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1.
Int J Oncol ; 61(6)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36321791

RESUMO

KRAS is a biomarker for non­small cell lung cancer­targeted therapy, but there is currently no effective KRAS­targeting medication. Realgar is an impelling anticancer drug, however its significance in KRAS mutant lung cancer is uncertain. According to our findings, the IC50 of H23 (KRAS mutant) cells is 2.99 times lower than that of H1650 (non­KRAS mutant) cells. Flow cytometry and the Hoechst 33258 staining assay revealed that H1650 cells treated with 4 µg/ml realgar had an apoptotic rate of 8.2%, while H23 cells had a rate of 21.46%. Accordingly, realgar was more sensitive to KRAS mutant cells. Transcriptome sequencing test indicated that there were 481 different expression genes in H23 cells treated with realgar. In H23 cells treated with realgar, mitochondria shrank, inner membrane folding was disturbed, and mitochondrial membrane potential crushed. Realgar boosted intracellular Fe2+, reactive oxygen species, malondialdehyde and glutathione levels, which were all reversed by ferroptosis inhibitor Fer­1. Realgar decreased phosphorylated p­Raf, p­ERK1/2 and increased p­p38 and p­JNK, whereas only p­Raf was abolished by Fer­1. Raf inhibitor Sorafenib accelerated the realgar­induced ferroptosis. On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in anti­KRAS mutant lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Sorafenibe/farmacologia , Apoptose , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
Front Neurol ; 13: 938612, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419531

RESUMO

Acute hyperglycemia is a powerful indicator of the severity of acute ischemic stroke (AIS); however, the relationship between these two factors is not very clear in patients with diabetes. We aimed to retrospectively evaluate data from 335 consecutive patients who experienced AIS from November 2015 to November 2016 to investigate whether a comprehensive assessment of blood glucose levels is a more valuable indicator of the severity of AIS or the presence of acute hyperglycemia in patients with diabetes. We collected demographic data, clinical manifestation information, clinical scores, and laboratory data [including fasting blood glucose and glycated hemoglobin (HbA1c) levels]. We estimated prehospital mean blood glucose concentrations using the following formula [1.59 * HbA1c (%) - 2.59] to calculate the "Acute-to-Chronic Glycemic Ratio" (AC ratio). The AC ratio differed significantly among patients grouped according to the National Institutes of Health Stroke Scale/Score (NIHSS) at admission (admission NIHSS) (p = 0.006). Univariate regression analysis revealed a correlation between the AC ratio and admission NIHSS [standardized ß-coefficient (Std. B) = 0.164, p = 0.004]. The adjusted linear regression analysis revealed a correlation between both HbA1c (Std. B = 0.368, p = 0.038) and the AC ratio (Std. B = 0.262, p = 0.022) and admission NIHSS. The AC ratio (Std. B = 0.161, p = 0.012) was related to admission NIHSS in the stepwise variable selection. For an admission NIHHS > 4, the AC ratio (Std. B = 0.186, p = 0.047) was related to admission NIHSS in the stepwise variable selection. The AC ratio (Std. B = 1.163, p = 0.006 and Std. B = 0.565, p = 0.021, respectively) were related to admission NIHSS in both large-artery atherosclerosis (LAA) and small-vessel occlusion (SVO) subgroups. Thus, the AC ratio is related to admission NIHSS in patients with diabetes who experienced AIS and may be a better indicator of severity than acute blood glucose levels.

4.
Molecules ; 27(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36363985

RESUMO

Simvastatin (SIM) particles are liposoluble drugs with large particle sizes, resulting in poor compatibility with electrospun polycaprolactone (PCL)/polyethylene glycol (PEG) nanofibers, so that part of them will be exposed to the electrospun nanofiber surface, which is easy to cause the burst release of drugs. Therefore, in this paper, stearic acid (SA) with good biocompatibility was innovatively added to increase the dispersion uniformity of SIM in the spinning solution, thus improving the performances of SIM-loaded PCL/PEG nanofiber membranes (NFMs). Accordingly, the effects of SA addition on the morphologies, mechanical properties, wettability, and drug release properties of the SIM-loaded NFMs were studied. The results showed that after SIM was dissolved in SA solution, the particle size of SIM was significantly reduced and could be evenly dispersed in the polymer spinning solution, thus obtaining the SIM-loaded composite NFMs with the best morphology and performance.


