Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. ...We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median range age at last follow-up: 16.3 years (1.2-41.0 years) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
•At least 65% of cases of pES may be genetically determined.•Genetic findings have prognostic significance and may guide the physician's choice of a targeted treatment.
Summary
Despite major therapeutic improvements, children with relapsed/refractory Acute Myeloid Leukaemia still have poor outcomes and overall survival does not exceed 40%. New treatments are ...required to improve their outcome; Gemtuzumab ozogamicin (GO), an anti‐CD33 immunoconjugate antibody, is a potent cytotoxic agent whose efficacy has been demonstrated mainly in adults. The main objective of this retrospective multicentre study was to assess the outcome of children treated, between February 2008 and August 2019, with GO at a single 4.5 mg/m2 dose, in combination with Fludarabine, Cytarabine and antssshracyclines, in context of a first relapse (n = 26) or refractory disease (n = 3). The remission rate was 83% (24/29 children) and 20 children (69%) were allografted. With a median follow‐up of 1.2 years (range: 0.1–8), the overall survival was 49% (CI95% = 33; 72). Most common adverse event was febrile neutropenia with microbiological identification in 55% of cases. Veno‐occlusive disease occurred in 6 patients (21%), of which 5 subvened after bone marrow transplantation, and resolved within 2–32 days (median 10.5 days). Administration of GO in combination with FLA‐anthracyclines chemotherapy appears to be a good reinduction regimen for relapsed or refractory AML with a good safety profile. These results warrant larger prospective study.
Malignant Peripheral Nerve Sheath Tumors (MPNST) are very rare and aggressive tumors, which can affect children, adolescents, and young adults. These tumors are frequently associated with type 1 ...neurofibromatosis (NF1). This study aims to determine prognostic factors in unselected pediatric MPNST to specify the risk stratification strategy.
A national multicenter retrospective study encompassing all French pediatric patients (0–18 years) treated for MPNST, confirmed by a pathology review, from 1995 to 2017.
Overall, 66 patients (median age 13.0 years range, 0.1–18.0) developed a MPNST located in the limbs (36%), trunk (27%), head and neck (21%) and para-vertebral area (15%). Forty-eight percent of patients had NF1, 50% had a histologic grade III tumor and 77% a large tumor (>5 cm), including 30% very large (>10 cm). Most patients (94%) had localized tumors. After a median follow-up of 7.6 years range, 0.4–18.7, the 5-year overall (OS) and event-free (EFS) survivals were 46.7% 95%CI, 35.8–60.8 and 40.8% 95%CI, 30.3–54.9, respectively. On multivariate analysis were found to be associated with a worse outcome (OS): metastatic disease (HR (Hazard-Ratio) 6.4 1.8; 22.0), grade 3 FNCLCC (HR 4.77 1.4; 15.8),> 10-cm size (HR 2.3 1.1; 4.8) and the presence of NF1 (HR 2.2 1.1; 4.4). Histologic subtypes of MPNST (classical, malignant Triton or epithelioid tumor) were not correlated with outcome.
The overall outcome of MPNST was poor in patients with NF1 and in high grade, very large and metastatic tumors. The identification of these risk factors allows us to define adapted risk stratification to propose new therapeutic strategies for high-risk cases.
•The prognosis of Pediatric MPNST is poor: 5y-OS 46.7% (95%CI, 35.8–60.8).•Type 1 neurofibromatosis is an independent risk factor in pediatric patients.•High grade, large and metastatic tumors are other major risk factors.•Histological subtype, such as malignant triton tumor, is not correlate with survival.
Primary Mediastinal large B-cell Lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase 2 trial in pediatric patients using ...dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. French prospective LMB2001 trial included all patients < 18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included 4 to 8 courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range 8-18). 21 patients were treated by chemotherapy plus rituximab. The median follow-up was 7.1 years (Interquartile range, 5.8-11.1). Five-year event-free (EFS) and overall survival (OS) were 88.1% (95%Confidence Interval (CI), 75.0%-94.8%) and 95.2% (95%CI, 84.0%-98.7%) for the whole population. The 5-year EFS was 81.0% (95%CI, 60.0%-92.3%) and 95.2% (95%CI, 77.3%-99.2%) (HR=0.24 (95%CI 0.03-2.2)) and 5-year OS was 90.5% (95%CI, 71.1%-97.3%) and 100% for patients treated without and with rituximab, respectively. Only 1/21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMB-based chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.
D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results ...of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.
Background
Solid tumors are uncommon in the neonatal period but represent an important cause of mortality and morbidity.
Procedure
Using the French National Registry of Childhood Solid Tumors ...database, all children, from birth to 28 days of age inclusive, with a primary malignant solid tumor diagnosed between 2000 and 2009 in mainland France were identified. Tumors were classified according to the third version of the International Classification of Childhood Cancer.
Results
Of total 285 solid tumors over 10 years, the most common cancer was neuroblastoma (47%), followed by germ cell tumors (29%), central nervous system tumors (10%), and soft tissue sarcomas (8%). The annual incidence was 36.6 per million live births. No statistically significant change in time trends of incidence was observed during 2000–2009. Routine ultrasonography during pregnancy established the diagnosis in 52% of cases. Thirteen neonates (4.5%) had congenital abnormalities associated with their tumors. For all solid tumors combined, overall survival was 84.2% (95% CI, 79.4–87.9) at 1 year and 83.8% (95% CI, 79.0–87.6) at 5 years. More favorable prognosis was significantly associated with neonates treated by surgery (65% of cases) compared to those without tumor excision. However, perioperative and postoperative mortality was 8%.
