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1.
J Intensive Care Med ; 39(5): 484-492, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-37981801

RESUMO

Background: Children with hemato-oncological diseases or following stem cell transplantation (SCT) are at high risk for life-threatening infections; sepsis in this population constitutes a substantial proportion of pediatric intensive care unit (PICU) admissions. The current pediatric prognostic scoring tools to evaluate illness severity and mortality risk are designed for the general pediatric population and may not be adequate for this vulnerable subpopulation. Methods: Retrospective analysis was performed on all PICU admissions for sepsis in children with hemato-oncological diseases or post-SCT, in a single tertiary pediatric hospital between 2008 and 2021 (n = 233). We collected and analyzed demographic, clinical, and laboratory data and outcomes for all patients, and evaluated the accuracy of two major prognostic scoring tools, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and the Pediatric Risk of Mortality III (PRISM III). Furthermore, we created a new risk-assessment model that contains additional parameters uniquely relevant to this population. Results: The survival rate for the cohort was 83%. The predictive accuracies of PELOD-2 and PRISM III, as determined by the area under the curve (AUC), were 83% and 78%, respectively. Nine new parameters were identified as clinically significant: age, SCT, viral infection, fungal infection, central venous line removal, vasoactive inotropic score, bilirubin level, C-reactive protein level, and prolonged neutropenia. Unique scoring systems were established by the integration of these new parameters into the algorithm; the new systems significantly improved their predictive accuracy to 91% (p = 0.01) and 89% (p < 0.001), respectively. Conclusions: The predictive accuracies (AUC) of the PELOD-2 and PRISM III scores are limited in children with hemato-oncological diseases admitted to PICU with sepsis. These results highlight the need to develop a risk-assessment tool adjusted to this special population. Such new scoring should represent their unique characteristics including their degree of immunosuppression and be validated in a large multi-center prospective study.


Assuntos
Hematologia , Neoplasias , Sepse , Criança , Humanos , Lactente , Estudos Retrospectivos , Estudos Prospectivos , Prognóstico , Unidades de Terapia Intensiva Pediátrica , Cuidados Críticos , Mortalidade Hospitalar
2.
Br J Haematol ; 196(5): 1248-1256, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862597

RESUMO

Most childhood acute lymphoblastic leukaemia (ALL) protocols include high-dose steroid therapy. However, the known potential of high-dose steroids to significantly elevate intraocular pressure (IOP) and lead to glaucomatous optic neuropathy has not been intensively investigated in children with ALL. Moreover, as children with ALL do not routinely undergo IOP measurements, the need for IOP monitoring and therapy is unknown. We prospectively measured IOP in 90 children with newly diagnosed ALL attending a tertiary paediatric haematology/oncology centre, at diagnosis and at the middle and end of induction therapy. Ocular hypertension (IOP > 21 mm Hg) at any time point was documented in 64 children (71%), and the prevalence increased during induction. Thirty-six children (40%) had elevated IOP at ALL diagnosis before therapy initiation, and stratification to non-standard ALL was a risk factor. IOP reduction therapy was administered to 13 children (14%); none required surgery. Values normalised in all cases. On multivariate logistic regression analysis, dexamethasone therapy was a significant risk factor for ocular hypertension. High body mass index was an additional risk factor in children with elevated IOP at ALL diagnosis. Routine evaluation of IOP during steroid therapy is very important in children with ALL to ensure early intervention which may prevent permanent ocular damage.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Dexametasona/efeitos adversos , Pressão Intraocular , Hipertensão Ocular/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos Hormonais/uso terapêutico , Índice de Massa Corporal , Criança , Pré-Escolar , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Lactente , Pressão Intraocular/efeitos dos fármacos , Masculino , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Estudos Prospectivos , Fatores de Risco
3.
Pediatr Blood Cancer ; 68(8): e29033, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33788395

RESUMO

BACKGROUND: Osteonecrosis is a major cause of acute and long-lasting complications of acute lymphoblastic leukemia (ALL) therapy in children. Our study aimed to evaluate the prevalence, characteristics, risk factors, and outcome of osteonecrosis in children with ALL. PROCEDURE: The cohort included 559 children aged 1-20 years diagnosed with ALL between 2003 and 2018 at two tertiary medical centers in Israel and enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. Symptomatic osteonecrosis was prospectively captured as an adverse event. RESULTS: Osteonecrosis occurred in 51 patients (9.1%). Ninety-four percent of the events were graded as moderate or severe (grades 3-4, Ponte di Legno Toxicity Working Group classification) and multiple bone involvement was common. Full resolution of osteonecrosis was documented in only 16% of the children (median follow-up 4.2 years). Stepwise logistic regression identified five risk factors for osteonecrosis, with a high predictive value (AUC = 0.88): older ageat ALL diagnosis, high-risk ALL group, T-cell immunophenotype, female gender, and a novel risk factor: bone pain at the time of leukemia diagnosis. In addition, osteonecrosis was less common among children of Arab ethnicity. Thrombophilia and an elevated age-adjusted body mass index were not confirmed as risk factors for osteonecrosis. CONCLUSION: Due to the low rates of osteonecrosis resolution and its debilitating long-term impact, the identification of patients at high risk for osteonecrosis is important for their inclusion in further studies evaluating potential therapeutic adjustments.


