Conservative management of congenital hepatic hemangioma complicated by ascites.

Involution of a rapidly involuting congenital hemangioma is an unknown cause of neonatal ascites. As involution phase is completed by 14 months after birth, conservative management with diuretics and drainage is possible and may avoid surgical resection.

Diagnostic Accuracy of a Reduced Immunohistochemical Panel in Medulloblastoma Molecular Subtyping, Correlated to DNA-methylation Analysis.

Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and ß-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate ß-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and ß-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations.

Prognostic Clinical and Biologic Features for Overall Survival after Relapse in Childhood Medulloblastoma.

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4-12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2-87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.

Role of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children.

BACKGROUND: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed. METHODS: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups. RESULTS: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up). CONCLUSION: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival. KEY POINTS: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.

Automated RBC exchange compared to manual exchange transfusion for children with sickle cell disease is cost-effective and reduces iron overload.

BACKGROUND: Chronic transfusion in sickle cell disease (SCD) remains the gold standard therapy for stroke prevention and for patients with severe disease despite adequate hydroxyurea treatment. The aim of our study was to assess the safety and efficacy of automated red blood cell exchange (aRBX) in patients with SCD previously treated with manual exchange transfusion (MET). Costs related to transfusion and chelation overtime were evaluated. STUDY DESIGN AND METHODS: Beginning in January 2012, children with SCD who weighed 30 kg or more on MET could switch to aRBX. Clinical, biological, and procedures' data, including costs, were recorded for the last 6 months on MET and compared to those after the first and the second year on aRBX. RESULTS: Ten patients switched from MET to aRBX at a median age of 11.8 years. After the switch, median hemoglobin S (HbS) increased significantly (33.5% on MET compared to 45% on aRBX; p < 0.001) but remained in the target values for all patients. Median ferritin decreased significantly (663.3 µg/L on MET compared to 126.8 µg/L on aRBX; p < 0.001) and intervals between procedures were significantly longer. The requirements of red blood cells (RBCs)/kg/year were not different on MET (0.88 unit/kg/year) than during the second year on aRBX (1.07 unit/kg/year; p = NS). MET costs were similar compared to aRBX since chelation was stopped in previously treated patients. CONCLUSION: Erythrocytapheresis reduces iron overload and allows a longer interval between procedures without a higher RBC requirement from the second year on aRBX. The cost did not increase as estimated in our Belgian Health Care System.

Neonatal screening improves sickle cell disease clinical outcome in Belgium.

Objectives To compare the outcomes of sickle cell disease patients diagnosed through neonatal screening with those who were not. Methods In an observational multicenter study in Belgium, 167 screened and 93 unscreened sickle cell disease patients were analyzed for a total of 1116 and 958 patient-years of follow-up, respectively. Both groups were compared with propensity score analysis, with patients matched on three covariates (gender, genotype, and central Africa origin). Bonferroni correction was applied for all comparisons. Results Kaplan-Meier estimates of survival without bacteremia were significantly higher in the screened group than the unscreened group (94.47%; [95% CI, 88.64-97.36%] versus 83.78% [95% CI, 72.27-90.42%]), p = 0.032. Non-significant differences between both groups were reported for survival without acute chest syndrome, acute anemia, cerebral complication, severe infection, and vaso-occlusive crisis. Significantly lower hospitalization rate and days per 100 patient-years were observed in the screened compared with the unscreened group (0.27 vs. 0.63 and 1.25 vs. 2.82, p = 0.0006 and <0.0001). Conclusion These data confirm the benefit of a neonatal screening programme in reducing bacteremia and hospitalization.

Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis.

Background: Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods: We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results: Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion: Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.

NUT carcinoma in children and adults: A multicenter retrospective study.

