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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.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.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.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.

Simple Summary Long-term quality of life and its potential risk factors in childhood acute lymphoblastic leukemia (ALL) patients remain uncertain. In this cross-sectional study, we investigated daily life quality and life challenges in adult survivors of ALL using multiple self-report questionnaires. Furthermore, risk factors, including gender, age at diagnosis, relapse/second neoplasm, risk group, and cranial radiotherapy, were explored in detail. Younger, female, and relapsed patients appeared to encounter more life challenges, while physical challenges occurred more often in relapsed and high-risk patients. More positive effects on socializing were found in the older patients compared to younger patients. This study provides important information for individual and specialized support. Abstract 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). 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.

BackgroundSudden death is frequent in haemodialysis (HD) patients. Both hyperkalaemia and change of plasma potassium (K) concentrations induced by HD could explain this. The impact of increasing dialysate K by 1 mEq/L on plasma K concentrations and electrocardiogram (ECG) results before and after HD sessions was studied.MethodsPatients with pre-dialysis K >5.5 mEq/L were excluded. ECG and K measurements were obtained before and after the first session of the week for 2 weeks. Then, K in the dialysate was increased (from 1 or 3 to 2 or 4 mEq/L, respectively). Blood and ECG measurements were repeated after 2 weeks of this change.ResultsTwenty-seven prevalent HD patients were included. As expected, a significant decrease in K concentrations was observed after the dialysis session, but this decrease was significantly lower after the switch to an increased dialysate K. The pre-dialysis K concentrations were not different after changing, but post-dialysis K concentrations were higher after switching (P ConclusionsA simple increase of 1 mEq/L of K in the dialysate is associated with a lower risk of hypokalaemia and a lower QT dispersion after the dialysis session. Further study is needed to determine if such a strategy is associated with a lower risk of sudden death.

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2/day) versus prednisolone (60 mg/m2/day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts, SCOPUS: ar.j, info:eu-repo/semantics/published

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, 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).

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.

Introduction: Diffuse intrinsic pontine glioma is a rare disease with a high mortality. Our primary aim was to determine the incidence of this disease in Belgium. Secondly, we wanted to compare the treatment approach of Belgian pediatric oncology centres, to investigate possibilities for improvement. Methods: We retrospectively collected and analysed data on DIPG-patients diagnosed between 1994 and 2018 and recorded in the Belgian Cancer Registry. We included patients ≤ 18 years who were followed in one of the eight Belgian pediatric oncology centres. Results: We included 100 patients. Files were complete in 87 patients. We observed an increase in diagnoses with an incidence of 3.1 per 1,000,000 persons (aged 0–≤ 18) per year over the last 5 years compared to an overall incidence of 1.8. Biopsy was performed at diagnosis in 51.7% of patients. In one fifth this was study-related. Mutation analysis was known in eight patients, of which six showed the H3 K27M-mutation. 58.8% of patients received chemotherapy, without a significant survival benefit. 12.6% of patients were included in a clinical trial. Biopsy rate and the use of chemotherapy differed widely between centres. Mean OS and PFS were 10.49 and 4.87 months respectively. We observed an improved survival over time. Conclusions: Over the past 25 years, we observed an increase of new DIPG-diagnoses. Outcome in our cohort is comparable with literature findings. We demonstrate an important heterogeneity in treatment approach between different centres and limited inclusion in clinical trials. Therefore, collaboration between centres and inclusion of patients in clinical trials is much needed., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Left ventricular (LV) wall thickness is an important parameter for the diagnosis of hypertrophic cardiomyopathy (HCM) and is also associated with long-term clinical outcome in HCM patients. However, conventional tools have failed to analyze the mechanisms of structural and functional abnormalities that occur at the cellular level in hypertrophied myocardial tissue. Recently, technological progression of 2D-speckle tracking echocardiography (2D-STE) has enabled the estimation of layer-specific strain (LSS), such as epicardial, mid-myocardial, and endocardial longitudinal strain, respectively. LSS may have the potential to elucidate the detailed mechanisms of myocardial dysfunction. Purpose The aim of this study was (i) to clarify the detailed mechanisms of structural and functional abnormalities of myocardial tissue in HCM using LSS (ii) to investigate the diagnostic accuracy of LSS for HCM. Methods Forty-one patients with HCM and preserved LV ejection fraction (LVEF) (66% male, 52±18 years, LVEF 62.9±3.7%) and 41 controls matched for age and sex (66% male, 52±20 years, LVEF 63.5±8.2%) underwent 2D-STE (GE-Healthcare, Vivid-E9). Quantitative strain values of epicardial, mid-myocardial, and endocardial layers were measured. Results LV wall thickness including interventricular septum thickness (HCM vs. Controls; 18.9±5.0 vs. 9.1±1.8, p Conclusions In HCM patients with preserved LVEF, (i) LSS was lower and End/Epi ratio was higher than in controls. (ii) End/Epi ratio (≥1.3) was the strongest predictor of abnormal wall thickness of HCM. The mechanism of higher End/Epi ratio in HCM might be attributable to the more common myofibrillar disarray in mid- and epicardial layers. Variations of LSS represented by End/Epi ratio might have the potential to accurately detect HCM and to elucidate the pathophysiology of impaired LV wall motion at cellular level in HCM. Funding Acknowledgement Type of funding source: None

