Long-term neurotoxicity among childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC Children Leukemia Group studies.

Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15-22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971-1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10-17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).

[Pediatric refractory acute immune thrombocytopenic purpura secondary to asymptomatic SARS-CoV2]. / Face à la COVID-19. Purpura thrombopénique immunologique pédiatrique réfractaire secondaire à une infection asymptomatique à SARS-CoV2.

Acute immune thrombocytopenic purpura (ITP) has been revealed as an uncommon complication of COVID-19 in children. Severe bleeding may occur but is rarely life threatening. Management is based on the severity of bleeding symptoms and the degree of thrombocytopenia. We report the case of a 7-year-old girl with severe acute ITP secondary to a COVID-19 infection -without any respiratory symptoms. The initial clinical examination showed a large bulging mediodorsal hematoma, purpuric lesions, and posterior pharyngeal hemorrhage. The patient was monitored in a pediatric intensive care unit. Initial medical management consisted of intravenous immunoglobulins and systemic steroids. Despite this treatment, bleeding and thrombocytopenia worsened, and secondary macroscopic haematuria occurred, requiring 6-hourly platelet transfusions and increased steroid doses to obtain sufficient hemostasis. This case presents a rare and severe acute pediatric ITP secondary to asymptomatic SARS-COV2 which was refractory to initial management and opens the discussion to second line therapeutic interventions.

Le purpura thrombopénique immunologique aigu (PTI) s'est révélé comme une complication inhabituelle de la COVID-19 en pédiatrie. Une hémorragie sévère peut survenir, mais constitue rarement une menace vitale. La prise en charge dépend de la sévérité des signes hémorragiques et du niveau de la thrombopénie. Nous rapportons le cas clinique d'une enfant de 7 ans avec diagnostic de PTI sévère aigu secondaire à la COVID-19, sans symptôme respiratoire. L'examen clinique initial mettait en évidence un large hématome médiodorsal bombant, des lésions purpuriques, ainsi qu'un saignement pharyngé postérieur. Une surveillance en unité de soins intensifs avec administration d'immunoglobulines intraveineuses et de corticoïdes systémiques a été initiée. Malgré la thérapeutique, les saignements se sont intensifiés, avec apparition secondaire d'une hématurie macroscopique justifiant la réalisation de transfusions plaquettaires continues et la majoration des doses de corticoïdes jusqu'à l'obtention de l'hémostase. Ce cas clinique relate un cas rare et sévère de PTI aigu pédiatrique secondaire à une infection à SARS-COV2 réfractaire au traitement habituel et ouvre la discussion aux thérapeutiques de deuxième ligne.

Socio-economic outcomes among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: Results of the 58LAE study.

OBJECTIVE: The objective of this study is to evaluate the socio-economic outcomes of survivors of childhood acute lymphoblastic leukaemia (ALL). METHODS: Childhood ALL adult survivors, enrolled in EORTC trials between 1971 and 1998 in France and Belgium, were invited to fill out a questionnaire with information about their socio-economic situation (living with a partner, having a university degree, having a job, working part time and history of having a paid job). The outcomes were compared with two matched control populations. RESULTS: Among 1418 eligible patients, 507 (35.8%) participated, including 39 (8%) and 61 (12%) patients who received a haematopoietic stem cell transplantation (HSCT) and a cranial radiotherapy (CRT), respectively. The median time to follow-up was 20 years, and median age was 25 years. Survivors showed a socio-economic level at least as good as controls. HCST and CRT were associated with a higher probability of not obtaining a bachelor degree (respectively OR = 3.49, 95% CI: 1.46-8.35 and OR = 2.31, 95% CI: 1.04-5.15), HSCT was associated with unemployment (OR = 2.89, 95% CI: 1.09-7.65) and having a relapse was associated with a higher probability of not having a partner (OR = 1.88, 95% CI: 1.01-3.51) adjusting for confounders. CONCLUSION: Childhood ALL survivors showed a high level of socio-economic participation. HCST and CRT were associated with poorer functioning.

Quality of life of long-term childhood acute lymphoblastic leukemia survivors: Comparison with healthy controls.