BACKGROUND: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor defined by the presence of NUT rearrangement with a poor prognosis. This rare cancer is underdiagnosed and poorly treated. OBJECTIVE: The primary objective of this study was to describe the clinical, radiologic, and biological features of NUT carcinoma. The secondary objective was to describe the various treatments and assess their efficacy. METHODS: This retrospective multicenter study was based on review of the medical records of children and adults with NUT carcinoma with specific rearrangement or positive anti-NUT nuclear staining (>50%). RESULTS: This series of 12 patients had a median age of 18.1 years (ranges: 12.3-49.7 years). The primary tumor was located in the chest in eight patients, the head and neck in three patients, and one patient had a multifocal tumor. Nine patients presented regional lymph node involvement and eight distant metastases. One-half of patients were initially misdiagnosed. Specific NUT antibody was positive in all cases tested. A transient response to chemotherapy was observed in four of 11 patients. Only two patients were treated by surgery and five received radiotherapy with curative intent. At the end of follow-up, only one patient was still in remission more than 12 years after the diagnosis. Median overall survival was 4.7 months (95% confidence interval [CI]: 2.1-17.7). CONCLUSION: NUT carcinoma is an aggressive disease refractory to conventional therapy. Early diagnosis by NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma to identify the specific rearrangement of NUT gene is useful to propose the optimal therapeutic strategy.

Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study.

BACKGROUND: Asparaginase (Asp) and corticosteroid (CS) treatment in patients with acute lymphoblastic leukaemia (ALL) is associated with an increased risk of thrombotic events. OBJECTIVE: Characterization of global haemostatic phenotypes of patients with ALL during Asp therapy. PROCEDURE: Thrombin generation (TG) was monitored in platelet-poor plasma of 56 children treated for a B lineage ALL (36 with native, 20 with PEG Asp) using 1 pM tissue factor and 4 µM phospholipids, with and without thrombomodulin. Protein C activity (PC), free protein S (PS), antithrombin (AT) and fibrinogen levels were also measured. RESULTS: Elevated endogenous thrombin potential (ETP) and peak of TG were noted at diagnosis, throughout the Induction phase and Late Intensification but was significantly less for PEG than for native Asp (P < 0.001), while age, sex, type of corticosteroid during Induction and molecular response had no significant effect. The reduction of ETP after addition of thrombomodulin was significantly lower in ALL children compared with that in controls, suggesting impairment in PS/PC pathway. Three patients experienced thrombosis: two treated with native and one with PEG Asp. The two patients with native Asp had, at the time of thrombosis, a prothrombotic profile. CONCLUSIONS: Treatment with Asp, in combination with CS, enhances TG in children with ALL, more significantly with native than PEG Asp, which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This is consistent with the high incidence of thrombotic events described during these phases of therapy. The less pronounced effect of PEG Asp remains to be elucidated.

Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

OBJECTIVE: To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease-modifying treatments (DMT). METHOD: The Registry created in 2008 included patients of eight centers. All available data in 2008 were retrospectively encoded in the database. After 2008 and until 2012, all data were recorded prospectively for already registered patients as well as newly diagnosed subjects. Data were registered from neonatal screening or from diagnosis (first contact) until last follow-up or death. Data included diagnosis, demography, and outcome data. RESULTS: We collected data from 469 patients over a 5,110 patient years (PY) follow-up period. The global mortality rate was low (0.25/100 PY), although 13 patients died (2.8%) and was similar between children, adolescents (10-18 years), and young adults (P = 0.76). Out of the cohort, 185 patients received hydroxyurea at last follow-up (median duration of treatment: 10.3 years), 90 underwent hematopoietic stem cell transplantation (HSCT), 24 were chronically transfused, and 170 had never had any DMT. Hydroxyurea showed significant benefit on patients outcome as reflected by a lower mortality rate compared to transplanted individuals or people without DMT (0.14, 0.36, and 0.38 per 100 PY, respectively) and by higher Kaplan-Meier estimates of 15 year survival (99.4%) compared to HSCT (93.8%; P = 0.01) or no DMT groups (95.4%; P = 0.04). CONCLUSION: SCD mortality in Belgium is low with no increase observed in young adults. Patients treated with hydroxyurea demonstrate a significant benefit in survival when compared to those without DMT or transplanted.

A pilot study of manual chronic partial exchange transfusion in children with sickle disease.

Objective Red cell exchange transfusion is frequently used in the management of patients with sickle cell disease (SCD) either electively or chronically to maintain hemoglobin S (HbS) <30%. The purpose of this retrospective study was to evaluate the results of manual chronic partial exchange transfusion (MCPET) on level of Hb and HbS, on iron load and on the need for chelation, on risk of immunization, monitoring transfusion-transmitted viral infection, and clinical outcome. Methods We reviewed the long-term effect of MCPET in 10 children (six men and four women) with SCD and evaluated the iron balance during a median follow-up of 20 months (range: 6-36) in which 248 exchanges were performed. Results The pre-exchange median Hb value was 9.5 g/dl (range: 7.7-10.9 g/dl) and the median post-exchange value was 9.4 g/dl (range: 8.4-11.1 g/dl).The majority of patients reached an HbS of <50% with a median HbS value of 40.04% (range: 30-54). At start of the MCPET program, the median ferritin was 439 ng/ml (range: 80-1704 ng/ml). In the final evaluation, the median value of ferritin was 531 ng/ml (range: 84-3840 ng/ml). The annual calculated iron balance was 0. 28 ± 0.08 mg/kg/day. MCPET was well tolerated, and adverse effects were limited. Discussion MCPET in children with SCD is safe to prevent iron overload, and is effective and easy to use in our cohort. Conclusion Indication for chronic exchange blood transfusion is essential for patients with SCD with recurrent and frequent crises who do not respond to hydroxyurea. However, there is no consensual study for the period at which chronic transfusion can safely be stopped and further research in large population of patients with SCD will need to clarify this question.

Is Pica under-reported in children with sickle cell disease? A pilot study in a Belgian cohort.

BACKGROUND: For centuries, writers have recorded their observations on pica. Nevertheless the association of pica with sickle cell disease (SCD) was poorly documented. METHODS: Cross-sectional evaluation performed on SCD children and caregivers attending the outpatient clinic who were invited to complete questionnaires assessing behavior of pica. RESULTS: Out of 55 sickle cell children, 31(56.4%) reported practicing pica regularly. Substances ingested by patients covered a broad spectrum. Compared with the non-pica group, subjects who reported pica were younger and had lower hemoglobin (8.3 g/dl (7.6-9.7) vs. 9.1 g/dl (7.9-10.5): P < 0.01). The level of ferritin, zinc, copper, and lead was similar between the pica and non-pica groups (P > 0.05). Discussion In this series, there are many substances consumed by SCD children and adolescents, and we did not find an occurrence of similar substances among this select group. Pica children were younger and more anemic than non-pica patients. CONCLUSION: This study suggests that pica remains an unknown and under-reported clinical problem in children with SCD and seems to be related to the severity of anemia. The next step of this project aims to clarify causal mechanisms for pica and its association with SCD in a larger population.

Reduction of the six-minute walk distance in children with sickle cell disease is correlated with silent infarct: results from a cross-sectional evaluation in a single center in Belgium.

BACKGROUND: The 6-minute walk test (6 MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity. METHODS: We analyzed factors affecting the 6 MWT in 46 Sickle Cell Disease children. Forty-two were treated with hydroxyurea (HU). Patients with normal test (>80% of the age-standardized predicted value) were compared to patients with abnormal test (≤ 80%). Baseline hematological values, clinical events, cerebrovascular disease, cardio-pulmonary parameters and disease-modifying treatment were compared according to the performance of the test. RESULTS: Among the 46 patients, 14 had an abnormal 6 MWT. In univariate analysis, both groups were similar for biological and clinical data. Six of the 14 patients with an abnormal 6 MWT had silent infarct (SI) compared to 6/32 with a normal test (P = 0.09). When excluding chronically transfused patients, 4 of the 11 patients with an abnormal 6 MWT had SI compared to 1/26 (P = 0.02). Baseline pulse oximetry was normal in both groups but slightly lower in patients with abnormal 6 MWT (P = 0.02). No patient presented exercise-induced desaturation. In multivariate analysis, the only factor associated with abnormal 6 MWT was the presence of SI (P = 0.045). CONCLUSIONS: In our cohort of 46 patients characterized by high exposure rate to HU and by the absence of severe cardiopulmonary disease, the sole factor independently associated with 6 MWT was the presence of SI. The lower exercise capacity of children with SI may reflect some subclinical neurological impairment as they do not differ by hemoglobin level or cardiopulmonary parameters.

Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients.

