients achieved neutrophil engraftment, except for a case of early death. The cumulative incidences of grades II-IV and III-IV acute GVHD were 36.7% and 16.7%, respectively. The overall survival at 1 year, relapse, and non-relapse mortality rates was 30.1%, 38.9%, and 44.3%, respectively. Considering the poor prognosis of posttransplant relapse, 2-haplo-mismatch HSCT can be an alternative option in a second or third transplantation.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/prevención & control , Haplotipos , Humanos , Estudios Prospectivos , Recurrencia , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. OBJECTIVE: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. METHODS: The target voriconazole trough concentration (Cmin ) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut-offs for AEs. RESULTS: A total of 401 patients were included. Among 108 patients with high initial Cmin , voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin , voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut-offs were 3.5 µg/mL for hepatotoxicity and 4.2 µg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. CONCLUSIONS: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.
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Antifúngicos , Enfermedad Hepática Inducida por Sustancias y Drogas , Voriconazol , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Monitoreo de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis/tratamiento farmacológico , Estudios Retrospectivos , Voriconazol/administración & dosificación , Voriconazol/efectos adversos , Voriconazol/uso terapéuticoRESUMEN
We evaluated the impact of FLT3-ITD, NPM1 mutations, and double mutant CEBPa (dmCEBPa) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16-65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed FLT3-ITD, NPM1 mutations and CEBPa using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with dmCEBPa. Patients with FLT3-ITD had significantly worse OS after relapse than those without (19% vs 41%, p = 0.002), while OS was comparable between patients with and without NPM1 mutations (37% vs 34%, p = 0.309). Patients with dmCEBPa had improved OS than those without (61% vs 32%, p = 0.006). By multivariate analysis, FLT3-ITD was independently associated with worse OS after relapse [hazard ratio (HR) 1.99, 95% CI 1.27-3.12, p = 0.003], and dmCEBPa with improved OS (HR 0.40, 95% CI 0.17-0.93, p = 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.
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Proteínas Potenciadoras de Unión a CCAAT/genética , Estudios de Asociación Genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Citogenética , Toma de Decisiones , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Nucleofosmina , Pronóstico , Estudios Retrospectivos , Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Letermovir (LMV) is a new antiviral drug used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. It has been reported to increase tacrolimus (TAC) exposure and decrease voriconazole (VRCZ) exposure in healthy participants. However, VRCZ inhibits the metabolism of TAC. Thus, the effects of LMV on TAC exposure in patients receiving VRCZ are unknown. This retrospective, observational, single-center study was conducted between May 2018 and April 2019. The TAC concentration/dose (C/D) ratio, VRCZ concentration, and VRCZ C/D ratio for 7 days before and for the first and second 7-day periods after the initiation of LMV administration were evaluated. Fourteen HSCT recipients receiving VRCZ were enrolled. There was no significant difference in the TAC C/D ratio for 7 days before and for the first and second 7-day periods after initiating LMV administration (median: 866 [IQR: 653-953], 842 [IQR: 636-1031], and 906 [IQR: 824-1210] [ng/mL]/[mg/kg], respectively). In contrast, the VRCZ C/D ratio and concentration for the first and second 7-day periods after LMV initiation were significantly lower than those before initiating LMV administration (mean 1.11 ± 0.07, 0.12 ± 0.08, and 0.22 ± 0.12 [µg/mL]/[mg/kg] and 0.7 ± 0.5, 0.8 ± 0.5, and 1.3 ± 0.7 µg/mL, respectively; n = 12). This can be explained by the increase in TAC concentration caused by CYP3A4 inhibition due to LMV and by the decrease in TAC concentration ascribed to the decrease in VRCZ concentration by CYP2C19 induction due to LMV. These results suggest that it is unnecessary to adjust the dose of TAC based on LMV initiation; however, it is necessary to adjust the dose of TAC based on conventional TAC concentration measurements.
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Acetatos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Quinazolinas/uso terapéutico , Tacrolimus/farmacocinética , Voriconazol/uso terapéutico , Adulto , Antivirales/uso terapéutico , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Tacrolimus/sangre , Voriconazol/sangre , Voriconazol/farmacocinéticaRESUMEN
BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of Ë3 nephrotoxic drugs.