Assuntos
Nanofibras , Polietilenoglicóis , Sinvastatina , Preparações de Ação Retardada , Poliésteres , Liberação Controlada de Fármacos
5.
Transplant Cell Ther ; 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36402457

RESUMO

Between 2020 and 2021, 31,525 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout mainland China. In this report, we describe the activity and current trends for HSCT in China during the SARS-CoV-2 pandemic. In 2020, a total of 13,415 cases of HSCT were reported from 166 transplant teams, and 75% (10,042 cases) were allogeneic HSCTs. In 2021, a total of 18,110 cases of HSCT were reported from 174 transplant teams, and 70% (12,744 cases) were allogeneic HSCTs. Haploidentical donor (HID) transplantation accounted for 63% (7977 cases) of allogeneic HSCTs in 2021. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (23%), and the largest proportion of nonmalignant disease comprised aplastic anemia (AA) (13%). The PB stem cell source accounted for 41% of HIDs and 75% of MSDs. The BuCy-based regimen (57%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu-based regimen (28%) and TBI-based regimen (11%). This survey provides comprehensive information about the current activities and might benefit clinical physicians' decision planning for HSCT.

6.
Acta Pharmacol Sin ; 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411339

RESUMO

Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.

7.
Cancer Commun (Lond) ; 2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36274263

RESUMO

BACKGROUND: Patients with refractory or relapsed acute myeloid leukemia (AML) have poor survival, necessitating the exploration of optimized therapeutic strategy. Here, we aimed to investigate clinical outcomes and health-related quality of life (HR-QoL) after total therapy, which included allogeneic hematopoietic stem cell transplantation (allo-HSCT), and prophylactic donor lymphocyte infusion (DLI) in the early phase after transplantation, followed by multiple measurable residual disease (MRD) and graft-versus-host disease (GvHD)-guided DLIs. METHODS: Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study. If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse, severe infection, organ failure, and active GvHD at the time of planned DLI, prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen (HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT. Subsequently, multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation. RESULTS: A total of 105 patients were eligible. Eighty-seven patients received prophylactic DLI (group B), while 18 did not receive prophylactic DLI (group A). Among 105 patients, the cumulative incidence of grade 2-4 acute GvHD and chronic GvHD was 40.6% (95% confidence interval [CI] = 30.6%-50.6%) and 73.3% (95% CI = 67.4%-79.2%), respectively. The cumulative incidence of relapse (CIR), transplant-related mortality (TRM), and leukemia-free survival (LFS) at 5 years after transplantation were 31.5% (95% CI = 21.9%-41.1%), 22.1% (95% CI = 11.3%-32.9%), and 46.4% (95% CI = 36.8%-56.0%), respectively. In group B, the CIR, TRM, and LFS at 5 years after transplantation were 27.6% (95% CI = 17.6%-37.6%), 21.6% (95% CI = 11.2%-32.0%), and 50.8% (95% CI = 40.0%-61.6%), respectively. At the end of follow-up, 48 patients survived, and more than 90% of survivors had satisfactory recoveries of HR-QoL. CONCLUSIONS: Our study indicated that total therapy is not only associated with decreased CIR, comparable TRM, and better long-term LFS, but also with satisfactory HR-QoL for refractory or relapsed AML, compared with those of standard of care therapy reported previously. Therefore, total therapy may be an optimized therapeutic strategy for refractory or relapsed AML.

8.
Transplant Cell Ther ; 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36272528

RESUMO

As a serious complication after allogenic hematopoietic stem cell transplantation (allo-HSCT), venous thromboembolism (VTE) is significantly related to increased nonrelapse mortality. Therefore distinguishing patients at high risk of death who should receive specific therapeutic management is key to improving survival. This study aimed to establish a machine learning-based prognostic model for the identification of post-transplantation VTE patients who have a high risk of death. We retrospectively evaluated 256 consecutive VTE patients who underwent allo-HSCT at our center between 2008 and 2019. These patients were further randomly divided into (1) a derivation (80%) cohort of 205 patients and (2) a test (20%) cohort of 51 patients. The least absolute shrinkage and selection operator (LASSO) approach was used to choose the potential predictors from the primary dataset. Eight machine learning classifiers were used to produce 8 candidate models. A 10-fold cross-validation procedure was used to internally evaluate the models and to select the best-performing model for external assessment using the test cohort. In total, 256 of 7238 patients were diagnosed with VTE after transplantation. Among them, 118 patients (46.1%) had catheter-related venous thrombosis, 107 (41.8%) had isolated deep-vein thrombosis (DVT), 20 (7.8%) had isolated pulmonary embolism (PE), and 11 (4.3%) had concomitant DVT and PE. The 2-year overall survival (OS) rate of patients with VTE was 68.8%. Using LASSO regression, 8 potential features were selected from the 54 candidate variables. The best-performing algorithm based on the 10-fold cross-validation runs was a logistic regression classifier. Therefore a prognostic model named BRIDGE was then established to predict the 2-year OS rate. The areas under the curves of the BRIDGE model were 0.883, 0.871, and 0.858 for the training, validation, and test cohorts, respectively. The Hosmer-Lemeshow goodness-of-fit test showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that VTE patients could benefit from the clinical application of the prognostic model. A BRIDGE risk score calculator for predicting the study result is available online (47.94.162.105:8080/bridge/). We established the BRIDGE model to precisely predict the risk for all-cause death in VTE patients after allo-HSCT. Identifying VTE patients who have a high risk of death can help physicians treat these patients in advance, which will improve patient survival.

