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1.
Exp Hematol Oncol ; 11(1): 25, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505384

RESUMO

BACKGROUND: Acute graft-versus-host disease (aGVHD) remains the major cause of early mortality after haploidentical related donor (HID) hematopoietic stem cell transplantation (HSCT). We aimed to establish a comprehensive model which could predict severe aGVHD after HID HSCT. METHODS: Consecutive 470 acute leukemia patients receiving HID HSCT according to the protocol registered at https://clinicaltrials.gov (NCT03756675) were enrolled, 70% of them (n = 335) were randomly selected as training cohort and the remains 30% (n = 135) were used as validation cohort. RESULTS: The equation was as follows: Probability (grade III-IV aGVHD) = [Formula: see text], where Y = -0.0288 × (age) + 0.7965 × (gender) + 0.8371 × (CD3 + /CD14 + cells ratio in graft) + 0.5829 × (donor/recipient relation) - 0.0089 × (CD8 + cell counts in graft) - 2.9046. The threshold of probability was 0.057392 which helped separate patients into high- and low-risk groups. The 100-day cumulative incidence of grade III-IV aGVHD in the low- and high-risk groups was 4.1% (95% CI 1.9-6.3%) versus 12.8% (95% CI 7.4-18.2%) (P = 0.001), 3.2% (95% CI 1.2-5.1%) versus 10.6% (95% CI 4.7-16.5%) (P = 0.006), and 6.1% (95% CI 1.3-10.9%) versus 19.4% (95% CI 6.3-32.5%) (P = 0.017), respectively, in total, training, and validation cohort. The rates of grade III-IV skin and gut aGVHD in high-risk group were both significantly higher than those of low-risk group. This model could also predict grade II-IV and grade I-IV aGVHD. CONCLUSIONS: We established a model which could predict the development of severe aGVHD in HID HSCT recipients.

2.
Front Cell Infect Microbiol ; 12: 862526, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35392613

RESUMO

Objective: We aimed to establish a model that can predict refractory/recurrent cytomegalovirus (CMV) infection after haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT). Methods: Consecutive acute leukemia patients receiving HID HSCT were enrolled (n = 289). We randomly selected 60% of the entire population (n = 170) as the training cohort, and the remaining 40% comprised the validation cohort (n = 119). Patients were treated according to the protocol registered at https://clinicaltrials.gov (NCT03756675). Results: The model was as follows: Y = 0.0322 × (age) - 0.0696 × (gender) + 0.5492 × (underlying disease) + 0.0963 × (the cumulative dose of prednisone during pre-engraftment phase) - 0.0771 × (CD34+ cell counts in graft) - 1.2926. The threshold of probability was 0.5243, which helped to separate patients into high- and low-risk groups. In the low- and high-risk groups, the 100-day cumulative incidence of refractory/recurrent CMV was 42.0% [95% confidence interval (CI), 34.7%-49.4%] vs. 63.7% (95% CI, 54.8%-72.6%) (P < 0.001) for total patients and was 50.5% (95% confidence interval (CI), 40.9%-60.1%) vs. 71.0% (95% CI, 59.5%-82.4%) (P = 0.024) for those with acute graft-versus-host disease. It could also predict posttransplant mortality and survival. Conclusion: We established a comprehensive model that could predict the refractory/recurrent CMV infection after HID HSCT. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT03756675.


Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Doença Aguda , Infecções por Citomegalovirus/etiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Recém-Nascido , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Estudos Retrospectivos
3.
Elife ; 112022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35199645

RESUMO

Atmospheric Particulate Matter (PM) is one of the leading environmental risk factors for the global burden of disease. Increasing epidemiological studies demonstrated that PM plays a significant role in CNS demyelinating disorders; however, there is no direct testimony of this, and yet the molecular mechanism by which the occurrence remains unclear. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that PM exposure aggravates neuroinflammation, myelin injury, and dysfunction of movement coordination ability via boosting microglial pro-inflammatory activities, in both the pathological demyelination and physiological myelinogenesis animal models. Indeed, pharmacological disturbance combined with RNA-seq and ChIP-seq suggests that TLR-4/NF-kB signaling mediated a core network of genes that control PM-triggered microglia pathogenicity. In summary, our study defines a novel atmospheric environmental mechanism that mediates PM-aggravated microglia pathogenic activities, and establishes a systematic approach for the investigation of the effects of environmental exposure in neurologic disorders.


