RESUMO
To optimize cyclosporine A (CsA) dosing regimen in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), we aimed to provide clinicians with a validated decision support tool for determining the most suitable first dose of intravenous CsA. We used a 10-year monocentric data set of pediatric patients undergoing HSCT. Discretization of all variables was performed according to literature or thanks to algorithms using Shannon entropy (from information theory) or equal width intervals. The first 8 years were used to build the Bayesian network model. This model underwent a 10-fold cross-validation, and then a prospective validation with data of the last 2 years. There were 3.3% and 4.1% of missing values in the training and the validation data set, respectively. After prospective validation, the Tree-Augmented Naïve Bayesian network shows interesting prediction performances with an average area under the receiver operating characteristic curve of 0.804, 32.8% of misclassified patients, a true-positive rate of 0.672, and a false-positive rate of 0.285. This validated model allows good predictions to propose an optimized and personalized initial CsA dose for pediatric patients undergoing HSCT. The clinical impact of its use should be further evaluated.
Assuntos
Ciclosporina/administração & dosagem , Sistemas de Apoio a Decisões Clínicas , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Adolescente , Fatores Etários , Teorema de Bayes , Peso Corporal , Criança , Pré-Escolar , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente , Masculino , Curva ROC , Fatores SexuaisAssuntos
Displasia Ectodérmica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Quinase I-kappa B/genética , Doenças da Imunodeficiência Primária/genética , Candidíase/genética , Infecções por Citomegalovirus/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Fenótipo , Pneumonia por Pneumocystis/genética , RecidivaRESUMO
PURPOSE: Managing the pharmacokinetic variability of immunosuppressive drugs after pediatric hematopoietic stem cell transplantation (HSCT) is a clinical challenge. Thus, the aim of our study was to design and validate a decision support tool predicting the best first cyclosporine oral dose to give when switching from intravenous route. METHODS: We used 10-years pediatric HSCT patients' dataset from 2008 to 2018. A tree-augmented naïve Bayesian network model (method belonging to artificial intelligence) was built with data from the first eight-years, and validated with data from the last two. RESULTS: The Bayesian network model obtained showed good prediction performances, both after a 10-fold cross-validation and external validation, with respectively an AUC-ROC of 0.89 and 0.86, a percentage of misclassified patients of 28.7% and 35.2%, a true positive rate of 0.71 and 0.65, and a false positive rate of 0.12 and 0.14 respectively. CONCLUSION: The final model allows the prediction of the most likely cyclosporine oral dose to reach the therapeutic target specified by the clinician. The clinical impact of using this model needs to be prospectively warranted. Respecting the decision support tool terms of use is necessary as well as remaining critical about the prediction by confronting it with the clinical context.
Assuntos
Ciclosporina/administração & dosagem , Técnicas de Apoio para a Decisão , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Administração Intravenosa , Administração Oral , Adolescente , Teorema de Bayes , Criança , Pré-Escolar , Ciclosporina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/farmacocinética , MasculinoAssuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Anemia de Fanconi/patologia , Síndromes Mielodisplásicas/patologia , Criança , Anemia de Fanconi/complicações , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Evolução Fatal , Feminino , Humanos , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapiaRESUMO
In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2Shigh patients were found to be younger than TET2low patients without a difference in the rate of complete remission. However, TET2E2Shigh patients exhibited a significantly lower CIR (p<10-4). TET2E2S and FLT3-ITD, but not age or NPM1 mutation status were independent prognostic factors for DFS and event-free survival (EFS), while TET2E2S was the sole prognostic factor that we identified for overall survival (OS). In both the intermediate-1 and favorable ELN genetic categories, TET2E2S remained significantly associated with prolonged survival. There was no correlation between TET2E2S status and outcomes in 34 additional AML patients who were unfit for IC. Therefore our results suggest that assessments of TET2 exon 2 splicing status might improve risk stratification in CN-AML patients treated with IC.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/genética , Fatores Etários , Citogenética , Dioxigenases , Intervalo Livre de Doença , Éxons , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Medição de Risco , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
BACKGROUND: Percutaneous biopsy is the reference diagnostic procedure for adult musculoskeletal tumors. Its place in pediatrics is controversial and open biopsy remains recommended. OBJECTIVE: To assess diagnostic performance and feasibility of percutaneous biopsy performed on children and young adults for suspected malignant bone tumors. MATERIALS AND METHODS: We conducted a 5-year retrospective study including patients ≤21 years who underwent a bone biopsy for a suspected malignant bone tumor. We assessed diagnostic yield (percentage of analyzable biopsies), accuracy (percentage of accurate diagnoses among all analyzable biopsies) and efficacy (percentage of accurate diagnoses among all biopsies), costs, anesthetic requirements and sample availability for biomedical research. Patients diagnosed with an open biopsy were used to compare diagnostic performances, anesthetic requirements and costs. RESULTS: We included 90 percutaneous and 27 open biopsies in 117 patients. For percutaneous biopsy, diagnostic yield was 95.5% (95% confidence interval [CI] 88.8-98.7%), accuracy was 96.2% (95% CI 86.8-99.5%) and efficacy was 89.3% (95% CI 78.1-96.0%). There was no statistical difference with open biopsy (Fisher exact test, P > 0.05). Mean costs were reduced with percutaneous biopsy: 1,937 (standard deviation [SD] 2,408) versus 6,362 (SD 5,033; Mann-Whitney, P < 0.0001). Thirty-two of the 48 (67%) patients included in clinical trials and diagnosed with percutaneous biopsy had suitable samples for ancillary analyses. CONCLUSION: Percutaneous biopsy is a valid alternative to open biopsy for diagnosing pediatric and young adult primary malignant bone tumors.