9.
Foods ; 11(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36230051

RESUMO

Improving milling and baking properties is important during wheat breeding. To determine changes in milling and baking quality of hard winter wheat, 23 adapted cultivars released in the Great Plains between 1870 and 2013 were grown in triplicate in a single location (Mead, NE, USA) over two crop years (2018 and 2019). Grain yield and kernel hardness index increased by release year (p < 0.05). The observed increase in hardness index was accompanied by a decrease in percent soft kernels (p < 0.05). Diameter and weight decreased with release year in 2019 (p < 0.05), and their standard deviation increased with the release year (p < 0.05). Flour protein content decreased with release year (p < 0.05) and dough mixing quality increased (p < 0.05). No significant relationship was found for baking property variables, but bran water retention capacity (BWRC), which is correlated with whole wheat bread quality, increased with release year (p < 0.05). In conclusion, wheat kernels have become harder but more variable in shape over a century of breeding. Mixing quality showed significant improvements, and loaf volume and firmness remained constant, even in the presence of a decrease in protein concentration. Bran quality decreased across release year, which may have implications for whole grain baking quality and milling productivity.

10.
Artigo em Inglês | MEDLINE | ID: mdl-36260584

RESUMO

High-quality 4D reconstruction of human performance with complex interactions to various objects is essential in real-world scenarios, which enables numerous immersive VR/AR applications. However, recent advances still fail to provide reliable performance reconstruction, suffering from challenging interaction patterns and severe occlusions, especially for the monocular setting. To fill this gap, in this paper, we propose RobustFusion, a robust volumetric performance reconstruction system for human-object interaction scenarios using only a single RGBD sensor, which combines various data-driven visual and interaction cues to handle the complex interaction patterns and severe occlusions. We propose a semantic-aware scene decoupling scheme to model the occlusions explicitly, with a segmentation refinement and robust object tracking to prevent disentanglement uncertainty and maintain temporal consistency. We further introduce a robust performance capture scheme with the aid of various data-driven cues, which not only enables re-initialization ability, but also models the complex human-object interaction patterns in a data-driven manner. To this end, we introduce a spatial relation prior to prevent implausible intersections, as well as data-driven interaction cues to maintain natural motions, especially for those regions under severe human-object occlusions. We also adopt an adaptive fusion scheme for temporally coherent human-object reconstruction with occlusion analysis and human parsing cue. Extensive experiments demonstrate the effectiveness of our approach to achieve high-quality 4D human performance reconstruction under complex human-object interactions whilst still maintaining the lightweight monocular setting.