Conclusions
Because of their relative rarity, there is a paucity of objective information on the epidemiology, optimal treatment, and long‐term outcome of neonatal solid tumors. But to obtain a clearer picture of the epidemiology of neonatal tumors, it is essential to have some recommendations on the methodological approach used to study them.
The prevalence of the metabolic syndrome among adults from the French LEA childhood acute leukemia survivors' cohort was prospectively evaluated considering the type of anti-leukemic treatment ...received, and compared with that of controls. The metabolic profile of these patients was compared with that of controls. A total of 3203 patients from a French volunteer cohort were age- and sex-matched 3:1 to 1025 leukemia survivors (in both cohorts, mean age: 24.4 years; females: 51%). Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. Metabolic syndrome was found in 10.3% of patients (mean follow-up duration: 16.3±0.2 years) and 4.5% of controls, (OR=2.49;
<0.001). Patients transplanted with total body irradiation presented the highest risk (OR=6.26;
<0.001); the other treatment groups also showed a higher risk than controls, including patients treated with chemotherapy only. Odd Ratios were 1.68 (
=0.005) after chemotherapy only, 2.32 (
=0.002) after chemotherapy and cranial irradiation, and 2.18 (
=0.057) in patients transplanted without irradiation. Total body irradiation recipients with metabolic syndrome displayed a unique profile compared with controls: smaller waist circumference (91
99.6 cm;
=0.01), and increased triglyceride levels (3.99
1.5 mmol/L;
<0.001), fasting glucose levels (6.2
5.6 mmol/L;
=0.049), and systolic blood pressure (137.9
132.8 mmHg;
=0.005). By contrast, cranial irradiation recipients with metabolic syndrome had a larger waist circumference (109
99.6 cm;
=0.007) than controls. Regardless of the anti-leukemic treatment, metabolic syndrome risk was higher among childhood leukemia survivors. Its presentation differed depending on the treatment type, thus suggesting a divergent pathophysiology. This study is registered at
.
This prospective study aimed to analyze determinants that can influence bone mineral density evolution in childhood acute leukemia survivors. Patients included were selected from the long‐term ...follow‐up LEA cohort and had dual energy radiograph absorptiometry scan between 10 and 18 years and after the age of 18. All scans were centrally reviewed. Bone mineral density was measured at the lumbar spine, femoral neck, total hip, and whole body, and expressed as z‐score. Eighty‐nine patients (female 39, lymphoblastic leukemia 68, relapse 25, hematopoietic stem cell transplantation 44, and mean age 15.4 and 20.1 years at the first and second scans, respectively) were studied. The first and second scan z‐scores were significantly correlated (P < 10−3). Mean femoral neck and total hip z‐scores improved significantly between the first and second scans, whereas no significant evolution occurred at the lumbar spine and whole‐body level. On the second evaluation, 14.6% of patients had z‐score <−2 at the lumbar spine and 4.3% at the femoral neck level. Gender, type of leukemia, transplantation, relapse, cumulative corticosteroid doses, or growth hormone deficiency did not have any significant impact on z‐score variation. Younger age at diagnosis (≤8.5 years) proved an unfavorable risk factor for z‐score evolution at the lumbar spine (P = 0.041); the trend did not reach statistical significance for metabolic syndrome (P = 0.054). At the femoral neck, both were associated with unfavorable z‐score evolution (P = 0.003 and 0.025, respectively). Patients treated at a younger age and those with metabolic syndrome seem to be at higher risk of bone mineral density decline and should benefit from specific interventions.
Cardiovascular conditions are serious long-term complications of childhood acute leukemia. However, few studies have investigated the risk of metabolic syndrome, a known predictor of cardiovascular ...disease, in patients treated without hematopoietic stem cell transplantation. We describe the overall and age-specific prevalence, and the risk factors for metabolic syndrome and its components in the L.E.A. (Leucémie de l'Enfant et de l'Adolescent) French cohort of childhood acute leukemia survivors treated without hematopoietic stem cell transplantation. The study included 650 adult patients (mean age at evaluation: 24.2 years; mean follow-up after leukemia diagnosis: 16.0 years). The prevalence of metabolic syndrome was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively. The prevalence of decreased high-density lipoprotein cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively. Risk factors significantly associated with metabolic syndrome in the multivariate analysis were male sex (OR 2.64; 95% CI 1.32-5.29), age at last evaluation (OR 1.10; 95% CI 1.04-1.17) and body mass index at diagnosis (OR 1.15; 95% CI 1.01-1.32). The cumulative steroid dose was not a significant risk factor. Irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients. Survivors of childhood acute leukemia are at risk of metabolic syndrome, even when treated without hematopoietic stem cell transplantation or central nervous system irradiation. A preventive approach with regular screening for cardiovascular risk factors is recommended. clinicaltrials.gov identifier:01756599.
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