SummaryDespite the finding of elevated Tricuspid Regurgitant Velocity (TRV) in children below 5 years of age, the prevalence and evolution of Pulmonary Hypertension (PH) in young children with sickle cell disease (SCD) are unclear. In order to identify predictive factors of precocious PH development, SCD children ‡3 years old, at steady state, underwent annual echocardiography and Tissue Doppler Imaging (TDI). Patients receiving chronic transfusion were excluded. Thirty-seven of seventy-five patients were ‡3 years, with measurable TRV. In our young population (mean age 6AE2 years) of mainly African, HbS/HbS patients, 8/37 (21AE6%) had TRV ‡2AE5 m/s, 8% being only 3 years old. Significant correlation was found between precocious TRV elevation and high platelet and reticulocyte counts and frequent acute chest syndromes (ACS). In multivariate analysis, ACS was the only variable predicting TRV ‡2AE5 m/s. TDI of the 37 patients showed signs of diastolic dysfunction of the left ventricle. At follow-up all eight patients with high TRV displayed further increase and seven more developed TRV ‡2AE5 m/s. PH seems to begin in children earlier than expected. Factors involved in its early onset might be different from the ones causing its development in older children or adults. African children might benefit from early screening and re-assessment once a year.
Minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been recently shown as a strong and independent prognostic marker of relapse in pediatric AML (pedAML) when measured at specific time points during Induction and/or Consolidation therapy. Hence, MFC-MRD has the potential to refine the current strategies of pedAML risk stratification, traditionally based on the cytogenetic and molecular genetic aberrations at diagnosis. Consequently, it may guide the modulation of therapy intensity and clinical decision making. However, the use of non-standardized protocols, including different staining panels, analysis, and gating strategies, may hamper a broad implementation of MFC-MRD monitoring in clinical routine. Besides, the thresholds of MRD positivity still need to be validated in large, prospective and multi-center clinical studies, as well as optimal time points of MRD assessment during therapy, to better discriminate patients with different prognosis. In the present review, we summarize the most relevant findings on MFC-MRD testing in pedAML. We examine the clinical significance of MFC-MRD and the recent advances in its standardization, including innovative approaches with an automated analysis of MFC-MRD data. We also touch upon other technologies for MRD assessment in AML, such as quantitative genomic breakpoint PCR, current challenges and future strategies to enable full incorporation of MFC-MRD into clinical practice.
Acute erythroid leukemia (AEL) is characterized by distinct morphology, mutational spectrum, a lack of preclinical models and poor prognosis. Here, using multiplexed genome editing of mouse hematopoietic stem and progenitor cells and transplant assay, we developed preclinical models of AEL and non-erythroid acute leukemia and demonstrated the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1 and Nfix resulted in the development of leukemia with erythroid phenotype, and were accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational co-occurrence, with clones harboring a higher number of founder and secondary lesions (e.g. mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the PARP inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a mutant AEL and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has demonstrated the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors and therapeutic tractability in erythroid leukemogenesis.
Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture.
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