Both in adult and children, high-grade gliomas (WHO grades III and IV) account for a high proportion of death due to cancer. This poor prognosis is a direct consequence of tumor recurrences occurring within few months despite a multimodal therapy consisting of a surgical resection followed by chemotherapy and radiotherapy. There is increasing evidence that glioma stem cells (GSCs) contribute to tumor recurrences. In fact, GSCs can migrate out of the tumor mass and reach the subventricular zone (SVZ), a neurogenic niche persisting after birth. Once nested in the SVZ, GSCs can escape a surgical intervention and resist to treatments. The present review will define GSCs and describe their similarities with neural stem cells, residents of the SVZ. The architectural organization of the SVZ will be described both for humans and rodents. The migratory routes taken by GSCs to reach the SVZ and the signaling pathways involved in their migration will also be described hereafter. In addition, we will debate the advantages of the microenvironment provided by the SVZ for GSCs and how this could contribute to tumor recurrences. Finally, we will discuss the clinical relevance of the SVZ in adult GBM and pediatric HGG and the therapeutic advantages of targeting that neurogenic region in both clinical situations.

In children, high-grade gliomas (HGG) and diffuse midline gliomas (DMG) account for a high proportion of death due to cancer. Glioma stem cells (GSCs) are tumor cells in a specific state defined by a tumor-initiating capacity following serial transplantation, self-renewal, and an ability to recapitulate tumor heterogeneity. Their presence was demonstrated several decades ago in adult glioblastoma (GBM), and more recently in pediatric HGG and DMG. In adults, we and others have previously suggested that GSCs nest into the subventricular zone (SVZ), a neurogenic niche, where, among others, they find shelter from therapy. Both bench and bedside evidence strongly indicate a role for the GSCs and the SVZ in GBM progression, fostering the development of innovative targeting treatments. Such new therapeutic approaches are of particular interest in infants, in whom standard therapies are often limited due to the risk of late effects. The aim of this review is to describe current knowledge about GSCs in pediatric HGG and DMG, i.e., their characterization, the models that apply to their development and maintenance, the specific signaling pathways that may underlie their activity, and their specific interactions with neurogenic niches. Finally, we will discuss the clinical relevance of these observations and the therapeutic advantages of targeting the SVZ and/or the GSCs in infants.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. With dramatic improvements in survival observed since the 70's, it progressively became evident that the long-term survivors faced late morbidity, late mortality and psychosocial troubles. In 2010, the EORTC developed the retrospective 58LAE study in order to evaluate the long-term outcome of the 2621 eligible childhood ALL survivors enrolled between 1971 and 1998. The first sub-project project showed that ETV6-RUNX1 positive patients had better long-term outcome and had specific sensitivities to treatments. The second sub-project showed that omission of cranial radiotherapy did not increase the risk of relapse and was associated with a higher incidence of second neoplasms and late toxicities in medium and high-risk patients, without central nervous system (CNS) involvement. The third sub-project identified hematopoietic stem cell transplantation, cranial radiotherapy and having a relapse as risk factors for worse socio-economic outcome. Finally, the fertility status of the survivors was also evaluated. The 58LAE project has raised several challenges when translated into the "real-life" setting, which include the difficulties of following childhood cancer survivors throughout their transition to adult life; the statistical analysis of a cohort of patients treated in multiple clinical trials and along different years; the need for combining different approaches to gather sufficient quality patient data; and the challenge of overcoming the healthcare administrative and regulatory obstacles. New ways of addressing survivorship studies are needed to address these challenges.