Assuntos
Doenças Desmielinizantes , NF-kappa B , Animais , Doenças Desmielinizantes/patologia , Microglia/patologia , Material Particulado/toxicidade , Receptor 4 Toll-Like/genética
4.
Front Immunol ; 13: 757002, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154096

RESUMO

For allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, preemptive interferon-α (IFN-α) therapy is considered as a useful method to eliminate the minimal residual disease (MRD). Our purpose is to assess the long-term efficacy of preemptive IFN-α therapy in acute myeloid leukemia (AML) patients following allo-HSCT based on two registry studies (#NCT02185261 and #NCT02027064). We would present the final data and unpublished results of long-term clinical outcomes with extended follow-up. We adopted polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) to monitor MRD, and a positive result of bone marrow specimen examined by either of them would be identified as the MRD-positive status. Subcutaneous injections of recombinant human IFN-α-2b were performed for 6 cycles, and prolonged IFN-α therapy could be permitted at the request of patients. The median cycles were 3.5 (range, 0.5-30.5) cycles. A total of 9 patients suffered from grade ≥3 toxicities (i.e., infectious: n = 6; hematologic: n = 3). The 6-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 13.0% (95% confidence interval [CI], 5.4-20.6%) and 3.9% (95%CI, 0.0-17.6%), respectively. The probability of disease-free survival at 6 years following IFN-α therapy was 83.1% (95%CI, 75.2-91.9%). The probability of overall survival at 6 years following IFN-α therapy was 88.3% (95%CI, 81.4-95.8%). The cumulative incidences of total chronic graft-versus-host disease (cGVHD) and severe cGVHD at 6 years following IFN-α therapy were 66.2% (95%CI, 55.5-77.0%) and 10.4% (95%CI, 3.6-17.2%), respectively. Multivariable analysis showed that an alternative donor was associated with a lower risk of relapse and the better disease-free survival. Thus, preemptive IFN-α therapy could clear MRD persistently, prevent relapse truly, and improve long-term survival in AML patients following allo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores Imunológicos/administração & dosagem , Interferon alfa-2/administração & dosagem , Leucemia Mieloide Aguda/terapia , Sistema de Registros , Prevenção Secundária/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos , Recidiva , Transplante Homólogo/efeitos adversos , Adulto Jovem
5.
Ther Adv Hematol ; 13: 20406207211072838, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35096361

RESUMO

PURPOSE: Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT. METHODS: MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0-2.0) × 106/kg once a week. RESULTS: A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8-1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1-7) and 3 (range, 2-12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16-118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22-84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1). CONCLUSION: MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.

6.
Br J Haematol ; 196(3): 735-742, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34741461

RESUMO

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.


Assuntos
Anemia Aplástica/mortalidade , Anemia Aplástica/terapia , Algoritmos , Anemia Aplástica/diagnóstico , Anemia Aplástica/epidemiologia , Causas de Morte , Tomada de Decisão Clínica , Estudos de Coortes , Árvores de Decisões , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mortalidade , Prognóstico , Índice de Gravidade de Doença , Transplante Haploidêntico , Resultado do Tratamento
8.
Front Immunol ; 12: 720354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539656

RESUMO

Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosa-associated invariant T (MAIT) cells are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT cells in the occurrence of gut aGVHD in humans. In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyze the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAIT cells. The number and distribution of MAIT cells in intestinal tissues were analyzed by immunofluorescence technology. Our study showed that the number and frequency of MAIT cells in infused grafts in gut aGVHD patients were lower than those in no-gut aGVHD patients. Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early posttransplantation period (+14 days). At the onset of gut aGVHD, the number of MAIT cells decreased in peripheral blood, and the activation marker CD69, chemokine receptors CXCR3 and CXCR4, and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAIT cells secreted more granzyme B, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ under the interleukin (IL)-12/IL-18 stimulation [non-T-cell receptor (TCR) signal] and secreted most of the IL-17 under the cluster of differentiation (CD)3/CD28 stimulation (TCR signal). MAIT cells inhibited the proliferation of CD4+ T cells in vitro. In conclusion, the lower number of MAIT cells in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAIT cells in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAIT cells and promoted the expression of intestinal protective factors to affect the occurrence of gut aGVHD in humans.