Despite improvements in medical management, sickle cell disease (SCD) remains associated with severe morbidity and decreased survival. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative approach. We report the outcome of 50 consecutive children with severe SCD that received HSCT in our unit between November 1988 and April 2013. The stem cell source was bone marrow (n = 39), cord blood (n = 3), bone marrow and cord blood (n = 7) and peripheral blood stem cells (n = 1). All patients had ≥1 severe manifestation: 37 presented with recurrent vaso-occlusive crises/acute chest syndrome, 27 cerebral vasculopathy and 1 nephropathy. The conditioning regimen consisted of busulfan + cyclophosphamide (BuCy) before November 1991 and BuCy + rabbit antithymocyte globulin after that date. Since 1995, all patients have been treated with hydroxycarbamide (HC) prior to transplantation for a median duration of 2·7 years. Median age at transplantation and median follow-up was 8·3 and 7·7 years, respectively. Acute graft-versus-host disease (GVHD) and chronic GVHD were observed in 11 and 10 patients, respectively. An excellent outcome was achieved, with 8-year overall survival and event-free survival (EFS) rates of 94·1% and 85·6%, respectively. Since HC introduction, no graft failure occurred and EFS reached 97·4%. Prior treatment with HC may have contributed to successful engraftment.

Transient leukemia in a newborn without Down syndrome: case report and review of the literature.

UNLABELLED: Transient neonatal leukemia occurs almost exclusively in Down syndrome babies. We report here the unusual case of a newborn without Down syndrome who presented neonatal transient leukemia and who achieved spontaneously complete remission. Trisomy 21 and GATA1 mutation were both present in leukemic cells. While close follow-up is advised since true leukemia may develop later, the patient is still in remission for 2.5 years. We performed a literature review of 15 other similar cases. CONCLUSION: Our case of transient leukemia without Down syndrome and the literature review highlight the important role of trisomy 21 and GATA1 mutation in the development of transient neonatal leukemia.

Vitamin B12 deficiency in a 9-month-old boy.

UNLABELLED: We present a 9-month-old boy with megaloblastic anaemia, neutropenia and hypogammaglobulinaemia due to vitamin B12 deficiency. The deficiency was secondary to prolonged exclusive breastfeeding with inadequate nutritional amounts of vitamin B12 from the mother. There were no clinical or biological signs of maternal anaemia or macrocytosis. Treatment with oral vitamin B12 rapidly improved the biological findings of the child. Vitamin B12 deficiency should be considered in infants older than 2 months presenting with failure to thrive, neurocognitive retardation or even pancytopenia and hypogammaglobulinaemia, even in the absence of any signs of maternal anaemia or macrocytosis. Therefore, evaluation of vitamin B12 status during pregnancy and lactation is necessary in order to prevent B12 deficiency and its possible long-term effects in infants. CONCLUSION: Further studies should be conducted to evaluate the optimal oral dosage of vitamin B12 in children since limited data on the use of oral B12 substitution are available.

QTc interval prolongation and QTc dispersion in children and adolescents with type 1 diabetes.

OBJECTIVES: To evaluate whether QT interval, QT interval corrected for heart rate (QTc), and QTc dispersion changes are already present in children and adolescents with diabetes. STUDY DESIGN: QT interval, QTc, and QTc dispersion were measured on a 12-lead surface electrocardiogram in 60 children and adolescents with stable type 1 diabetes and in 63 sex- and age-matched control subjects. Differences were evaluated by using the Kolmogorov-Smirnov Z test. The number of patients with QTc > 440 ms was compared in the two groups. The possible influence of age, sex, diabetes duration, and glycosylated hemoglobin (HbA(1c)) was examined by using Spearman correlation analysis. RESULTS: Diabetic children had significantly longer QTc intervals and a significantly larger QTc dispersion. The number of individuals with a QTc >440 ms was significantly higher in the diabetic group (14/60) than in the control group (2/63). The effect of age on R-R interval and QTc dispersion in healthy children was less pronounced in children with diabetes. HbA(1C) values did not significantly correlate with any of the parameters. CONCLUSIONS: QTc prolongation and a larger QTc dispersion are already present in a significant proportion of children and adolescents with diabetes.