Aims To obtain the normal range for 2D echocardiographic (2DE) measurements of left ventricular (LV) layer-specific strain from a large group of healthy volunteers of both genders over a wide range of ages. Methods and results A total of 287 (109 men, mean age: 46 ± 14 years) healthy subjects were enrolled at 22 collaborating institutions of the EACVI Normal Reference Ranges for Echocardiography (NORRE) study. Layer-specific strain was analysed from the apical two-, three-, and four-chamber views using 2DE software. The lowest values of layer-specific strain calculated as ±1.96 standard deviations from the mean were −15.0% in men and −15.6% in women for epicardial strain, −16.8% and −17.7% for mid-myocardial strain, and −18.7% and −19.9% for endocardial strain, respectively. Basal-epicardial and mid-myocardial strain decreased with age in women (epicardial; P = 0.008, mid-myocardial; P = 0.003) and correlated with age (epicardial; r = −0.20, P = 0.007, mid-myocardial; r = −0.21, P = 0.006, endocardial; r = −0.23, P = 0.002), whereas apical-epicardial, mid-myocardial strain increased with the age in women (epicardial; P = 0.006, mid-myocardial; P = 0.03) and correlated with age (epicardial; r = 0.16, P = 0.04). End/Epi ratio at the apex was higher than at the middle and basal levels of LV in men (apex; 1.6 ± 0.2, middle; 1.2 ± 0.1, base 1.1 ± 0.1) and women (apex; 1.6 ± 0.1, middle; 1.1 ± 0.1, base 1.2 ± 0.1). Conclusion The NORRE study provides useful 2DE reference ranges for novel indices of layer-specific strain.

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983–1989). Median follow-up was 20 years (range 4–32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28–1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57–1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53–1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL., SCOPUS: ar.j, info:eu-repo/semantics/published

Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11¸2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities, SCOPUS: ar.j, info:eu-repo/semantics/published

Aims The present study sought to assess the impact of aortic stenosis (AS) on myocardial function as assessed by layer-specific longitudinal strain (LS) and its relationship with symptoms and outcome. Methods and results We compared 211 patients (56% males, mean age 73 ± 12 years) with severe AS and left ventricular ejection fraction (LVEF) ≥50% (114 symptomatic, 97 asymptomatic) with 50 controls matched for age and sex. LS was assessed from endocardium, mid-myocardium, and epicardium by 2D speckle-tracking echocardiography. Despite similar LVEF, multilayer strain values were significantly lower in symptomatic patients, compared to asymptomatic and controls [global LS: 17.9 ± 3.4 vs. 19.1 ± 3.1 vs. 20.7 ± 2.1%; endocardial LS: 20.1 ± 4.9 vs. 21.7 ± 4.2 vs. 23.4 ± 2.5%; epicardial LS: 15.8 ± 3.1 vs. 16.8 ± 2.8 vs. 18.3 ± 1.8%; P Conclusion In patients with severe AS, LS impairment involves all myocardial layers and is more prominent in the advanced phases of the disease, when the symptoms occur. In this setting, the endocardial LS is independently associated with symptoms and patient outcome.

Resume En tant que tumeur pediatrique la plus frequente, de surcroit grevee d’un excellent pronostic global, la leucemie lymphoblastique aigue (LAL) represente la plus grande pourvoyeuse de survivants exposes a la toxicite des traitements chimiotherapeutiques. L’osteonecrose est une complication bien decrite du traitement de la leucemie touchant jusqu’a un enfant sur dix, avec un tropisme particulier pour les adolescents atteints de leucemie a haut risque. Cette complication est liee a l’emploi des corticoides, dont la toxicite osseuse est potentialisee par l’emploi d’autres molecules, telles l’asparaginase et le methotrexate. L’incidence de cette complication est plus elevee chez les patients recevant la dexamethasone a titre de corticoide principal. De recents protocoles therapeutiques ont adopte, dans le but de reduire l’incidence de l’osteonecrose, l’usage du schema therapeutique baptise « split dexamethasone », une initiative du Children's Oncology Group (COG) consistant a marquer une pause de quelques jours dans l’administration de la dexamethasone lors de la phase de reintensification. A ce jour, seuls un modele animal et deux essais randomises controles du COG ont evalue l’interet de cette pratique. Ces derniers mettent en evidence un benefice de la methode, avec une reduction de l’incidence d’osteonecrose a 5 ans de l’ordre de 50 % pour le CCG 1961 et de 33 % chez les patients entre 10 et 12 ans pour le AALL0232, sans modification de la survie sans evenement a 5 ans (EFS-5), qui reste de l’ordre de 75 % chez ces patients a haut risque. En conclusion, la prevention de l’apparition des lesions d’osteonecrose via des amendements therapeutiques, tel le « split dexamethasone » est non seulement realisable et efficace, mais semble egalement sans danger sur le plan pronostic.

