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1.
J Clin Oncol ; : JCO2002333, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33405950

RESUMO

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). RESULTS: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

3.
Hematol Oncol ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809224

RESUMO

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population.

4.
J Infect Dis ; 2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32860509

RESUMO

BACKGROUND: Little is known about characteristics of seasonal human coronavirus (HCoV) (NL63, 229E, OC43 and HKU1) after allogeneic stem cell transplantation (allo-HCT). PATIENTS AND METHODS: this is a collaborative Spanish and European bone marrow transplantation groups retrospective multicentre study, which included allo-HCT recipients (adults and children) with upper and/or lower respiratory tract disease (U/LRTD) caused by seasonal HCoV diagnosed through multiplex PCR assays from January 2012 to January 2019. RESULTS: We included 402 allo-HCT recipients who developed 449 HCoV U/LRTD episodes. Median age of recipients was 46 years (range 0.3-73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n=170, 38%). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%) and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 x10 9/mL [hazard ratio (HR), 10.8], corticosteroid (HR 4.68) and ICU admission (HR 8.22) (p<0.01). CONCLUSIONS: Seasonal HCoV after allo-HCT may involve the LRTD in many instances, leading to a significant morbidity.

5.
Biol Blood Marrow Transplant ; 26(11): 2034-2039, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32712327

RESUMO

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.

6.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

7.
Br J Haematol ; 190(1): 105-114, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32057100

RESUMO

Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2-day interval of IM administrations.

9.
Rheumatology (Oxford) ; 59(3): 668-677, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504941

RESUMO

OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.


Assuntos
Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Interferon-alfa/farmacologia , Lúpus Eritematoso Sistêmico/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos B/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Br J Haematol ; 189(2): 351-362, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31837008

RESUMO

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

11.
J Clin Med ; 8(11)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717804

RESUMO

Several components of the clotting system are modified towards hypercoagulability in sickle cell disease (SCD). To date, hematopoietic stem cell transplantation (HSCT) is the only validated curative treatment of SCD. Here, we investigated the changes in the hemostatic potential of SCD children who've received a successful HSCT. Seventeen children with severe SCD were enrolled in the study. Thrombin generation (TG) was performed on citrated platelet-poor plasma, obtained before and 3, 6, 9, 12 and 15 months after HSCT. TG was triggered using 1 pM tissue factor and 4 µM phospholipids with or without thrombomodulin (TM). Before the HSCT, SCD children showed a higher endogenous thrombin potential (ETP), higher peak, higher velocity and shorter time-to-peak of TG than the normal controls (NC). ETP did not significantly change following the HSCT. However, the peak, velocity and time-to-peak of TG reversed to normal ranges from 3 months post-HSCT and remained so up to 15 months post-HSCT. The reduction of ETP after the addition of thrombomodulin (RETP) was dramatically reduced in SCD children before HSCT as compared with the NC. A partial reversal of RETP was observed from 3 months through 15 months post-HSCT. No statistical difference was observed for patient age or donor hemoglobinopathy status. In summary, successful HSCT improves the kinetics of TG but not the total thrombin capacity in SCD children.

12.
J Clin Oncol ; 37(31): 2857-2865, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513482

RESUMO

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.


Assuntos
Histiocitose de Células de Langerhans/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/uso terapêutico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Resistência a Medicamentos , Europa (Continente) , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Humanos , Lactente , Masculino , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Índice de Gravidade de Doença , Transdução de Sinais , Fatores de Tempo , Resultado do Tratamento , Vemurafenib/efeitos adversos
13.
J Clin Oncol ; 37(25): 2246-2256, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283407

RESUMO

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS: Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS: A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION: Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Rearranjo Gênico , Mutação em Linhagem Germinativa , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mercaptopurina/administração & dosagem , Mitoxantrona/administração & dosagem , Proteína de Leucina Linfoide-Mieloide/genética , Taxa de Sobrevida , Resultado do Tratamento
14.
Br J Haematol ; 186(5): 741-753, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31124581

RESUMO

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2 /day) versus prednisolone (60 mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109 /l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 109 /l, representing approximately 50% of T-ALL patients.


Assuntos
Ensaios Clínicos como Assunto/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Análise de Sobrevida , Resultado do Tratamento
16.
Proc Natl Acad Sci U S A ; 116(4): 1241-1250, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30626647

RESUMO

Neutropenia represents an important problem in patients with genetic deficiency in either the glucose-6-phosphate transporter of the endoplasmic reticulum (G6PT/SLC37A4) or G6PC3, an endoplasmic reticulum phosphatase homologous to glucose-6-phosphatase. While affected granulocytes show reduced glucose utilization, the underlying mechanism is unknown and causal therapies are lacking. Using a combination of enzymological, cell-culture, and in vivo approaches, we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-K M hexokinases, which catalyze the first step in glycolysis in most tissues. We show that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol, a compound normally present in human plasma, by side activities of ADP-glucokinase and low-K M hexokinases. Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (∼3 mM) that strongly inhibit hexokinase activity. In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death. Treating G6PC3-deficient mice with an inhibitor of the kidney glucose transporter SGLT2 to lower their blood level of 1,5-anhydroglucitol restored a normal neutrophil count, while administration of 1,5-anhydroglucitol had the opposite effect. In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.


