RESUMO
In the maintenance phase of Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)- Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m2 /day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2,000-3,000 cells/µL. Pediatric patients with ALL (n = 290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; boys: 56.9%) were enrolled mainly in 4 medium-large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st-3rd quartile) follow-up time of 4.43 (3.82-5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl-derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by high performance liquid chromatography with ultraviolet detection. Single-nucleotide polymorphisms (SNPs; (rs1800462, rs1800460, and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA, and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact of TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in children with ALL of the intermediate risk arm compared with those in standard risk arm (3.44, 95% confidence interval (CI), 1.31-9.05, P = 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared with those with the CC genotype (heterozygotes CT: HR, 2.32, 95% CI, 0.90-5.97, P = 0.081; and homozygous TT: HR, 4.14, 95% CI, 1.54-11.11, P = 0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP-BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome.
RESUMO
BACKGROUND: l-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). METHODS: Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500 IU/m2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. RESULTS: Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p < .0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p = .061) and silent inactivation (3/12 vs. 0/35; p = .014) were observed in comparison with the reference cohort. CONCLUSIONS: Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.
Assuntos
Antineoplásicos , Asparaginase , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Criança , Escherichia coli , Humanos , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de RemissãoRESUMO
Following the spread of the SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) to a global pandemic, concerns have arisen for the disease impact in at-risk populations, especially in immunocompromised hosts. On the other hand, clinical studies have clarified that the COVID-19 clinical burden is mostly due to over-inflammation and immune-mediated multiorgan injury. This has led to downsizing the role of immunosuppression as a determinant of outcome, and early reports confirm the hypothesis that patients undergoing immunosuppressive treatments do not have an increased risk of severe COVID-19 with respect to the general population. Intriguingly, SARS-CoV-2 natural reservoirs, such as bats and mice, have evolved mechanisms of tolerance involving selection of genes optimizing viral clearance through interferon type I and III responses and also dampening inflammasome response and cytokine expression. Children exhibit resistance to COVID-19 severe manifestations, and age-related features in innate and adaptive response possibly explaining this difference are discussed. A competent recognition by the innate immune system and controlled pro-inflammatory signaling seem to be the pillars of an effective response and the premise for pathogen clearance in SARS-CoV-2 infection. Immunosuppression-if not associated with other elements of fragility-do not represent per se an obstacle to this competent/tolerant phenotype in children. Several reports confirm that children receiving immunosuppressive medications have similar clinical involvement and outcomes as the pediatric general population, indicating that maintenance treatments should not be interrupted in suspect or confirmed SARS-CoV-2 infection.
RESUMO
Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Corticosteroides/uso terapêutico , Adulto , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Biomarcadores , COVID-19/genética , COVID-19/terapia , Calgranulina B/genética , Calgranulina B/imunologia , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ferritinas/genética , Ferritinas/imunologia , Perfilação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lactoferrina/genética , Lactoferrina/imunologia , Lipocalina-2/genética , Lipocalina-2/imunologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Análise Multivariada , NF-kappa B/genética , NF-kappa B/imunologiaRESUMO
Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies.
Assuntos
Proteínas de Ciclo Celular/genética , Sistema Nervoso Central/metabolismo , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/genética , Animais , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Proteoglicanas de Sulfatos de Condroitina/genética , Proteínas de Ligação a DNA , Perfilação da Expressão Gênica , Predisposição Genética para Doença/genética , Histona Desacetilases/genética , Humanos , Camundongos , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas/genética , Proteínas Repressoras/genética , CoesinasRESUMO
Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates.