Post-viral idiopathic purpura fulminans is associated with inherited thrombophilia and anti-cardiolipin antibodies.

Introduction: Idiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication. Method: This is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aß2GP1). Results: Among the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aß2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.

CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951.

AIM: To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial. PATIENTS AND METHODS: From 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5g/m2), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients. RESULTS: The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse. CONCLUSIONS: CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy. This trial was registered at https://clinicaltrials.gov/under/NCT00003728.

Functional analysis of young patients with desmoid-type fibromatosis: Initial surveillance does not jeopardize long term quality of life.

BACKGROUND: With recent conservative strategies, prognosis of patients with desmoid-type fibromatosis (DTF) is about function preservation. We analyzed the long-term quality of life (QoL) of pediatric patients with DTF. METHODS: All French young patients (<21years) treated between 2005 and 2016 for a DTF in the EpSSG NRSTS-05 study were analyzed. A first wait-and-see strategy was recommended. Patients' QoL was analyzed with the internationally validated Child Health Questionnaire (CHQ). We focused on the relevant subscales scores: physical functioning (PF), role social limitations physical (RP), bodily pain (BP), general health perception (GH) and physical (PhS) and psychosocial (PsS) summary measures. RESULTS: Among the 81 patients, 52 families answered the CHQ (median delay since diagnosis = 6.2years; min2.2-max13.3 years). Median age at diagnosis was 11.5 years. Primary site: limbs (52%), head/neck (27%), or trunk (21%). Five year-Progression Free Survival was 39.1% (95%CI: 27.7-50.5%). As initial management for these 52 patients, 30 patients were first observed (57%), 13 had surgery (25%) and 9 received chemotherapy (18%). Total burden of therapy was exclusive surgery (9pts/18%), exclusive chemotherapy (18pts/35%), surgery + chemotherapy (13pts/25%), chemotherapy + radiotherapy (1 pt), surgery + chemotherapy + radiotherapy (1 pt), wait and see (10 pt). Regarding the parent forms, patients have significant lower PF (86.0vs.96.1; p = 0.03), RP (82.0vs.93.6; p = 0.04), GH (60vs.73; p < 0.005) and PhS (46.2 vs.53; p = 0.02) scores compared to healthy population. Comparison of QoL subscales scores according to initial strategy (wait-and-see vs.surgery/chemotherapy) did not reveal any difference (PF = 87.3vs.84.9; p = 0.80/RP = 83.4vs.78.7; p = 0.72/BP = 78.9vs.78.2; p = 0.95/GH = 59.7vs60; p = 0.97). Similar results were found using the children or adult forms. CONCLUSIONS: Initial wait-and-see strategy does not affect long term functional impairment.

Genetic polymorphisms of Th2 interleukins, history of asthma or eczema and childhood acute lymphoid leukaemia: Findings from the ESCALE study (SFCE).

BACKGROUND: Previous studies on the putative role of allergy in the aetiology of childhood leukaemia have reported contradictory results. The present study aimed to analyse the relation between a medical history of asthma or eczema and childhood acute lymphoid leukaemia (ALL) in light of potential candidate gene-environment interactions. METHODS: Analyses were based on a subset of 434 cases of ALL and 442 controls successfully genotyped and of European ancestry children enrolled in a French population-based case-control study conducted in 2003-2004. Information about medical history was obtained during a standardized interview with the mothers. Candidate polymorphisms in genes of the Th2 cytokines IL4, IL10, IL13 and IL4-receptor, were genotyped or imputed. RESULTS: None of the variant alleles were directly associated with childhood acute lymphoid leukaemia. A medical history of asthma or eczema was reported more often in the control group (OR = 0.7 [0.5-1.0]). This association was mostly seen in the group of children not carrying the IL13-rs20541 variant allele (Interaction Odds Ratio IOR 1.9, p-interaction = 0.07) and in those carrying the IL10 triple variant haplotype (IOR 0.5, p-interaction = 0.04). No interaction was observed with the candidate polymorphisms in IL4 and IL4R. CONCLUSION: This study provides a new insight into the relationship between allergic symptoms and childhood acute lymphoid leukaemia, by suggesting this inverse association could be limited to children carrying certain genetic polymorphisms. If confirmed, these results could help better understand the biological mechanisms involved in the development of childhood acute lymphoid leukaemia.

[Thromboembolic disease in pediatric oncology]. / La maladie thrombo-embolique veineuse en oncologie pédiatrique.

The survival rate of children with cancer is now close to 80 %, as a result of continuous improvement in diagnostic and treatment procedures. Prevention and treatment of treatment-associated complications is now a major challenge. Thromboembolic venous disease, due to multifactorial pathogenesis, is a frequent complication (up to 40 % asymptomatic thrombosis in children with cancer), responsible for significant morbidity. Predominantly in children with acute lymphoblastic leukemia, lymphoma, or sarcoma, thromboembolic disease justifies primary prophylaxis in certain populations at risk, whether genetic or environmental. The curative treatment, well codified, is based on the administration of low-molecular-weight heparin. In the absence of robust pediatric prospective studies, this article proposes a concise decision tree summarizing the preventive and curative strategy.

[Acute methotrexate-related neurotoxicity and pseudo-stroke syndrome]. / Neurotoxicité aiguë secondaire au méthotrexate et « pseudo-stroke ¼ syndrome.

Treatment of acute lymphoblastic leukemia requires high-dose systemic and/or intrathecal methotrexate to prevent and/or treat central nervous system disorders. Acute neurotoxicity of methotrexate, of unknown etiopathogenesis, is characterized by the polymorphism of clinical manifestations, responsible for a potentially harmful diagnostic delay in these immunosuppressed patients. We describe five episodes of transient acute leukoencephalopathy mimicking a stroke, reported in the literature as "pseudo-stroke syndrome". Neurologic symptoms occurred 3-10 days after IV or IT methotrexate and manifested as aphasia and alternating sensorimotor deficit. The fluctuating symptomatology regressed completely within a few days. Brain MRI, which is essential for diagnosis, demonstrated early white matter diffusion restriction in the affected cerebral area. These anomalies disappeared in one week, while hyperintense T2 FLAIR signals developed in the corresponding brain areas. The long-term progression of these pseudo-stroke patients was favorable, without any therapeutic modification. Nevertheless, the involvement of transient acute leukoencephalopathy episodes in the progressive onset of neuro-cognitive disorders is discussed.

[First requests for a regional pediatric palliative care team: A prospective and observational study]. / Recours initial à une équipe régionale ressource de soins palliatifs pédiatriques : étude observationnelle prospective.

INTRODUCTION: In France, 26 regional pediatric palliative care teams (ERRSPP) were created between 2008 and 2012. We conducted the first prospective French study to describe the main specifications of the initial contact with an ERRSPP and to analyze the responses given. DESIGN AND METHODS: All the requests for interventions on the part of the ERRSPP were collected between September 2013 and September 2014. We prospectively completed a questionnaire on the patient's clinical and demographic data (age, sex, disease), details regarding the request (type of applicant, unit's specialty, request pattern), and the answers provided (interval between diagnosis and request, duration of care by ERRSPP, death, changes compared to the initial request). The diseases were classified within one of the six groups of palliative pediatric care diseases, based on the standards of the Canadian palliative care association. RESULTS: We gathered 67 requests, 61 relating to patients. The median age at the request was 49.8 months (range: 2.3-145). The original pattern was multiple: multidisciplinary decision-making (42 %), coordination of care (34 %), symptom management (21 %), logistic support for home care (19 %), education (9 %) and case discussion (6 %). Requests concerning multidisciplinary decision-making were predominant within the neonatal period (61 %); coordination of care was significant for children and adolescents (78 % after 4 years of age). The study of the median time from diagnosis to request compared to the groups of diseases revealed a short time in group 5 (neonatology: 0.36 months) and a long time in group 4 (irreversible and nonscalable diseases: 54.6 months) (P<0.001). At the end of the study, the follow-up of 50.8 % of the patients by ERRSPP was still going on (median duration of care by the ERRSPP of Languedoc-Roussillon region [ERRSPP-LR], 3.4 months [range: 0.2-5.5]). No request was formulated by a general practitioner. CONCLUSION: This study shows the heterogeneity of the initial contact made with an ERRSPP, confirming its different assignments and the need for a multidisciplinary team. The ERRSPP's answer was expanded in half of the cases, attesting to the changing needs over time.

