RESUMO
BACKGROUND: Patients with idiopathic inflammatory myopathy (IIM) often express a different type of myositis-specific autoantibodies (MSAs), each associated with different clinical symptoms. Understanding the immunopathogenesis of various IIM subgroups can help improve the diagnosis and prognosis of IIM patients with different MSAs. However, the immune cell profiles of these IIM patients with anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies remain unclear. We focused on the immune cell profiles of IIM patients with anti-ARS or anti-MDA5 autoantibodies. RESULTS: The peripheral blood from IIM patients with anti-MDA5 autoantibody (MDA5 + group, n = 24) or one of the anti-ARS autoantibodies (ARS + group, n = 40) autoantibodies, and healthy controls (HC group, n = 60) were collected and examined. We found that IIM patients had a lower CD3 T cell population compared to the HC group. IIM patients showed a significantly lower TN cell population and a higher TEMRA cell population. Higher Th17 and Treg cell populations were found in these IIM patients than in the HC group. In these IIM patients, the MDA5 + group exhibited the higher percentages of Th17 and Treg cells than the ARS + group. It is noteworthy that the percentage of Th1 cells in the survival subgroup was higher than in the death subgroup in IIM patients with ARS + or MDA5 + . Furthermore, in the MDA5 + group, the percentage of Treg cells was higher in the survival subgroup compared to the death subgroup. CONCLUSIONS: Our study demonstrated that elevated Th1 may be a good prognostic indicator in IIM patients with ARS + or MDA5 + . Elevated Treg may also help predict a good prognosis in MDA5 + IIM patients. However, more large-scale studies and clinical samples are needed to verify the significance of Th1 and Treg cell subsets in clinical outcomes for these IIM patients with ARS + or MDA5 + . These data may help design a therapeutic approach that specifically targets the pathogenic immune molecular responsible for autoimmune attacks in IIM.
Assuntos
Aminoacil-tRNA Sintetases , Miosite , Humanos , Autoanticorpos , Miosite/diagnóstico , Prognóstico , Diferenciação Celular , Estudos RetrospectivosRESUMO
Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. In this comprehensive review, we summarized the current understanding about the involvement of MSCs in the pathogenesis of acquired idiopathic AA, along with the clinical application of MSCs for patients with the disease. The pathophysiology of AA, the major properties of MSCs, and results of MSC therapy in preclinical animal models of AA are also described. Several important issues regarding the clinical use of MSCs are discussed finally. With evolving knowledge from basic studies and clinical applications, we anticipate that more patients with the disease can benefit from the therapeutic effects of MSCs in the near future.
Assuntos
Anemia Aplástica , Células-Tronco Mesenquimais , Pancitopenia , Animais , Anemia Aplástica/patologia , Medula Óssea/patologia , Células-Tronco Mesenquimais/fisiologiaRESUMO
Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1ß, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.
Assuntos
Lesão Pulmonar Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , NF-kappa B , Cordão Umbilical , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/terapia , Animais , Modelos Animais de Doenças , Humanos , Imunomodulação , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Cordão Umbilical/citologia , Cordão Umbilical/metabolismoRESUMO
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.
Assuntos
Lesão Pulmonar Aguda , COVID-19 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Síndrome do Desconforto Respiratório , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/terapia , Animais , COVID-19/terapia , Imunomodulação , Transplante de Células-Tronco Mesenquimais/métodos , Modelos Animais , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2RESUMO
BACKGROUND: IKZF1deletion is an unfavorable factor in Philadelphia negative (Ph -) B-cell acute lymphoblastic leukemia. However, the effects of IKZF1 deletions co-existing genetic alterations in Ph (-) ALL have not been extensively studied. METHODS: Bone marrow samples from 368 children with Ph (-) ALL were analyzed by using multiplex ligation-dependent probe amplification kit for detection of gene deletions and Sanger sequencing for mutational analysis of RAS pathway genes. The outcome was analyzed on 215 patients treated with Taiwan Pediatric Oncology Group-ALL-2002 protocol. RESULTS: IKZF1 deletions were present in 12.8% and IKZF1plus in 6.3% of patients. Mutations of RAS pathway genes were detected in 25.0% of IKZF1-deleted patients. The 10-year event-free survival (EFS) of IKZF1-undeleted patients was significantly better compared with IKZF1-deleted patients (80.0% vs. 47.8%, p = 0.001). Compared with outcome of patients harboring IKZF1 deletion alone, no difference in EFS was observed in patients with IKZF1plus , whereas three patients carried both IKZF1 and ERG deletions had a superior 10-year EFS (100%). The 10-year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with wild-type genes (79.1% vs. 61.6%, p = 0.033). In multivariate analysis, RAS pathway mutations and IKZF1 deletion were independent predictors of inferior EFS. Co-existence of IKZF1 deletion with RAS pathway mutations had a worst 10-year EFS (11.1 ± 10.5%) and 10-year OS (53.3 ± 17.6%). CONCLUSIONS: Our results showed that RAS pathway mutation is an added-value biomarker in pediatric IKZF1-deleted Ph (-) ALL patients.
Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas ras/genética , Criança , Pré-Escolar , Feminino , Deleção de Genes , Humanos , Lactente , Masculino , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Transdução de Sinais , Proteínas ras/metabolismoRESUMO
Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.
Assuntos
Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/terapia , Metaloproteinases da Matriz/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Criança , HumanosRESUMO
Iron overload-induced cardiomyopathy is the leading cause of death in patients with transfusion-dependent thalassemia (TDT). The mortality is extremely high in these patients with severe cardiac complications, and how to rescue them remains a challenge. It is reasonable to use combined chelation with deferiprone (L1) and deferoxamine (DFO) because of their shuttle and synergistic effects on iron chelation. Here, seven consecutive patients with TDT who had severe cardiac complications between 2002 and 2019 and received combined chelation therapy with oral high-dose L1 (100 mg/kg/day) and continuous 24-h DFO infusion (50 mg/kg/day) in our hospital were reported. Survival for eight consecutive patients receiving DFO monotherapy for their severe cardiac complications between 1984 and 2001 was compared. We found that combined chelation therapy with high-dose L1 and DFO was efficient to improve survival and cardiac function in patients with TDT presenting severe cardiac complications. Reversal of arrhythmia to sinus rhythm was noted in all patients. Their 1-month follow-up left ventricular ejection fraction increased significantly (P < 0.001). There were no deaths, and all patients were discharged from hospital with good quality of life. In contrast, all the eight patients receiving DFO monotherapy died (P < 0.001). Accordingly, combined chelation therapy with high-dose L1 and DFO should be considered in patients with TDT presenting cardiac complications.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Terapia por Quelação/métodos , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia/terapia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Transfusão de Sangue , Deferiprona/administração & dosagem , Desferroxamina/administração & dosagem , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/etiologia , Masculino , Qualidade de Vida , Estudos Retrospectivos , Talassemia/complicações , Reação Transfusional , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
Childhood cancer management has improved considerably, with the overall objective of preventing early-life cancers completely. However, cancer remains a major cause of death in children, with the survivors developing anticancer treatment-specific health problems. Therefore, the anticancer treatment needs further improvement. Melatonin is a effective antioxidant and circadian pacemaker. Through multiple mechanisms, melatonin has significant positive effects on multitude adult cancers by increasing survival and treatment response rates, and slowing disease progression. In addition, melatonin appears to be safe for children. As an appealing therapeutic agent, we herein address several key concerns regarding melatonin's potential for treating children with cancer.
Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/metabolismo , Antioxidantes/metabolismo , Criança , Progressão da Doença , Humanos , Melatonina/metabolismo , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Steroid-insensitive asthma-related airway inflammation is associated with the expression of epidermal growth factor receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium. Proinflammatory cytokines IL-6 and IL-8 are related to steroid-insensitive asthma. It is currently unknown how EGFR-tyrosine kinase inhibitors (EGFR-TKIs) affects house dust mite (HDM)-induced asthma in terms of inflammatory cytokines related to steroid-resistant asthma and further signaling pathway. Cytokine expressions and EGFR signaling pathway were performed by ELISA, reverse transcriptase PCR, real-time PCR, and Western blot in cell-line models. AMP-activated protein kinase (AMPK) pathway-related inhibitors were applied to confirm the association between EGFR-TKI and AMPK pathway. HDM induced IL-6 and IL-8 in a dose-dependent manner. Both Erlotinib (Tarceva) and Osimertinib (AZD-9291) reduced the levels of HDM-stimulated IL-6 and IL-8 levels in BEAS-2B cells. AZD-9291 was more effective than Erlotinib in inhibiting phospho-EGFR, and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and phopho-signal transducer and activator of transcription 3 (p-STAT3) pathway signaling. In addition, AMPK pathway-related inhibitor, Calcium-/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, down-regulated IL-8, but EGFR-TKI had no effect on AMPK pathway. Our findings highlight EGFR-TKIs, Tarceva, and AZD-9291, attenuate HDM-induced inflammatory IL-6 and IL-8 cytokines via EGFR signaling axis pathway, but not AMPK signaling pathway.
Assuntos
Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Dermatophagoides pteronyssinus/imunologia , Células Epiteliais/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Asma/imunologia , Asma/prevenção & controle , Linhagem Celular , Relação Dose-Resposta a Droga , Células Epiteliais/imunologia , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Humanos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Transdução de SinaisRESUMO
BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.
Assuntos
Antineoplásicos/administração & dosagem , Irradiação Craniana/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central , Criança , Pré-Escolar , Irradiação Craniana/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Injeções Espinhais , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Análise de Sobrevida , Tempo para o Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Although immune-mediated pathogenesis is considered an important aspect of severe aplastic anemia (SAA), its underlying mechanisms remain unclear. Mesenchymal stem cells (MSCs) are essential to the formation of specialized microenvironments in the bone marrow (BM), and MSC insufficiency can trigger the development of SAA. METHODS: To find MSC alterations in the SAA BM, we compared BM MSCs from five children with SAA and five controls. Peripheral blood mononuclear cells (PBMCs) were cocultured with MSCs to evaluate the supportive effects of MSCs on hematopoiesis. Cytometric bead array immunoassay was used to determine cytokine excretion by MSCs. The immune functions of MSCs and their conditioned medium (CM) were evaluated by PBMC proliferation assays. RESULTS: SAA MSCs were characterized by a high percentage of cells in the abnormal sub-G1 phase of the cell cycle, which suggests an increased rate of apoptosis in SAA MSCs. In comparison with control MSCs, PBMCs cocultured with SAA MSCs displayed significantly reduced PBMC proliferation (P = 0.009). Aberrant cytokine profiles were secreted by SAA MSCs, with increased concentrations of interleukin-6, interferon-γ, tumor necrosis factor-α, and interleukin-1ß in the CM. PBMC proliferation assays demonstrated additional immunosuppressive effects of SAA MSCs (P = 0.016) and their CM (P = 0.013). CONCLUSIONS: Our data revealed increased apoptosis and PBMC suppression of SAA MSCs. The alterations of MSCs may contribute to the formation of functionally abnormal microenvironments in SAA BM.
Assuntos
Anemia Aplástica/patologia , Células da Medula Óssea/patologia , Leucócitos Mononucleares/fisiologia , Células-Tronco Mesenquimais/patologia , Anemia Aplástica/imunologia , Apoptose , Ciclo Celular , Células Cultivadas , Microambiente Celular , Criança , Técnicas de Cocultura , Meios de Cultivo Condicionados , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Células-Tronco Mesenquimais/metabolismoRESUMO
High-dose methotrexate (HDMTX) is important for children with acute lymphoblastic leukemia (ALL). There is no effective treatment for patients with oral mucositis, which is a major side effect associated with HDMTX. Here, we reviewed the medical records of patients younger than 18 yr with newly diagnosed ALL in our hospitals from 2002 to 2013. According to the nationwide protocol (TPOG-ALL-2002), each patient received four courses of HDMTX (2.5 or 5 g/m2) during consolidation therapy. HDMTX courses with glutamine therapy were as the glutamine group, and intravenous glutamine (0.4 g/kg/day) was started within 48 h after the initiation of HDMTX for 3 consecutive days. HDMTX courses without glutamine were as the control group. A total of 347 HDMTX courses were administrated in the 96 children with ALL during the study period. The incidence of oral mucositis was significantly lower in the glutamine group than in the control group (3.8% vs. 17.6%; P = 0.004). In the glutamine group, no patients suffered from severe oral mucositis. No severe adverse effects associated with glutamine administration were noted. Accordingly, parenteral glutamine appears to be feasible and safe to prevent oral mucositis in patients receiving HDMTX.
Assuntos
Glutamina/farmacologia , Metotrexato/efeitos adversos , Nutrição Parenteral/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estomatite/induzido quimicamente , Adolescente , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Estomatite/prevenção & controleRESUMO
BACKGROUND: While transfusion and iron chelation therapy for thalassemia major (TM) has improved dramatically in recent years, the consequences of this improvement (current rates of survival and TM-related complications) remain unknown. METHODS: This nationwide population-based cohort study analyzed 2007-2011 data obtained from the Taiwanese National Health Insurance Research Database. RESULTS: After excluding those patients receiving hematopoietic stem cell transplantation, we enrolled 454 patients with TM who received transfusion and chelation therapy (median age, 17.2 years). Among these patients, the mortality rate was 2.9% in 2007, 2.3% in 2008, 2.9% in 2009, 2.6% in 2010, and 0.7% in 2011. Heart was the most common target organ of TM-related complications. There were 80 patients (17.6%) with arrhythmia and 86 patients (18.9%) with congestive heart failure. Dysfunction of endocrine organs was common, and the most common endocrinopathy was hypogonadism (23.1%), followed by diabetes (21.2%). There were 75 patients (16.5%) with liver cirrhosis and 79 patients (17.4%) with osteoporosis. CONCLUSIONS: Adequate red blood cell transfusion and iron chelation is available to all patients with TM in Taiwan under the universal health insurance system, and has resulted in reduction of TM-related mortality to very low levels. As these patients get older, early detection of complications and adequate intervention are important to quality-of-life improvement.