Assuntos
Suscetibilidade a Doenças , Gastroenteropatias/etiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Adolescente , Adulto , Biomarcadores , Citocinas/metabolismo , Disbiose , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transdução de Sinais , Transplante Homólogo/efeitos adversos , Adulto Jovem
9.
Blood Adv ; 5(24): 5479-5489, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34507352

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI], 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia
10.
Transplant Cell Ther ; 27(10): 870.e1-870.e7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229053

RESUMO

Late-onset severe pneumonia (LOSP) is defined as severe pneumonia developing during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of the high mortality in patients with LOSP, it is important to identify prognostic factors. In this study, we aimed to develop a risk score system with broad applicability that can help predict the risk of LOSP-associated mortality. We retrospectively analyzed 100 patients with LOSP after allo-HSCT between June 2009 and July 2017. The assessment variables included immune, nutritional, and metabolic parameters at the onset of LOSP. Of these 100 patients, 45 (45%) eventually died, and 55 (55%) were positive for organisms, most commonly viruses. In the multivariate analysis, higher monocyte count (≥0.20 × 109/L versus <0.20 × 109/L; P = .001), higher albumin level (≥30.5 g/L versus <30.5 g/L; P = .044), lower lactic dehydrogenase level (<250 U/L versus ≥250 U/L; P = .008) and lower blood urea nitrogen concentration (<7.2 mmol/L versus ≥7.2 mmol/L; P = .026) at the onset of LOSP were significantly associated with better 60-day survival. A risk score system based on the foregoing results showed that the probability of 60-day survival decreased with increasing risk factors, from 96.3% in the low-risk group to 49.1% in the intermediate-risk group and 12.5% in the high-risk group. Our results indicate that this scoring system using 4 variables can stratify patients with different probabilities of survival after LOSP, which suggests that patients' immune, nutritional, and metabolic status are crucial factors in determining outcome.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Pneumonia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pneumonia/diagnóstico , Prognóstico , Estudos Retrospectivos , Transplante Homólogo
11.
Ann Hematol ; 100(5): 1267-1281, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33712867

RESUMO

The prognosis of 11q23/KMT2A-rearranged (KMT2A-r) acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. Minimal residual disease (MRD) is an important prognostic factor for relapse. Thus, we aimed to identify the evolution of KMT2A before and after allo-HSCT and the efficacy of preemptive immunotherapies for KMT2A-r AL patients receiving allo-HSCT. KMT2A expression was determined through TaqMan-based RQ-PCR technology. Preemptive immunotherapies included interferon-α and donor lymphocyte infusion. We collected 1751 bone marrow samples from 177 consecutive KMT2A-r AL patients. Pre-HSCT KMT2A positivity was correlated with post-HSCT KMT2A positivity (correlation coefficient=0.371, P<0.001). The rates of achieving KMT2A negativity after allo-HSCT were 96.6%, 92.9%, and 68.8% in the pre-HSCT low-level group (>0, <0.1%), intermediate-level group (≥ 0.1%, <1%), and high-level group (≥1%), respectively. The rates of regaining KMT2A positivity after allo-HSCT were 7.7%, 35.7%, 38.5%, and 45.5% for the pre-HSCT KMT2A-negative, low-level, intermediate-level, and high-level groups, respectively (P<0.001). The 4-year cumulative incidence of relapse after allo-HSCT was as high as 53.7% in the pre-HSCT KMT2A expression ≥ 0.1% group, which was compared to the KMT2A-negative group (15.1%) and KMT2A <0.1% group (31.2%). The clinical outcomes of patients with post-HSCT KMT2A positivity were poorer than those of patients with persistent KMT2A negativity. Although post-HSCT preemptive immunotherapies might help to achieve KMT2A negativity, the long-term efficacy was unsatisfactory. Thus, pre-HSCT KMT2A positivity was significantly associated with post-HSCT KMT2A positivity. The clinical outcomes of patients with post-HSCT KMT2A positivity were poor, which might not be overcome by commonly used immunotherapies.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Rearranjo Gênico , Humanos , Imunoterapia , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Neoplasia Residual/terapia , Prognóstico , Transplante Homólogo , Adulto Jovem
12.
BMC Cancer ; 21(1): 292, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740924