Assuntos
Osteonecrose , Dor , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Israel , Modelos Logísticos , Masculino , Osteonecrose/diagnóstico , Osteonecrose/etiologia , Dor/diagnóstico , Dor/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores de Risco , Centros de Atenção Terciária , Adulto Jovem
4.
Pediatr Blood Cancer ; 68(10): e29138, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34019335

RESUMO

BACKGROUND: Inflammatory manifestations (IM) are well described in adult patients with myelodysplastic syndrome (MDS), but the presentation is highly variable and no standardized treatment exists. This phenomenon is rarely reported in children. As more pediatric patients are hematopoietic stem cell transplantation (HSCT) candidates, the role of anti-inflammatory treatment in relation to HSCT should be defined. PROCEDURE: Here, we report a series of five children from a tertiary center. We describe the clinical presentation, molecular findings, and treatment options. RESULTS: All patients presented with advanced MDS with blast percentages ranging 10-30%, all had severe IM. One patient had MDS secondary to severe congenital neutropenia, the other four patients had presumably primary MDS. All four were found to harbor a PTPN11 gene driver mutation, which is found in 35% of cases of juvenile myelomonocytic leukemia (JMML). The mutation was present in the myeloid lineage but not in T lymphocytes. Three had symptoms of Behcet's-like disease with trisomy 8 in their bone marrow. All patients were treated with anti-inflammatory medications (mainly systemic steroids) in an attempt to bring them to allogeneic HSCT in a better clinical condition. All demonstrated clinical improvement as well as regression in their MDS status post anti-inflammatory treatment. All have recovered from both MDS and their inflammatory symptoms post HSCT. CONCLUSION: Primary pediatric MDS with IM is driven in some cases by PTPN11 mutations, and might be on the clinical spectrum of JMML. Anti-inflammatory treatment may reverse MDS progression and improve the outcome of subsequent HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicas , Criança , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Resultado do Tratamento , Trissomia
5.
Br J Haematol ; 184(6): 994-998, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632137

RESUMO

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.


Assuntos
Heparina de Baixo Peso Molecular/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Trombofilia/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Criança , Etnicidade , Feminino , Humanos , Masculino , Programas de Rastreamento , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Risco
6.
Genes Chromosomes Cancer ; 55(4): 328-39, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26684414

RESUMO

Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.


Assuntos
MicroRNAs/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/fisiopatologia , Prognóstico , Recidiva
7.
Leuk Lymphoma ; 62(9): 2211-2218, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33749493

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, yet data regarding long-term ovarian reserve of female survivors are limited. The aim of this study was to investigate whether there is a differential pattern of anti-Mullerian hormone (AMH) levels in female childhood ALL survivors compared with the normal age-matched population. In a cohort of 56 female childhood ALL survivors (median age 29 years; median follow-up 20.6 years), a negative correlation was found between age at leukemia diagnosis and age-adjusted anti-Mullerian hormone (AMH) levels (r = -0.334, p = .031). Despite alkylating agent therapy, AMH levels did not differ significantly from age-related nomograms (age < 30, p = .17; age ≥ 30, p = .94). The mean number of children per fertile woman adjusted for maternal age was similar to the national average (2.76 versus 3.11, p = .19). Our results imply that reproductive outcomes are not significantly hampered in female pediatric ALL survivors. Long-term surveillance of ovarian reserve may enable personalized survivorship counseling.


Assuntos
Reserva Ovariana , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Hormônio Antimülleriano , Criança , Feminino , Fertilidade , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Sobreviventes
8.
Cancers (Basel) ; 12(10)2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32992771

RESUMO

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1-19 years diagnosed with ALL between 2003-2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

9.
Br J Haematol ; 147(1): 113-24, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19694717

RESUMO

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistema Nervoso Central/patologia , Infiltração Leucêmica/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Irradiação Craniana , Seguimentos , Humanos , Lactente , Injeções Espinhais , Contagem de Leucócitos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
10.
J Pediatr Endocrinol Metab ; 30(8): 869-877, 2017 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-28742520