Assuntos
Terapia por Quelação/mortalidade , Transfusão de Eritrócitos/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Talassemia beta/complicações , Talassemia beta/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Taiwan/epidemiologia , Adulto Jovem , Talassemia beta/epidemiologia , Talassemia beta/terapiaRESUMO
BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. PROCEDURE: In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). RESULTS: Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. CONCLUSIONS: With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).
Assuntos
Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Translocação Genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 19/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , TaiwanRESUMO
BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. RESULTS: In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. CONCLUSIONS: For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Irradiação Craniana , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Discontinuation of E. coli l-asparaginase in patients with acute lymphoblastic leukemia (ALL) is unavoidable upon severe allergic reaction. We sought to examine outcomes following E. coli l-asparaginase discontinuation due to severe allergic reactions. PROCEDURE: We evaluated the outcome of children enrolled in Taiwan Pediatric Oncology Group-2002-ALL protocol between 2002 and 2012, who had E. coli l-asparaginase discontinued due to severe allergic reactions, and compared the outcomes of those who continued with Erwinia l-asparaginase (Erwinase) with those who did not. RESULTS: Among 700 patients enrolled in this study, 33 patients had E. coli l-asparaginase treatment discontinued due to severe allergic reactions. Five-year overall survival did not differ significantly among the 648 patients without discontinuation (81 ± 1.6%, mean ± SE), compared to 17 patients with allergic reactions and treated with Erwinase (88 ± 7.8%) and 16 patients with allergic reactions but not treated with Erwinase (87 ± 8.6%). Among 16 patients who did not receive Erwinase, all 10 who received ≥50% of the scheduled doses of E. coli l-asparaginase before discontinuation survived without events. CONCLUSIONS: Erwinase treatment may not be needed for some ALL patients with severe allergy to E. coli l-asparaginase if ≥50% of prescribed doses were received and/or therapy is augmented with other agents.
Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Hipersensibilidade a Drogas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Criança , Pré-Escolar , Intervalo Livre de Doença , Escherichia coli , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidadeRESUMO
The mechanisms of idiopathic severe aplastic anemia (SAA) in children are not completely understood. Insufficiency of the bone marrow microenvironment, in which mesenchymal stem cells (MSCs) are an important element, can be a potential factor associated with hematopoietic impairment. In the current study, we studied whether aberrant gene expression could be found in MSCs from children with SAA. Using microarray analysis, two different patterns of global gene expression were detected in the SAA MSCs. Fourteen genes (POLE2, HGF, KIF20A, TK1, IL18R1, KITLG, FGF18, RRM2, TTK, CXCL12, DLG7, TOP2A, NUF2, and TYMS), which are related to DNA synthesis, cytokines, or growth factors, were significantly downregulated. Further, knockdown of gene expression was performed using the small hairpin RNA (shRNA)-containing lentivirus method. We found that knockdown of CXCL12, HGF, IL-18R1, FGF18, or RRM2 expression compelled MSCs from the controls to behave like those from the SAA children, with decreased survival and differentiation potential. Among them, inhibition of CXCL12 gene expression had the most profound effects on the behavior of MSCs. Further experiments regarding re-introduction of the CXCL12 gene could largely recover the survival and differentiation potential in MSCs with inhibition of CXCL12 expression. Our findings suggest that MSCs from children with SAA exhibit aberrant gene expression profiles and downregulation of CXCL12 gene may be associated with alterations in the bone marrow microenvironment.
Assuntos
Anemia Aplástica/metabolismo , Quimiocina CXCL12/biossíntese , Regulação para Baixo/fisiologia , Perfilação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , Índice de Gravidade de Doença , Adolescente , Anemia Aplástica/diagnóstico , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , MasculinoRESUMO
Extraadrenal paragangliomas are rare pediatric tumors with variable symptoms that cause difficultly in diagnosis and delayed treatment. We report the case of a 10-year-old boy who presented to the pediatric emergency department with acute chest pain and dyspnea mimicking a non-ST-segment elevation acute myocardial infarction. He was subsequently found to have an extraadrenal paraganglioma after a series of imaging and laboratory examinations. The mass was subsequently removed, and the diagnosis of extraadrenal paraganglioma was confirmed histologically. Acute coronary syndrome as the presenting feature of extraadrenal paragangliomas in pediatric population is an even rarer clinical entity.