RESUMO

BACKGROUND: Sequential monitoring of Wilms' tumor gene 1 (WT1) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could predict relapse in adult acute myeloid leukemia (AML). However, the prognostic role of WT1 in pediatric AML after allo-HSCT is unclear. Thus, we determined to see whether sequential monitoring of WT1 after allo-HSCT could predict relapse in AML children. METHODS: Pediatric AML patients receiving allo-HSCT from January 21, 2012 to December 20, 2018 at the Peking University Institute of Hematology were included in this study. WT1 expression level was determined by TaqMan-based reverse transcription-polymerase chain reaction. WT1 sequential monitoring was performed 1, 2, 3, 4.5, 6, 9, and 12 months post-transplantation and at 6-month intervals thereafter. The primary end point was relapse. The secondary end points included disease-free survival (DFS), overall survival (OS), and non-relapse mortality (NRM). Kaplan-Meier analysis was used for DFS and OS estimates, while competing risk analysis was used for estimating relapse and NRM. RESULTS: Of the 151 consecutive patients included, the median age was 10 years (range, 1-17). The optimal cutoff value of WT1 within 1 year after allo-HSCT to predict relapse was 0.8% (80 WT1 copies/104 ABL copies), with a sensitivity of 60% and specificity of 79%. Compared with WT1 expression < 0.8%, WT1 expression ≥0.8% indicated significantly higher 5-year cumulative incidence of relapse (CIR, 35.1% vs. 11.3%; P = 0.001), lower 5-year disease-free survival (DFS, 60.4% vs. 80.8%; P = 0.009), and lower 5-year overall survival (OS, 64.9% vs. 81.6%; P = 0.038) rates. Multivariate analyses showed that WT1 was an independent risk factor for relapse (HR 2.89; 95% confidence interval (CI), 1.25-6.71; P = 0.014). Both the CIR (5-year CIR: 8.3% vs. 11.3%; P = 0.513) and DFS (5-year DFS: 91.7% vs. 80.8%; P = 0.208) were comparable between patients achieving minimal residual disease (MRD) negativity after preemptive interferon-α (IFN-α) treatment and those without MRD after allo-HSCT, which were better than those of MRD-positive patients without preemptive therapies. CONCLUSIONS: Sequential monitoring of WT1 could predict relapse in pediatric AML after allo-HSCT. WT1-directed immunotherapy may have the potential to prevent relapse and improve survival.


Assuntos
Biomarcadores Tumorais/metabolismo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/epidemiologia , Proteínas WT1/metabolismo , Adolescente , Biomarcadores Tumorais/análise , Medula Óssea/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Neoplasia Residual , Prognóstico , Medição de Risco/métodos , Transplante Homólogo , Proteínas WT1/análise
13.
Transplant Cell Ther ; 27(3): 253.e1-253.e9, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781524

RESUMO

Acute cholecystitis (AC) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, only limited information is available on its clinical features, outcomes, and risk management strategies. This retrospective, nested, case-control study included 6701 patients undergoing allo-HSCT at our center from January 2004 to June 2019. In total, 72 patients (1.1%) were diagnosed with AC; among these, acute acalculous cholecystitis had a slightly higher prevalence (42 patients, 58.3%). Patients with moderate and severe AC exhibited remarkably worse overall survival (P = .001) and non-relapse mortality (P = .011) than others. Survival of haploidentical HSCT recipients with AC was comparable to that for patients with human leukocyte antigen (HLA)-identical donors. Age ≥ 18 years, antecedent stage II to IV acute graft-versus-host disease, and total parenteral nutrition were identified as potential risk factors for AC following allo-HSCT, while haploidentical transplantations were not more susceptible to AC than HLA-identical HSCT. Based on these criteria, a risk score model was developed and validated to estimate the probability of AC following allo-HSCT. The model separates all patients into low-, intermediate-, and high-risk groups and thereby provides a basis for early detection of this complication in the management of allo-HSCT.