Prevalence and risk factors of iron overload after hematopoietic stem cell transplantation for childhood acute leukemia: a LEA study.

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l'Enfant et de l'Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2-47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73-15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63-10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47-7.13), allogeneic graft (OR=4.34, 95% CI: 2.07-9.12 for alternative donors and OR=2.53, 95% CI: 1.2-5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09-5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

[Septic shock following platelet transfusion contaminated with Citrobacter koseri in a child with postchemotherapy febrile neutropenia]. / Choc septique après transfusion d'un concentré plaquettaire contaminé par Citrobacter koseri chez une patiente en aplasie fébrile post-chimiothérapie.

The bacterial transfusion risk is currently the greatest infectious risk of blood transfusion. We report the case of a child with postchemotherapy febrile neutropenia who presented septic shock following platelet transfusion contaminated with Citrobacter koseri. The life-threatening development could have been avoided by strict compliance with good clinical practice. The stability of mortality rates due to adverse effects of bacterial proliferation during platelet transfusions in France since 1994 calls for optimization of all preventive measures throughout the transfusion chain and perfect knowledge of transfusion rules by medical staff and care givers.

Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute childhood leukemia: an LEA study.

We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis.

IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.

The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.

Achromobacter bacteraemia outbreak in a paediatric onco-haematology department related to strain with high surviving ability in contaminated disinfectant atomizers.

BACKGROUND: Achromobacter spp. are Gram-negative bacilli from aqueous environments, occasionally involved in bacteraemia in immunocompromised hosts and in outbreaks. AIM: We describe the characteristics of an achromobacter bacteraemia outbreak in a paediatric onco-haematology department. METHODS: Throughout a one-year period, 16 blood cultures from seven patients were positive for Achromobacter sp. All patients were immunocompromised, febrile, and central venous catheter (CVC) holders. A microbiological study was performed in patients' rooms, completed with an analysis of the disinfectant atomizers (didecyl diammonium chloride 0.25%, Surfanios, DMA). In total, 41 clinical and environmental strains were analysed by enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR), repetitive PCR, and random amplified polymorphic DNA (RAPD)-PCR, and pulsed-field gel electrophoresis (PFGE). The bactericidal activity of DMA was studied on two Achromobacter sp. representative strains and one Pseudomonas aeruginosa reference strain, comparing biofilm and planktonic growth models. FINDINGS: The seven patients, including two severe cases, were successfully treated by systemic antimicrobial therapy and/or catheter removal. The 25 environmental isolates were recovered with the following chronology: hospital filtered tap water, disinfectant atomizers, and patients' rooms. All environmental, patient, and atomizer strains had identical PCR and PFGE patterns. The disinfectant susceptibility assay revealed that the strain isolated from the atomizers had high survival abilities in biofilm conditions and remained resistant to DMA after short contact periods. CONCLUSION: The use of disinfectant atomizers associated with the survival of Achromobacter in the atomizer pipes may explain the contamination and colonization of the CVC. Control measures (non-atomizer containers and use of sterile water) allowed the eradication of the source and the outbreak control.

Radiofrequency ablation of metastases from osteosarcoma in patients under 25 years: the SCFE experience.

BACKGROUND: Radiofrequency ablation (RFA) has demonstrated its effectiveness in controlling metastases measuring less than 3 cm in several adult malignancies but not yet in osteosarcoma. We report our experience of RFA in the treatment of metastases in adolescents and young adults (AYA) with osteosarcoma. PROCEDURE: Sixteen patients treated for osteosarcoma in French Society of Childhood Cancer centers had undergone an RFA procedure between 2006 and 2012. RESULTS: Thirteen sessions were performed in 10 patients to treat 22 lung metastases. Seven patients were in complete remission at last follow up (range 19-51 months; median, 24 months after RFA). None had a recurrence at RFA sites. We report three cases each of hemoptysis and pneumothorax. Eight sessions were performed in seven patients to treat bone lesions. PROCEDURE was intended as: curative for a small metastatic lesion (n = 3, all in remission more than 3 years after); local control of small bone lesions in multi-metastatic diseases (n = 3); analgesia (n = 1). Complications included one first-degree burn, one fracture, and one soft tissue infection. CONCLUSIONS: RFA is feasible in AYA with osteosarcoma. It efficiently achieved local control of small peripheral lung metastases. Its role in the curative care of small secondary bone lesions remains to be confirmed.

[Infant rhabdoid tumors: a diagnostic emergency]. / Tumeurs rhabdoïdes du nourrisson : une urgence diagnostique.

Rhabdoid tumors are a heterogeneous family of aggressive tumors affecting young children. Their grouping within a single entity is recent, following the discovery of a bi-allelic inactivation of the hSNF5/INI1 tumor suppressor gene in tumoral cells. This bi-allelic inactivation of the hSNF5/INI1 gene found at the constitutional level in up to one-third of cases has led to the identification of a predisposal syndrome to rhabdoid tumors. Herein we report extrarenal rhabdoid tumors observed in three infants between 3 and 6 months of age, underlining the misleading feature of the clinical presentation and the aggressiveness of the disease. Finally, we also report the genetic patient care management strategy.

Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.

The purpose of this multicenter study was to compare the long-term impact of a preparative regimen with either BUBU or TBI on health status and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic SCT (HSCT). Two-hundred and forty patients were included. Sixty-six had received BU, while 174 had received TBI. Median follow-up from HSCT was 10.1 years. Multivariate analyses were performed to assess the occurrence of late effects according to treatment. QoL was assessed in 130 adults using SF-36 questionnaires. Patients developed fewer late complications after BU (2.35 vs 3.01, P=0.03) while the risk to present with at least one complication was equivalent in both groups (87.9% after BU and 93.1% after TBI, P=0.66). Detailed multivariate analyses revealed a lower risk of height growth failure (OR=0.2), cataract (OR=0.1) and iron overload (OR=0.2) after BU, and an increased risk of overweight (OR=3.9) and alopecia (OR=11.2). SF-36 mental and physical composite scores were similar in both treatment groups and proved significantly lower than French norms. Late effects induced by BU might differ from those experienced after TBI. Although less frequent, they are still of considerable importance and may affect patients' QoL.

[Genetic predisposition to childhood cancer]. / Oncogénétique en oncopédiatrie.

Tumor predisposition in children is rare, accounting for approximately 10% of all cancers in childhood. Tumor predisposition involves very rare tumors such as pleuropulmonary blastoma, adrenocortical carcinoma, hepatoblastoma, rhabdoid tumors, optic pathway glioma, as well as rare tumors such as retinoblastoma, medulloblastoma, nephroblastoma, or more frequent tumors such as sarcomas, neuroblastoma, and leukemias. The identification of these predispositions is important for improved management for both the child and relatives. Prenatal and preimplantation genetic diagnosis are options that could be considered for young parents in a perspective of future pregnancies. This manuscript describes the main tumor predispositions in childhood. From each histological subtype, the different diagnosis directions are discussed in view of these main tumor predispositions.