Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
ConclusionThus, even children receiving anti-cancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
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.
Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19 leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19 ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19 and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.
Single-agent vemurafenib leads to a rapid and sustained clinical response in severe multisystem LCH but does not eradicate the disease.Longitudinal assessment of V600E during treatment shows that clinical remission can occur despite significant amounts of mutated BRAF.
Bacterial infection is the most common complication in paediatric oncological patients during cancer treatment. A suitable tool for early prediction of unfavourable course of infection is still needed. We performed a prospective longitudinal observational study to evaluate of the role of serum biomarkers (C-reactive protein, procalcitonin, interleukin-6, presepsin) in the early diagnosis of bacteraemia (gram-negative versus gram-positive) in patients with haematological malignancies. We observed 69 febrile episodes in 33 patients (17 male, 16 female; 1.5-18.9 years, mean 7.31 years, median 5 years). Within this sample, there were 22 cases of positive blood cultures, 16 cases of sepsis, 38 cases of fever with no signs or symptoms of sepsis, and two deaths from infectious complications. All markers tested had good negative predictive value (73% -93%). CRP was characterized by good specificity for registration bacteraemia (96%, 95% CI: 85% -99%), but other results were inconclusive. We identified comparably balanced sensitivity (64% -81%) and specificity (61% -88%) for interleukin-6 and procalcitonin, and we proved their quality to predict positive blood culture and clinical signs of sepsis as well. Patients with gram-negative bacteraemia had significantly elevated levels of PCT and IL-6 in comparison with a group of patients with gram-positive bacteraemia (p = 0.04 for PCT and p = 0.005 for IL-6). Presepsin was characterized by poor specificity (27%, 95% CI: 15% -43%) and positive predictive value (24%, 95% CI: 12 -39%) for predicting bacteraemia, and by better sensitivity (84%, 95% CI: 55% -98%) and specificity (58%, 95% CI: 42% -73%) for predicting clinical signs of sepsis. Key words: C-reactive protein, procalcitonin, interleukin-6, presepsin, fever, sepsisBacterial infection is the most common treatment-related complication in patients with haematological malignancies [1]. Documented mortality associated with paediatric febrile neutropenia is 2% [2]. The potential for early diagnosis of bacteraemia through serum biomarkers has been the subject to extensive research [3]. In 2012 Phillips et al published large meta-analysis of 25 studies exploring 14 different biomarkers in 3,585 episodes of febrile neutropenia. CRP, PCT and IL-6 were subject to quantitative meta-analysis. The bivariate estimates of diagnostic precision of these biomarkers and outcomes were done. Data were available for meta-analysis for CRP for microbiologically or clinically documented infection (results: cut off > 50mg/dl, sensitivity 65%, specificity 73%), for PCT assessing microbiologically or clinically documented infection (results: cut off > 0.2 mg/ml, sensitivity 96%, specificity 85%), for IL-6 reporting microbiologically or clinically documented infection (results: cut off > 235 pg/ml, sensitivity 68%, specificity 94%), and gram-negative bacteraemia (results: cut off > 1000 pg/ml, sensitivity 78%, specificity 96%). Huge inconsistencies and heterogeneity in the studies included in this review were the most important limiting factors [...
Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico‐pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo‐ or adjuvant treatments can be challenging taking into account potential long‐term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union‐funded project PARTNER (Paediatric Rare Tumours Network ‐ European Registry).
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