Assuntos
Colecistite Aguda , Transplante de Células-Tronco Hematopoéticas , Adolescente , Estudos de Casos e Controles , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Fatores de Risco
14.
J Cell Physiol ; 236(9): 6726-6741, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33611789

RESUMO

Thrombocytopenia is a common complication of human cytomegalovirus (HCMV) infection in immunocompromised hosts, which contributes to poor prognosis even in patients receiving antiviral treatment. Here, we investigated the megakaryo/thrombopoiesis process, including the involvement of the c-Mpl/IEX-1 pathway, after HCMV infection, identified receptors mediating the interaction between megakaryocytes (MKs) and HCMV, and explored novel therapeutic targets. Our data shows that HCMV directly infects megakaryocytes in patients with HCMV DNAemia and influences megakaryopoiesis via the c-Mpl/IEX-1 pathway throughout megakaryocyte maturation, apoptosis, and platelet generation in vivo and in vitro. After treatment with inhibitors of PDGFRα and αvß3, the HCMV infection rate in MKs was significantly reduced, suggesting that IMC-3G3 and anti-αvß3 are potential therapeutic alternatives for viral infection. In summary, our study proposes a possible mechanism and potential treatments for thrombocytopenia caused by HCMV infection and other viral diseases associated with abnormal hemostasis.


Assuntos
Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas , Integrina alfaVbeta3/metabolismo , Megacariócitos/virologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Trombopoetina/metabolismo , Transdução de Sinais , Trombopoese , Adolescente , Adulto , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Criança , Citomegalovirus/ultraestrutura , Infecções por Citomegalovirus/patologia , Regulação para Baixo , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Ploidias , Fatores de Risco , Receptor 2 Toll-Like/metabolismo , Transplante Homólogo , Adulto Jovem
15.
Front Oncol ; 11: 773394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35070977

RESUMO

In patients with t(8;21) acute myeloid leukemia (AML), recurrent minimal residual disease (MRD) measured by RUNX1-RUNX1T1 transcript levels can predict relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to compare the efficacy of preemptive interferon (IFN)-α therapy and donor lymphocyte infusion (DLI) in patients with t(8;21) AML following allo-HSCT. We also evaluated the appropriate method for patients with different levels of RUNX1-RUNX1T1 transcripts. In this retrospective study, consecutive patients who had high-risk t(8;21) AML and received allo-HSCT were enrolled. The inclusion criteria were as follows: (1) age ≤65 years; (2) regained MRD positive following allo-HSCT. MRD positive was defined as the loss of a ≥4.5-log reduction and/or <4.5-log reduction in the RUNX1-RUNX1T1 transcripts, and high-level, intermediate-level, and low-level MRDs were, respectively, defined as <2.5-log, 2.5-3.5-log, and 3.5-4.5-log reductions in the transcripts compared with the pretreatment baseline level. Patients with positive RUNX1-RUNX1T1 could receive preemptive IFN-α therapy or DLI, which was primarily based on donor availability and the intentions of physicians and patients. The patients received recombinant human IFN-α-2b therapy by subcutaneous injection twice a week every 4 weeks. IFN-α therapy was scheduled for six cycles or until the RUNX1-RUNX1T1 transcripts were negative for at least two consecutive tests. The rates of MRD turning negative for patients with low-level, intermediate-level, and high-level RUNX1-RUNX1T1 receiving IFN-α were 87.5%, 58.1%, and 22.2%, respectively; meanwhile, for patients with intermediate-level and high-level RUNX1-RUNX1T1 receiving DLI, the rates were 50.0% and 14.3%, respectively. For patients with low-level and intermediate-level RUNX1-RUNX1T1, the probability of overall survival at 2 years was higher in the IFN-α group than in the DLI group (87.6% vs. 55.6%; p = 0.003). For patients with high levels of RUNX1-RUNX1T1, the probability of overall survival was comparable between the IFN-α and DLI groups (53.3% vs. 83.3%; p = 0.780). Therefore, patients with low-level and intermediate-level RUNX1-RUNX1T1 could benefit more from preemptive IFN-α therapy compared with DLI. Clinical outcomes were comparable between preemptive IFN-α therapy and DLI in patients with high-level RUNX1-RUNX1T1; however, they should be further improved.