Assuntos
Antiporters/metabolismo , Glucose-6-Fosfatase/metabolismo , Glucose/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Neutropenia/metabolismo , Fosforilação/fisiologia , Animais , Morte Celular/fisiologia , Linhagem Celular , Retículo Endoplasmático/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Ratos Wistar
17.
Transfusion ; 58(6): 1356-1362, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29574950

RESUMO

BACKGROUND: Chronic transfusion in sickle cell disease (SCD) remains the gold standard therapy for stroke prevention and for patients with severe disease despite adequate hydroxyurea treatment. The aim of our study was to assess the safety and efficacy of automated red blood cell exchange (aRBX) in patients with SCD previously treated with manual exchange transfusion (MET). Costs related to transfusion and chelation overtime were evaluated. STUDY DESIGN AND METHODS: Beginning in January 2012, children with SCD who weighed 30 kg or more on MET could switch to aRBX. Clinical, biological, and procedures' data, including costs, were recorded for the last 6 months on MET and compared to those after the first and the second year on aRBX. RESULTS: Ten patients switched from MET to aRBX at a median age of 11.8 years. After the switch, median hemoglobin S (HbS) increased significantly (33.5% on MET compared to 45% on aRBX; p < 0.001) but remained in the target values for all patients. Median ferritin decreased significantly (663.3 µg/L on MET compared to 126.8 µg/L on aRBX; p < 0.001) and intervals between procedures were significantly longer. The requirements of red blood cells (RBCs)/kg/year were not different on MET (0.88 unit/kg/year) than during the second year on aRBX (1.07 unit/kg/year; p = NS). MET costs were similar compared to aRBX since chelation was stopped in previously treated patients. CONCLUSION: Erythrocytapheresis reduces iron overload and allows a longer interval between procedures without a higher RBC requirement from the second year on aRBX. The cost did not increase as estimated in our Belgian Health Care System.


Assuntos
Anemia Falciforme/terapia , Transfusão de Eritrócitos/métodos , Sobrecarga de Ferro/prevenção & controle , Automação , Criança , Análise Custo-Benefício , Transfusão de Eritrócitos/economia , Transfusão de Eritrócitos/normas , Ferritinas/sangue , Hemoglobina Falciforme/metabolismo , Humanos
18.
Pediatr Blood Cancer ; 65(7): e27022, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29512872

RESUMO

BACKGROUND: Hydroxyurea (HU) reduces the severity of sickle cell disease (SCD) in children; nevertheless, its long-term safety is an important concern. This paper evaluates HU genotoxicity at dose ≤ 30 mg/kg/day after over 2 years of treatment. PROCEDURE: The study included 76 children: 32 SCD patients treated with HU, 27 SCD patients not treated with HU, and 17 unaffected children. HU patients were classified as good or poor responders according to their clinical response. Comet assay allows the comparison of DNA damage between both groups of patients and unaffected children. Maximal concentration (Cmax ) of HU in plasma was determined after drug administration. RESULTS: Mean values of DNA in the comet tail were 5.13 ± 6.84 for unaffected children, 5.80 ± 7.78 for patients with SCD treated with HU, and 5.61 ± 6.91 for patients with SCD not treated with HU. Significant differences were observed between unaffected children and children with SCD. No difference was evident between comets from SCD patients treated and not treated with HU. In the case of HU, mean DNA in the comet tail was significantly lower in good responders than in poor responders: 5.54 ± 7.77 and 6.69 ± 8.43, respectively. Mean Cmax value on plasma was 39.08 ± 15.65 mg/l; N = 31. CONCLUSIONS: SCD increases, slightly but significantly, DNA damage in lymphocytes from patients with SCD. Patients with SCD treated with HU do not present more nucleoid damage than patients with SCD not treated with HU. Good responders to the HU treatment have significantly less nucleoid damage than poor responders. HU treatment at ≤30 mg/kg/day does not expose patients to a genotoxic plasma concentration.


Assuntos
Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Antidrepanocíticos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/uso terapêutico , Adolescente , Anemia Falciforme/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico
19.
Oncotarget ; 9(3): 3779-3793, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29423082

RESUMO

The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives. A heterozygous mutation in ATM was identified in these 3 subjects but was not directly linked to the observed phenotype. However, the attenuation of ICL sensitivity was associated with a reduced recruitment of 53BP1 during the course of ICL repair, and increased HR levels. These results further demonstrate the importance of favoring HR over NHEJ for the survival of cells challenged with ICLs.

20.
J Med Screen ; 25(2): 57-63, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686106

RESUMO

Objectives To compare the outcomes of sickle cell disease patients diagnosed through neonatal screening with those who were not. Methods In an observational multicenter study in Belgium, 167 screened and 93 unscreened sickle cell disease patients were analyzed for a total of 1116 and 958 patient-years of follow-up, respectively. Both groups were compared with propensity score analysis, with patients matched on three covariates (gender, genotype, and central Africa origin). Bonferroni correction was applied for all comparisons. Results Kaplan-Meier estimates of survival without bacteremia were significantly higher in the screened group than the unscreened group (94.47%; [95% CI, 88.64-97.36%] versus 83.78% [95% CI, 72.27-90.42%]), p = 0.032. Non-significant differences between both groups were reported for survival without acute chest syndrome, acute anemia, cerebral complication, severe infection, and vaso-occlusive crisis. Significantly lower hospitalization rate and days per 100 patient-years were observed in the screened compared with the unscreened group (0.27 vs. 0.63 and 1.25 vs. 2.82, p = 0.0006 and <0.0001). Conclusion These data confirm the benefit of a neonatal screening programme in reducing bacteremia and hospitalization.


Assuntos
Anemia Falciforme/mortalidade , Triagem Neonatal , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Anemia Falciforme/diagnóstico , Anemia Falciforme/etnologia , Bélgica/epidemiologia , Criança , Pré-Escolar , Grupos Étnicos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Pontuação de Propensão , Análise de Sobrevida , Adulto Jovem
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