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Lesión Renal Aguda/etiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Insuficiencia Renal Crónica/etiología , Lesión Renal Aguda/patología , Adolescente , Adulto , Niño , Femenino , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Pronóstico , Inducción de Remisión , Insuficiencia Renal Crónica/patología , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p < 0.001, OS: p < 0.001). Moreover, stratified analysis of the chromosomal abnormalities t(8;21)(q22;q22) and inv(16)(p13.1q22), t(16;16)(p13.1;q22) showed that D816 mutation was associated with a significantly worse prognosis. In a further multivariate analysis of RFS and OS, D816 mutation was found to be an independent risk factor for significantly poorer prognosis. In the present study, we were able to establish that, of all KIT mutations, D816 mutation alone is an unfavorable prognostic factor.
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Cromosomas Humanos/genética , Leucemia Mieloide Aguda , Mutación Missense , Proteínas Proto-Oncogénicas c-kit/genética , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNFα, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. Cancer Res; 77(16); 4426-33. ©2017 AACR.
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Aminopiridinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteínas S100/metabolismo , Factores de Elongación Transcripcional/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Antialérgicos/administración & dosificación , Antialérgicos/farmacología , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteína A6 de Unión a Calcio de la Familia S100 , Proteínas S100/genética , Factores de Elongación Transcripcional/genética , Factor de Necrosis Tumoral alfa/administración & dosificaciónRESUMEN
In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P<0.0001) and in patients with intermediate cytogenetic risk (P<0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged ≤70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia.
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Metilación de ADN , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Bandeo Cromosómico , Terapia Combinada , Femenino , Duplicación de Gen , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Secuencias Repetidas en Tándem , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Objective In hematological malignancy patients, the complication of acute respiratory failure often reaches a degree of severity that necessitates mechanical ventilation. The objective of the present study was to investigate the therapeutic outcomes of mechanical ventilation in hematological malignancy patients with respiratory failure and to analyze the factors that are associated with successful treatment in order to identify the issues that should be addressed in the future. Methods The present study was a retrospective analysis of 71 hematological malignancy patients with non-cardiogenic acute respiratory failure who were treated with mechanical ventilation at Nippon Medical School Hospital between 2003 and 2014. Results Twenty-six patients (36.6%) were treated with mechanical ventilation in an intensive care unit (ICU). Non-invasive positive pressure ventilation (NPPV) was applied in 29 cases (40.8%). The rate of successful mechanical ventilation treatment with NPPV alone was 13.8%. The rate of endotracheal extubation was 17.7%. A univariate analysis revealed that the following factors were associated with the successful extubation of patients who received invasive mechanical ventilation: respiratory management in an ICU (p=0.012); remission of the hematological disease (p=0.011); female gender (p=0.048); low levels of accompanying non-respiratory organ failure (p=0.041); and the non-use of extracorporeal circulation (p=0.005). A subsequent multivariate analysis revealed that respiratory management in an ICU was the only variable associated with successful extubation (p=0.030). Conclusion The outcomes of hematological malignancy patients who receive mechanical ventilation treatment for respiratory failure are very poor. Respiratory management in an ICU environment may be useful in improving the therapeutic outcomes of such patients.
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Neoplasias Hematológicas/complicaciones , Respiración Artificial/métodos , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Respiración con Presión Positiva/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We performed a decision analysis comparing allogeneic hematopoietic cell transplantation (allo-HCT) versus chemotherapy in first complete remission for patients with cytogenetically intermediate-risk acute myeloid leukemia, depending on the presence or absence of FLT3-internal tandem duplication (ITD), nucleophosmin (NPM1), and CCAAT/enhancer binding protein alpha (CEBPA) mutations. Adjusted means of the patient-reported EQ-5D index were used as quality-of-life (QOL) estimates. In 332 patients for which FLT3-ITD status was available, FLT3-ITD was present in 60. In 272 patients without FLT3-ITD, NPM1 mutations were present in 83. CEBPA biallelic mutations were detected in 53 patients. For patients harboring FLT3-ITD, allo-HCT improved life expectancy (LE) (52 versus 32 months during 10-year observation) and QOL-adjusted life expectancy (QALE, 36 versus 21). Monte-Carlo simulation identified allo-HCT as the favored strategy in 100% of simulations. In patients without FLT3-ITD, allo-HCT improved LE/QALE with or without NPM1 mutations. However, sensitivity analyses showed that the results were not robust enough. For patients harboring CEBPA biallelic mutations, chemotherapy was favored (LE, 53 versus 84; QALE, 37 versus 59), whereas, for patients with monoallelic mutations or wild-type CEBPA, allo-HCT was favored (LE, 68 versus 54; QALE, 48 versus 37). Sensitivity analyses did not change the results in either group. In conclusion, based on a Markov decision analysis, allo-HCT was a favored postremission strategy in patients with FLT3-ITD, and chemotherapy was favored in patients with biallelic CEBPA mutations. A prospective study is warranted to determine the value of allo-HCT, especially in FLT3-ITD-negative patients.
Asunto(s)
Quimioterapia de Consolidación/normas , Análisis Citogenético , Técnicas de Apoyo para la Decisión , Trasplante de Células Madre Hematopoyéticas/normas , Leucemia Mieloide Aguda/terapia , Mutación , Adolescente , Adulto , Anciano , Proteína alfa Potenciadora de Unión a CCAAT/genética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Cadenas de Markov , Persona de Mediana Edad , Proteínas Nucleares/genética , Nucleofosmina , Calidad de Vida , Inducción de Remisión , Medición de Riesgo , Trasplante Homólogo , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs. Although the complex I inhibitory activities of all the new nafuredin-γ analogs were lower than that of 2, all were in the high nM range (IC50: 300-820nM).
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Diseño de Fármacos , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pironas/química , Pironas/farmacología , Aire , Estabilidad de Medicamentos , Inhibidores Enzimáticos/síntesis química , Concentración 50 Inhibidora , Pironas/síntesis químicaRESUMEN
OBJECTIVE: The prognosis for elderly patients with acute myeloid leukemia (AML) remains dismal. To explore the potential of immunotherapy for improving clinical outcomes for these patients, we performed a phase I clinical trial of dendritic cell (DC)-based immunotherapy for elderly patients with AML. MATERIALS AND METHODS: Autologus monocytes were obtained after reducing tumor burden by chemotherapy. Immature DCs induced with granulocyte-macrophage colony-stimulating factor and interleukin-4 were pulsed with autologous apoptotic leukemic cells as antigens. DCs were administered intradermally to four patients five times at 2-week intervals. To facilitate DC migration to lymph nodes, injection sites were pretreated with killed Streptococcus pyogenes OK-432 one day before. DCs were coinjected with OK-432 to induce maturation and interleukin-12 production in vivo. RESULTS: Antileukemic responses were observed by an interferon-γ enzyme-linked immunospot assay or a tetramer assay in two of four patients. In a human leukocyte antigen-A∗2402-positive patient, induction of CD8(+) T-cell responses to WT1- and human telomerase reverse transcriptase - derived peptides were observed, indicating cross-priming in vivo. The two patients with antileukemic immunity showed longer periods of disease stabilization than the other two patients. CONCLUSIONS: This study demonstrates the immunogenicity of autologous DCs that cross-present leukemia-associated antigens from autologous apoptotic leukemic cells in vivo in elderly patients with AML.
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Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Inmunoterapia/métodos , Leucemia Mieloide/terapia , Enfermedad Aguda , Anciano , Apoptosis/inmunología , Reactividad Cruzada/inmunología , Células Dendríticas/trasplante , Femenino , Fiebre/etiología , Citometría de Flujo , Humanos , Inmunoterapia/efectos adversos , Células K562 , Leucemia/inmunología , Leucemia/patología , Leucemia Mieloide/inmunología , Leucemia Mieloide/patología , Masculino , Picibanil/administración & dosificación , Picibanil/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hyperbaric air (HBA) is used to improve healing of wounds including diabetic ulcer. The aim of this study was to clarify the effects of HBA exposure on lipid and glucose metabolism in db/db mice. HBA did not influence the weight of db/db mice. Serum levels of free fatty acid and triglyceride, but not glucose and insulin, were significantly decreased after 6 weeks of treatment with HBA. The mRNA expressions of CPT-1, PPARα and PGC-1α genes, which are related to lipid metabolism, were significantly up-regulated in the muscle and liver. Increases in TNFα and MCP1 mRNA, which impaired lipid metabolism, were also attenuated by HBA treatment. These results suggest that exposure of HBA could have beneficial effects on lipid metabolism in patients with type 2 diabetes mellitus.