16.
Ann Hematol ; 99(11): 2659-2670, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32734550

RESUMO

Cytomegalovirus (CMV) can cause end-organ diseases including pneumonia, gastroenteritis, retinitis, and encephalitis in hematopoietic stem cell transplantation recipients. Potential differences among different CMV diseases remain uncertain. This study aimed to compare the clinical characteristics, risk factors, and mortality among different CMV diseases. A retrospective nested case-control study was performed based on a cohort of 3862 patients who underwent haploidentical hematopoietic stem cell transplantation at a single-center. CMV diseases occurred in 113 (2.92%) of 3862 haplo-HSCT recipients, including probable CMV pneumonia (CMVP, n = 34), proven CMV gastroenteritis (CMVG, n = 34), CMV retinitis (CMVR, n = 31), probable CMV encephalitis (CMVE, n = 7), and disseminated CMV disease (Di-CMVD, n = 7). Most (91.2%) cases of CMVG developed within 100 days, while most (90.3%) cases of CMVR were late onset. Refractory CMV infection and CMV viral load at different levels were associated with an increased risk of CMVP, CMVG, and CMVR. Compared with patients without CMV diseases, significantly higher non-relapse mortality at 1 year after transplantation was observed in patients with CMVP and CMVR, rather than CMVG. Patients with CMVP, Di-CMVD, and CMVE had higher overall mortality after diagnosis than that of patients with CMVG and CMVR (61.7%, 57.1%, 40.0% vs 27.7%, 18.6%, P = 0.001). In conclusion, the onset time, viral dynamics, and mortality differ among different CMV diseases. The mortality of CMV diseases remains high, especially for CMVP, Di-CMVD, and CMVE.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo
17.
Thromb Res ; 194: 168-175, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788111

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is regarded as a curative therapy for majority of hematologic malignancies and some non-malignant hematologic diseases. Venous thromboembolism (VTE) has become increasingly recognized as a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES: To show the characteristics of VTE after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and make comparisons with matched related donor HSCT (MRD-HSCT). PATIENTS/METHODS: A retrospective nested case-control study design was used, cases with VTE and matched controls were selected, with 3534 patients underwent HID-HSCT and 1289 underwent MRD-HSCT. RESULTS: During follow-up, 114 patients with VTE were identified. The incidence of VTE in HID-HSCT group was similar to that of MRD-HSCT group (2.4% versus 2.3%, P = 0.92). In HID-HSCT group, VTE occurred at a median time of 92.5 days, which was earlier than MRD-HSCT group (243.5 days). For HID-HSCT, advanced disease status, cardiovascular risk factors, acute graft-versus-host disease (aGVHD), and relapse were the independent risk factors for VTE. For MRD-HSCT, cardiovascular risk factors, aGVHD, and relapse were associated with VTE. Overall survival (OS) of patients following HID-HSCT and MRD-HSCT were similar, but the OS in patients with VTE was significantly lower than patients without VTE. CONCLUSIONS: There was no statistical difference in the incidence of VTE after HID-HSCT compared with MRD-HSCT. The development of VTE adversely impacted the OS after allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Tromboembolia Venosa , Estudos de Casos e Controles , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Irmãos , Tromboembolia Venosa/etiologia
18.
Zhen Ci Yan Jiu ; 45(7): 541-7, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32705827

RESUMO

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on intestinal Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in obese rats, so as to explore the mechanism of action of acupuncture in losing weight. METHODS: A total of 50 male Wistar rats were randomly divided into control and model groups. High-fat feed was used to establish a rat model of obesity, and after modeling, the 24 rats were randomly divided into model group, TLR4 inhibitor group, and EA group, with 8 rats in each group. The rats in the EA group were given EA at "Guanyuan" (CV4), "Zhongwan "(CV12), "Zusanli" (ST36), and" Fenglong" (ST40), 10 minutes each time, 3 times a week, and those in the TLR4 inhibitor group were given intraperitoneal injection of TAK-242 three times a week; the course of treatment was 8 weeks for both groups. Body weight and blood glucose were measured every two weeks. Co-immunoprecipitation was used to observe the interaction between TLR4 and NF-κB p65 in the intestinal tissue; electrophoretic mobility shift assay was used to measure the activity of NF-κB p65; Western blot was used to measure the protein expression of TLR4, phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (p-IκBα), and NF-κB p65; quantitative real-time PCR was used to measure the mRNA expression of TLR4, NF-κB p65, and IκBα. RESULTS: Compared with the control group, the model group had significant increases in body weight, blood glucose, and protein and mRNA expression of TLR4 and NF-κB p65 (P<0.01, P<0.05), as well as significant enhancement in the interaction between TLR4 and NF-κB p65 and activity of NF-κB p65 (P<0.05,P<0.01). Compared with the model group, the EA group had a significant reduction in body weight (P<0.05), both of the EA group and the TLR4 inhibitor group had significant reductions in blood glucose, and protein and mRNA expression of TLR4, p-IκBα, and NF-κB p65 (P<0.05,P<0.01), as well as significant reductions in the activity of NF-κB p65 (P<0.01). CONCLUSION: EA can effectively regulate intestinal TLR4, inhibit the interaction between TLR4 and NF-κB p65, and reduce the activity of NF-κB p65, which may be a potential mechanism of EA in reducing body weight and blood glucose in obese rats.