RESUMO

BACKGROUND: Survivors of acute lymphoblastic leukemia (ALL) may experience endocrine dysfunction. This study evaluated growth and pubertal patterns in survivors of childhood ALL. METHODS: Longitudinal assessment of anthropometric measurements and pubertal status was performed in a retrospective cohort of survivors (n=183). Median age at last endocrine visit was 16.1 years (range 8.2-27.6); median follow-up time was 8.7 years (range 3-21.4). RESULTS: Treatment with chemotherapy+prophylactic cranial radiation (pCRT, n=29) was associated with lower mean height standard deviation score (SDS) than chemotherapy alone (n=154) (p=0.001) and higher prevalence of adult short stature (13% vs. 2.2%). Mean age at pubertal onset was normal (girls: 10.3±1.3 years; boys: 12.0±1.3 years). Precocious puberty, diagnosed in 8.7% of patients, was more prevalent in pCRT-treated girls. Rates of overweight and obesity were 22.9% and 9.3%, respectively. Predictors of endocrine disorders were pCRT (p=0.031) and female gender (p=0.041); of obesity, higher body mass index (BMI)-SDS at diagnosis (p=0.001); and of short stature, lower height-SDS at diagnosis (p=0.038). CONCLUSIONS: Most childhood ALL survivors given chemotherapy alone attain normal adult height and puberty. Childhood ALL survivors are at increased risk of overweight, especially those with increased BMI at diagnosis. Clinicians should screen for overweight early in survivorship and introduce early interventions.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Estatura/fisiologia , Sobreviventes de Câncer , Desenvolvimento Infantil/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Puberdade/fisiologia , Adolescente , Adulto , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Adulto Jovem
11.
J Pediatr Surg ; 42(5): 862-4, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17502200

RESUMO

BACKGROUND: Aggressive chemotherapy/radiotherapy for cancer may cause gonadal failure in young female survivors. The putative aim of ovarian tissue cryopreservation is to restore fertility by transplantation of a patient's frozen-thawed ovarian tissue or, further into the future, by in vitro maturation of frozen-thawed oocytes followed by in vitro fertilization. This report presents our early experience with ovarian tissue preservation in young patients. METHODS: We conducted a database review of the techniques and outcomes of the ethics board-approved ovarian tissue cryopreservation procedures performed at our center since 1998 for young girls with malignancy. RESULTS: The study group included 23 patients (median age = 14 years) with various types of cancer (hematologic, bone, ovarian, or intracranial); 11 patients were scheduled for chemotherapy, 11 patients had already undergone some form of chemotherapy before the ovarian tissue harvesting, and 1 patient was not scheduled for chemotherapy. Ten underwent bone marrow transplantation after tissue retrieval. Twenty-one patients underwent laparoscopic harvesting of their ovarian tissue. In the other 2 patients, the ovary was preserved during inguinal hernia repair or tissue was obtained at laparotomy for a pelvic tumor. All patients had benign operative and postoperative courses. CONCLUSIONS: Laparoscopy for ovarian tissue retrieval for cryopreservation is safe in young cancer patients. Based on reports of successful cryopreservation of human ovarian tissue containing primordial follicles, we believe that this approach holds promise for female cancer survivors.


Assuntos
Criopreservação , Fertilidade , Laparoscopia/métodos , Neoplasias Ovarianas , Ovário/transplante , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/terapia , Transplante de Tecidos/métodos , Adolescente , Terapia Combinada/efeitos adversos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/radioterapia , Ovário/efeitos dos fármacos , Ovário/efeitos da radiação , Resultado do Tratamento
12.
J Comput Assist Tomogr ; 30(4): 689-94, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16845304

RESUMO

OBJECTIVE: To assess the role of 18F-Fluorodeoxyglucose (18F-FDG) PET/CT in pediatric patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). MATERIALS AND METHODS: 31 patients, mean age 12.9 +/- 5.1, HD (n = 24), and NHL (n = 7) underwent 18F-FDG PET/CT at diagnosis (n = 31 studies) and later in the course of the disease (n = 75 studies). The findings of PET/CT were correlated with diagnostic CT and clinical follow-up. RESULTS: PET/CT findings resulted in a change of disease staging in 10 patients (32.3%), upstaging in 7 (22.6%) and downstaging in 3 (9.6%). On a lesion analysis, 164 disease sites were detected by PET/CT of which 38 were overlooked by DCT. At mid-treatment, PET was negative in 28 out of 31 patients (90%) with negative predictive value of 96% as all latter patients except for 1, were disease free (mean 15.4 +/- 8.8 months). The positive predictive value of persistent increased 18F-FDG uptake was 100% as 3 patients with latter findings had active disease. On the CT part, 76 residual masses were identified in 22 patients. Increased 18F-FDG uptake was detected in 11 masses in 4 patients who had active disease. Remaining 65 PET negative masses were false positive findings. The positive predictive value of residual CT mass was 14%. CONCLUSIONS: PET/CT is associated with change in staging in approximately 1 out of 3 pediatric patients with HD and NHL. When used for monitoring response to treatment, a negative study is associated with disease-free period, even when residual mass is detected. A positive PET study indicates residual malignant disease.


Assuntos
Linfoma/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18 , Humanos , Interpretação de Imagem Assistida por Computador , Linfoma/patologia , Masculino , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos
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