11.
Exp Ther Med ; 24(5): 662, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36168411

RESUMO

The mitochondrial protein sirtuin 3 (SIRT3) can counteract cell damage caused by oxidative stress and inflammation, and contribute to cell survival primarily by improving mitochondrial function. However, the effects of SIRT3 in dopaminergic neuronal cells (DACs) remain unclear. In our previous studies, microglia activation-associated cytotoxicity was observed to promote the apoptosis of DACs, along with the decrease of SIRT3 expression. The aim of the present study was to explore the potential neuroprotective effect of SIRT3 expression against dopaminergic neuron injury caused by microglia activation, and clarify its possible mechanisms. SIRT3 overexpression in DACs reduced the production of intracellular reactive oxygen species (ROS), cell apoptosis rate, mitochondrial membrane potential (ΔΨm) depolarization, opening of mitochondrial permeability transition pore (mPTP) and cyclophilin D (CypD) protein level, and promoted cell cycle progression. However, SIRT3 siRNA-mediated knockdown further aggravated microglia activation-mediated cytotoxicity, including ROS accumulation, increased cell apoptosis and mPTP opening, elevated the CypD level, enhanced mitochondrial ΔΨm depolarization, concomitant to cell cycle arrest at G0/G1 phase. The mechanisms of SIRT3 mitigated microglia activation-induced DAC dysfunction, which included decreased mPTP opening and Bax/Bcl-2 ratio, inhibition of mitochondrial cytochrome c release to the cytoplasm, reduced caspase-3/9 activity, increased LC3II/LC3I and beclin-1 protein expression levels, and decreased nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 (NLRP3), caspase-1, IL-1ß and IL-18 protein expression. In conclusion, these results indicated that SIRT3 expression attenuated cell damage caused by microglia activation through the mitochondrial apoptosis pathway in DACs. The mitophagy-NLRP3 inflammasome pathway may also be associated with this neuroprotection. These findings may provide new intervention targets for the survival of dopaminergic neurons and the prevention and treatment of Parkinson's disease.

12.
Artigo em Inglês | MEDLINE | ID: mdl-36078579

RESUMO

Establishing a scientific and sustainable grading nursing care evaluation system is the key to realizing the rational distribution of medical and nursing resources in the combined medical and nursing care services. This study establishes a grading nursing care index system for medical and nursing institutions from both medical and nursing aspects, and proposes a grading nursing care evaluation model based on a combination of interval-valued intuitionistic fuzzy entropy and a two- stage gray synthetic clustering model for interval gray number under a social network context. Through case analysis, the proposed method can directly classify the elderly into corresponding grading nursing care grades and realize the precise allocation of medical and nursing resources, which proves the feasibility of the method.


Assuntos
Lógica Fuzzy , Instalações de Saúde , Idoso , Análise por Conglomerados , Humanos , Meio Social , Rede Social
13.
Sci China Life Sci ; 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36166182

RESUMO

Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.

14.
Phytochemistry ; 204: 113434, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36169036

RESUMO

Cyclocarya paliurus, a Chinese herbal medicine and new food resource, contains a triterpenic-acid-rich extract that demonstrated ameliorative effect on diabetic nephropathy (DN). A more in-depth discovery of functional components led to the isolation of seven new triterpenoids including two pentacyclic triterpenes, 1α,2α,3ß,23-tetrahydroxyolean-12-en-28-oic acid and 2α,3ß,22α-tirhydroxyurs-12-en-28-oic acid 28-O-ß-D-glucopyranoside, and five tetracyclic triterpenoid glycosides (cypaliurusides N-R), together with twelve known compounds from the leaves of C. paliurus. Their structures were determined using a comprehensive analysis of chemical and spectroscopic data. Partial compounds were assessed for anti-fibrotic activities in high-glucose and TGF-ß1 induced HK-2 cells. Compound 16 remarkably decreased the level of fibronectin with an inhibition rate of 37.1%. Furthermore, 16 effectively alleviated the epithelial-mesenchymal transformation (EMT) process by upregulating E-cadherin expression and downregulating α-SMA expression, and it significantly decreased the level of the transcriptional inhibitors (Snail and Twist) of E-cadherin. The discovery of anti-fibrotic compounds from C. paliurus provides the potential utilization and functional candidates for the DN prevention.

15.
Front Oncol ; 12: 916442, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936697

RESUMO

We aimed to identify the characteristics of immune reconstitution (IR) in patients who recovered from steroid-refractory acute graft-versus-host disease (SR-aGVHD) after basiliximab treatment. A total of 179, 124, 80, and 92 patients were included in the analysis for IR at 3, 6, 9, and 12 months, respectively, after haploidentical donor hematopoietic stem cell transplantation (HID HSCT). We observed that IR was fastest for monocytes and CD8+ T cells, followed by lymphocytes, CD3+ T cells, and CD19+ B cells and slowest for CD4+ T cells. Almost all immune cell subsets recovered comparably between patients receiving <5 doses and ≥5 doses of basiliximab. Most immune cell subsets recovered comparably between SR-aGVHD patients who recovered after basiliximab treatment and event-free HID HSCT recipients. Patients who recovered from SR-aGVHD after basiliximab treatment experienced satisfactory IR, which suggested that basiliximab may not have prolonged the negative impact on IR in these patients.

16.
Nanoscale Horiz ; 7(10): 1240-1249, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-35971913

RESUMO

Ferroelectric materials are widely recognized for their ability to generate photovoltaic voltages larger than their bandgap, making them ideal candidates for photodetector applications. Here, we report a self-powered UV photodetector based on a Bi0.5Na0.5TiO3 (BNT) thin film prepared by the sol-gel method. Compared with conventional photodetectors based on a single detection indicator, the demonstrated photodetector realizes UV light intensity detection over a wide linear range using a current and voltage dual indicator detection method. When the UV light intensity is lower than 1.8 mW cm-2, the voltage can be used to detect the light signal. Conversely, the current can be utilized to detect the signal. This method not only broadens the linear detection range of UV light intensity, making it possible to detect weak UV light of 45.2 nW cm-2, but also allows the detector to maintain relatively high sensitivity within the detectable range. To investigate the distribution of spatial UV light intensity, a self-powered photodetector array system has been utilized to record the output voltage signals as a map.

17.
medRxiv ; 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35982667

RESUMO

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID 1-3 . Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions 1-3 ; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

18.
BMC Cancer ; 22(1): 896, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974319

RESUMO

BACKGROUND: The presence of mixed-lineage leukaemia rearrangement (MLL-r) in paediatric patients with acute myeloid leukaemia (AML) is a poor prognostic predictor. Whether allogeneic haematopoietic stem cell transplantation (allo-HSCT) is beneficial in such cases remains unclear. METHODS: We evaluated the outcomes and prognostic factors of allo-HSCT in 44 paediatric patients with MLL-r AML in the first complete remission (CR1) between 2014 and 2019 at our institution. RESULTS: For all the 44 patients, the 3-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.5%, 64.1%, and 29.1%, respectively. Among them, 37 (84.1%) patients received haploidentical (haplo)-HSCT, and the 3-year OS, EFS, and CIR were 73.0%, 65.6%, and 26.4%, respectively. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) post-transplantation was 27.3%, and that of grade III-IV aGVHD was 15.9%. The overall 3-year cumulative incidence of chronic graft-versus-host disease (cGVHD) post-transplantation was 40.8%, and that of extensive cGVHD was 16.7%. Minimal residual disease (MRD)-positive (MRD +) status pre-HSCT was significantly associated with lower survival and higher risk of relapse. The 3-year OS, EFS, and CIR differed significantly between patients with MRD + pre-HSCT (n = 15; 48.5%, 34.3% and 59%) and those with MRD-pre-HSCT (n = 29; 89.7%, 81.4% and 11.7%). Pre-HSCT MRD + status was an independent risk factor in multivariate analysis. CONCLUSIONS: Allo-HSCT (especially haplo-HSCT) can be a viable strategy in these patients, and pre-HSCT MRD status significantly affected the outcomes.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Criança , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia , Neoplasia Residual , Estudos Retrospectivos , Transplante Homólogo
19.
Leuk Res ; 121: 106930, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36007342

RESUMO

Studies using third-generation tyrosine kinase inhibitor (TKI) as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) harboring the T315I mutation remain scarce. We conducted a cohort study to evaluate the safety and outcomes of ponatinib maintenance therapy after HCT in Ph+ALL patients with T315I mutation. BCR-ABL kinase domain mutations were assessed using direct sequencing. Twenty-six Ph+ALL patients with T315I mutation who received allogeneic HCT were enrolled. After HCT, ponatinib was administered as a prophylactic regimen (n = 12) or a preemptive therapy (n = 7). Seven patients did not receive maintenance therapy. Adverse events (AEs) occurred in 69.4 % of patients with ponatinib maintenance, but most presented with mild toxicities. Serious non-hematological AEs were not observed. The 5-year disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse in patients receiving prophylactic ponatinib were 81.5 %, 91.7 %, and 18.5 %, respectively, whereas they were 39.8 %, 46.0 %, and 48.4 % in the total cohort, respectively. The measurable BCR-ABL transcripts in the first three months after HCT was associated with poor DFS and OS, even with ponatinib therapy. We concluded that maintenance therapy with ponatinib is safe after HCT. Patients with T315I mutation who received prophylactic regimen showed promising results with an acceptable relapse rate and encouraging survival. However, patients with measurable BCR-ABL transcripts early post-transplant had poor outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Estudos de Coortes , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/uso terapêutico , Recidiva
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