Assuntos
Eletroacupuntura , Pontos de Acupuntura , Animais , Masculino , NF-kappa B , Obesidade , Ratos , Ratos Wistar , Receptor 4 Toll-Like
19.
Ann Hematol ; 99(7): 1643-1653, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458063

RESUMO

To explore the incidence, risk factors, and outcomes of central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and to compare the differences in CNS relapse between haploidentical donor HSCT (HID-HSCT) and HLA-identical sibling donor HSCT (ISD-HSCT). We performed a retrospective nested case-control study on patients with CNS relapse after allo-HSCT. The cumulative incidence of CNS relapse was 4.06% after allo-HSCT in ALL, with a significantly poor prognosis. The incidence was 3.91% and 5.36% in HID-HSCT and ISD-HSCT, respectively (p = .227). Among the patients with CNS relapse, the overall survival (OS) at 3 years was 56.2 ± 6.8% in the HID-HSCT subgroup and 76.9 ± 10.2% in the ISD-HSCT subgroup (p = .176). The 3-year cumulative incidence of systemic relapse was also comparable between the two subgroups (HID-HSCT, 40.6 ± 7.4%; ISD-HSCT, 13.3 ± 8.7%, respectively, p = .085). Younger age (p = .045), T-ALL (p = .035), hyperleukocytosis at diagnosis (p < .001), advanced disease stage at transplant (p < .001), pre-HSCT CNS involvement (p < .001), and absence of chronic graft vs host disease (cGVHD) (p < .001) were independent risk factors for CNS relapse after allo-HSCT. In conclusion, CNS relapse was a significant complication after allo-HSCT in ALL and was associated with poor prognosis. The incidences and outcomes were comparable between HID-HSCT and ISD-HSCT.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/secundário , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irmãos , Transplante Haploidêntico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/terapia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Teste de Histocompatibilidade/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Recidiva , Estudos Retrospectivos , Doadores de Tecidos/estatística & dados numéricos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/estatística & dados numéricos , Resultado do Tratamento , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto Jovem
20.
Biosci Rep ; 40(4)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32239175

RESUMO

Congenital heart disease (CHD) is a group of anatomic malformations in the heart with high morbidity and mortality. The mammalian heart is a complex organ, the formation and development of which are strictly regulated and controlled by gene regulatory networks of many signaling pathways such as TGF-ß. KAT2B is an important histone acetyltransferase epigenetic factor in the TGF-ß signaling pathway, and alteration in the gene is associated with the etiology of cardiovascular diseases. The aim of this work was to validate whether KAT2B variations might be associated with CHD. We sequenced the KAT2B gene for 400 Chinese Han CHD patients and evaluated SNPs rs3021408 and rs17006625. The statistical analyses and Hardy-Weinberg equilibrium tests of the CHD and control populations were conducted by the software SPSS (version 19.0) and PLINK. The experiment-wide significance threshold matrix of LD correlation for the markers and haplotype diagram of LD structure were calculated using the online software SNPSpD and Haploview software. We analyzed the heterozygous variants within the CDS region of the KAT2B genes and found that rs3021408 and rs17006625 were associated with the risk of CHD.


Assuntos
Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Fatores de Transcrição de p300-CBP/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Epigênese Genética , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem , Fatores de Transcrição de p300-CBP/metabolismo
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