OBJECTIVE: Improved treatment landscape has led to better outcomes for paediatric acute lymphoblastic leukemia (ALL) survivors. As the number of survivors increase, we need to elucidate the long-term quality of life (QoL) and domains of complaints in these patients. Furthermore, the main priorities of these patients need to be clarified. We assessed long-term QoL outcomes of survivors of childhood ALL compared to matched population controls. METHODS: QoL data were collected from survivors recruited in France and Belgium between 2012 and 2017, including the Short Form Health Survey (SF-12) and the Quality of Life Systemic Inventory (QLSI). The Wilcoxon test was used to compare SF-12 scale scores between survivors and matched population controls. For the QLSI, comparisons were mainly descriptive. RESULTS: One hundred and eighty-six survivors (mean age: 27.6 years; range: 18.1-52.8) at follow-up completed QoL measures, amongst whom 180 were matched to controls. Overall, survivors had higher QoL on all SF12 scale scores, indicating that they had better functioning compared to controls. Statistically significant differences on the SF12 were observed for Vitality, Social Functioning, Role Limitations due to Emotional Problems and Mental Health scales. QLSI outcomes suggested that survivors were happier than controls with Couple and Social Relations. Controls were unhappiest compared to survivors with Money, Love life, Self-esteem, Nutrition and Paid Work. CONCLUSIONS: Our findings suggest that survivors of childhood ALL have better QoL outcomes on some domains compared to the general population, specifically around social and emotional functioning, and that they tend to prioritize their relationships more. Interventions for improving QoL outcomes, might build on existing positive experiences with family, friends and partners.

Pairing parents and offspring's HemoTypeSC Test to validate results and confirm sickle cell pedigree: a case study in Kisangani, the Democratic Republic of the Congo.

OBJECTIVES: HemoTypeSCTM is one of the immunoassay methods currently used for the early diagnosis of Sickle Cell Disease (SCD) in newborns. Earlier diagnosis remains the key strategy for early preventive care needs and parents' education about the child's future well-being throughout his life. Before considering these children as sick and aligning them for regular medical monitoring, it may be valuable to confirm the HemoTypeSC result with a secondary laboratory testing method. In resource-limited settings, where confirmatory methods are not always available, we propose testing the parents to validate the HemoTypeSC result. METHODS: This study explored this approach in the city of Kisangani. It was a prospective diagnostic accuracy study using genotype biological parents to evaluate HemoTypeSC's performance in the newborn. RESULTS: Fifty-eight children born to 46 known mothers, and 37 known fathers, have been tested. The phenotyping showed that 41 (70.7%) children were SS, whose 37 were born to a couple AS/AS and 4 to a couple AS/xx. Of the 41 SS children, 8 (19.5%) were newborns and 33 (80.4%) were children; 12 (20.6%) children were AS, one of whom was born to a couple SS/AA and 11 to a couple AA/SS; 5 (8.6%) children were AA. In this population, the probability of offspring born to AS/AS parents being SS rather than AS is high (odds, 1.25). No statistical difference was observed between girls and boys. The pedigree of all 58 children has been confirmed. CONCLUSION: We demonstrated that testing biological parents with HemoTypeSC is a reliable confirmatory method for newborn screening but it presents some limitations discussed in the present article.

Immunoglobulin Heavy Chain High-Throughput Sequencing in Pediatric B-Precursor Acute Lymphoblastic Leukemia: Is the Clonality of the Disease at Diagnosis Related to Its Prognosis?

High-throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH) locus is a recent very efficient technique to monitor minimal residual disease of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It also reveals the sequences of clonal rearrangements, therefore, the multiclonal structure, of BCP-ALL. In this study, we performed IgH HTS on the diagnostic bone marrow of 105 children treated between 2004 and 2008 in Belgium for BCP-ALL in the European Organization for Research and Treatment of Cancer (EORTC)-58951 clinical trial. Patients were included irrespectively of their outcome. We described the patterns of clonal complexity at diagnosis and investigated its association with patients' characteristics. Two indicators of clonal complexity were used, namely, the number of foster clones, described as clones with similar D-N2-J rearrangements but other V-rearrangement and N1-joining, and the maximum across all foster clones of the number of evolved clones from one foster clone. The maximum number of evolved clones was significantly higher in patients with t(12;21)/ETV6:RUNX1. A lower number of foster clones was associated with a higher risk group after prephase and t(12;21)/ETV6:RUNX1 genetic type. This study observes that clonal complexity as accessed by IgH HTS is linked to prognostic factors in childhood BCP-ALL, suggesting that it may be a useful diagnostic tool for BCP-ALL status and prognosis.

Deciphering the Non-Coding RNA Landscape of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (pedAML) is a heterogeneous blood cancer that affects children. Although survival rates have significantly improved over the past few decades, 20-30% of children will succumb due to treatment-related toxicity or relapse. The molecular characterization of the leukemic stem cell, shown to be responsible for relapse, is needed to improve treatment options and survival. Recently, it has become clear that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a role in the development of human diseases, including pediatric cancer. Nevertheless, non-coding RNA expression data in pedAML are scarce. Here, we explored lncRNA (n = 30,168) and miRNA (n = 627) expression in pedAML subpopulations (leukemic stem cells (LSCs) and leukemic blasts (L-blasts)) and their normal counterparts (hematopoietic stem cells and control myeloblasts). The potential regulatory activity of differentially expressed lncRNAs in LSCs (unique or shared with the L-blast comparison) on miRNAs was assessed. Moreover, pre-ranked gene set enrichment analyses of (anti-) correlated protein-coding genes were performed to predict the functional relevance of the differentially upregulated lncRNAs in LSCs (unique or shared with the L-blast comparison). In conclusion, this study provides a catalog of non-coding RNAs with a potential role in the pathogenesis of pedAML, paving the way for further translational research studies.

Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report.

We report a case of severe pancytopenia in a 15-year-old patient due to a severe deficiency in vitamin B12 and folic acid, probably of nutritional origin. The clinical and biological course was favorable after vitamin supplementation. With this case, we discuss the diagnostic approach of pancytopenia with megaloblastic anemia in children and adolescents, as well as the mechanisms involved in vitamin B12 and B9 deficiency. Hypovitaminosis B12 is known in its severe form but its diagnosis is often made difficult by insidious signs and symptoms. Traditional intramuscular replacement therapy has now proven to be effective orally. The clinical manifestations of folic acid deficiency are relatively similar to those of vitamin B12 deficiency, reflecting their intricate co-enzymatic functions. Its supplementation is administered orally.

Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.

STUDY QUESTION: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors? SUMMARY ANSWER: We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors. WHAT IS KNOWN ALREADY: Survival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies. STUDY DESIGN, SIZE, DURATION: Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046). LIMITATIONS, REASONS FOR CAUTION: The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls. WIDER IMPLICATIONS OF THE FINDINGS: Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors. STUDY FUNDING/COMPETING INTEREST(S): This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared. TRIAL REGISTRATION NUMBER: NCT01298388 (clinicaltrials.gov).

Validation of a PCR-Based Next-Generation Sequencing Approach for the Detection and Quantification of Minimal Residual Disease in Acute Lymphoblastic Leukemia and Multiple Myeloma Using gBlocks as Calibrators.

Detection of minimal residual disease (MRD) to guide therapy has been a standard practice in treatment of childhood acute lymphoblastic leukemia (ALL) for decades. In multiple myeloma (MM), a clear correlation is found between absence of MRD and longer survival. Quantitative allele-specific oligonucleotide (qASO)-PCR is the standard molecular method for MRD detection in these hematologic malignant tumors. However, this technique has some drawbacks that can be overcome by next-generation sequencing (NGS). In this study, NGS is validated as an alternative method for qASO-PCR for MRD detection in both ALL and MM. MRD results obtained by NGS and qASO-PCR were compared in 59 and 39 bone marrow samples of 33 and 14 patients with ALL and MM, respectively. Our results indicate that the use of gBlocks as calibrators makes the NGS approach a powerful tool to quantify MRD. With an input of 400 ng of DNA (corresponding to approximately 7 × 104 cells), a limit of detection of 0.01% can be achieved. The specificity of the NGS-MRD technique was 100%, and a correlation with qASO-PCR for quantifiable MRD results of 0.93 and 0.91 was found in ALL and MM, respectively. Especially for MM, the higher applicability (100%) of the NGS-MRD protocol, compared with qASO-PCR (57%), was clearly demonstrated. These results demonstrate that NGS is an even better alternative to qASO-PCR.

Sociodemographic and Medical Determinants of Quality of Life in Long-Term Childhood Acute Lymphoblastic Leukemia Survivors Enrolled in EORTC CLG Studies.

BACKGROUND: due to increasing survival rates in childhood acute lymphoblastic leukemia (ALL), the number of survivors has been expanding. A significant proportion of these survivors can experience long-term emotional and psychosocial problems. However, the exact risk factors remain inconclusive. We investigated potential risk factors for decreased daily life quality and life challenges in long-term childhood ALL survivors enrolled between 1971 and 1998 in EORTC studies. METHODS: self-report questionnaires were collected from 186 survivors (109 females; mean age at diagnosis 5.62 years, range 0.2-14.7; median time since diagnosis of 20.5 years (12.9-41.6)), including the Short-Form Health Survey (SF-12) and Impact of Cancer-Childhood Survivors (IOC-CS). Multivariable linear regression models were used to assess the impact of gender, age at diagnosis, relapse/second neoplasm, National Cancer Institute (NCI) risk group and cranial radiotherapy on 2 subscales of the SF-12 (physical and mental health) and five subscales of the IOC-CS (life challenges, body and health, personal growth, thinking and memory problems and socializing). RESULTS: mental component scores of SF-12 were not significantly associated with any risk factor. Physical component scores were lower in relapsed, irradiated and NCI high-risk patients. Regarding IOC-CS negative impact subscales, life challenges was more negatively impacted by cancer in female, younger (i.e., <6 years) and relapsed patients. Regarding the positive impact scales, personal growth was more positively impacted in relapsed patients, whereas body and health, and socializing, were less positively impacted in these patients, compared to non-relapsed patients. Socializing was more positively impacted in older patients (>6 years). CONCLUSIONS: this study demonstrates that long-term outcomes can be both adverse and positive, depending on the patient's demographic and clinical characteristics. Younger, female, and relapsed patients might encounter more life challenges years after their disease, while physical challenges could occur more often in relapsed and high-risk patients. Finally, the positive effect on socializing in the older patients sheds new light on the importance of peer interactions for this subgroup. Specific individual challenges thus need specialized support for specific subgroups.

Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach.

BACKGROUND: Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers. METHODS: Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis. RESULTS: Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast. CONCLUSION: Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML. IMPACT: Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.

Neonatal Cancer Epidemiology and Outcome: A Retrospective Study.

OBJECTIVE: Our study aimed at describing neonatal cancer incidence, distribution by type, location, outcome, and long-term toxicity, by comparison with tumors occurring later in infancy. METHODS: The authors led a single-center retrospective analysis of 118 cases of tumors diagnosed in the first year of life and compared tumors' types incidence, presentation, location, and outcome according to age group at diagnosis (below or over 28 d of life). RESULTS: The most frequent neonatal tumor types in our series were germ cell tumors, mainly teratoma, followed by neuroblastoma and renal tumors, whereas in children below 1 year of age, brain tumors, neuroblastoma, and leukemia were the most common types. Genetic predisposition syndromes were present in 14% of these infants and antenatal sonography enabled 68% of diagnosis for tumors presenting at birth. Other patients presented with mass syndrome, hydrops, or skin lesions. Six percent of neonates with cancer died from their malignancies, and up to 18% experienced a chronic health condition as a consequence of therapy. CONCLUSIONS: Tumor pattern differs in neonates and infants, with a higher percentage of benign tumors in children below 28 days of life. Yet, long-term therapy-related toxicity is significant in younger patients. Enhancing knowledge of neonatal tumors, their epidemiology, clinical presentation, genetic background, and prognosis should help promote better management and introduce follow-up programs to improve surviving rates and the quality of life of survivors.

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.

Neonatal Screening for Sickle Cell Disease in Belgium for More than 20 Years: An Experience for Comprehensive Care Improvement.

Our previous results reported that compared to sickle cell patients who were not screened at birth, those who benefited from it had a lower incidence of a first bacteremia and a reduced number and days of hospitalizations. In this context, this article reviews the Belgian experience on neonatal screening for sickle cell disease (SCD). It gives an update on the two regional neonatal screening programs for SCD in Belgium and their impact on initiatives to improve clinical care for sickle cell patients. Neonatal screening in Brussels and Liège Regions began in 1994 and 2002, respectively. Compiled results for the 2009 to 2017 period demonstrated a birth prevalence of sickle cell disorder above 1:2000. In parallel, to improve clinical care, (1) a committee of health care providers dedicated to non-malignant hematological diseases has been created within the Belgian Haematology Society; (2) a clinical registry was implemented in 2008 and has been updated in 2018; (3) a plan of action has been proposed to the Belgian national health authority. To date, neonatal screening is not integrated into the respective Belgian regional neonatal screening programs, the ongoing initiatives in Brussels and Liège Regions are not any further funded and better management of the disease through the implementation of specific actions is not yet perceived as a public health priority in Belgium.

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.

Osteopetrosis mimicking juvenile myelomonocytic leukemia.

A 5-month-old boy developed splenomegaly, anemia, thrombocytopenia with elevated white cells, monocytosis and immature granulocytes in the peripheral blood. Bone marrow showed dysplasia without blastosis. Increased colony-forming unit-granulocyte-macrophage was found in the peripheral blood, mimicking granulocyte-macrophage colony-stimulating factor hypersensitivity. These findings fulfilled the diagnosis criteria for juvenile myelomonocytic leukemia (JMML), but no mutations in the CBL, NRAS, KRAS, or PTPN11 genes were detected. In addition to these findings severe hypogammaglobulinemia and elevated alkaline phosphatase were present. Bone X-ray showed dense and radiopaque bones with a bone-in-bone appearance characteristic of infantile malignant osteopetrosis (IMO). Genetic mutation in T-cell, immune regulator 1 (TCIRG1) was identified, confirming the diagnosis of IMO. Careful differential diagnosis including osteopetrosis, is therefore recommended in patients with clinical features and hematologic findings consistent with JMML.

Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years.

Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.