Rectal prolapse is rare in children and usually benign. However, there are various diseases that can be associated with it, such as cystic fibrosis or other causes of increased abdominal pressure. Here, we review the various underlying conditions that pediatricians or pediatric gastroenterologists should consider in the case of rectal prolapse. We report on three cases of children with a rectal prolapse and intra-abdominal tumors. Current recommendations and practice do not include a systematic check via abdominal imaging in cases of rectal prolapse. However, in some situations, imaging is indicated to detect a possible expansive process. Thus, in the presence of recurrent prolapse or of associated urinary or neurological signs, imaging is justified so as to allow for an early diagnosis and treatment of these neoplasms. Given its lack of radiation exposure and good sensitivity in children, ultrasound imaging is the first choice.

Failure of the anterior neuropore can lead to three main types of anomalies: nasal dermal sinus, encephalocele and nasal glioma or heterotopia. In this report, we describe a case of intracranial and extracranial glial heterotopia that probably resulted from a common failure of anterior neuropore development. We describe the prenatal radiological assessment based on ultrasound and MRI results, and consider their limitation for early fetal diagnosis. We also discuss the embryogenesis and the possible pathogenic mechanisms involved.

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.

Background: Since the last decades, pediatric ALL classification has integrated new cytogenetic and genomic data, and several genetic risk factors are identified for treatment stratification. Hyperdiploidy, which is the most common cytogenetic abnormality pattern of pediatric B-lineage ALL, is known since the early 80s and is found in 25-30% of cases. It has been recognized as an isolated good prognostic factor, especially High Hyperdiploidy (HeH), defined by a modal chromosome number higher than 50. In addition, treatment descalations were performed based on NCI criteria for low risk ALL (low leucocytosis < 10 x 109/L and/or age from 1 to ²10 years old) and/or lack of high risk features. Aim: The aim of this study was to assess whether age, under or over 10 years old, has a prognostic impact on the outcome in children presenting B-cell ALL with low risk criteria, and whether therapeutic intensification might improve the outcome within each age group. Methods: Among 2039 patients treated in EORTC 58951 (BFM backbone) from 1998 to 2008, 370 children with B-cell ALL and low risk criteria such as HeH (with classical profile of chromosome gains), low leucocytosis (< 10x109/L), a lack of CNS or gonadal involvement and a lack of very high features (poor response to prephase) were included in this study. Hyperdiploidy was determined either by cytogenetics or flow cytometry. Patients were stratified into 2 risk groups: very low risk (VLR) group or standard risk (AR1) group. VLR group was defined by the criteria indicated above. It led to a less intensive treatment, particularly lower number of injections of anthracyclines and alkylating agents. AR1 group included children with surreptitious or hemorrhagic CNS involvement, and/or HeH with mismatch between modal chromosome number and DNA index. The upper limit of age in the EORTC 58951 was less than 18 years. Main endpoints were Event-Free Survival (EFS) and Overall Survival (OS). Results: Overall patients with low risk hyperdiploid B-cell ALL features treated according to a VLR or AR1 protocol had 6-year EFS and OS rates of 90.3% and 96.2% respectively. These results were comparable to previous published studies on hyperdiploidy in childhood B-lineage ALL. All patients but one reached complete remission after the induction phase. There were 315 children aged less than 10 years old and 55 patients aged 10 to 17 years old. Among children aged 10 years and older treated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 86.7% and 96.4%. In comparison, among less than 10 year old childrentreated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 89.8% (p=0.42) and 95.9% (p=0.93). Age did not appear as a significant prognostic factor in the outcome. Furthermore, among children aged 10 years and older, those treated in the standard risk group (AR1) had 6-year EFS and OS rates of 90% and 100% respectively. This seemed better than for children treated in the very low risk group, with respectively 84% and 92% rates. However, no significant gain was found for children who received standard risk treatment (for EFS and OS rates: p=0.47 and p=0.12 respectively). Relapse and treatment toxicity rates were comparable in both groups. Concerning long-term cardiac toxicity, despite the fact that no significant difference was found between the two risk groups of treatment, standard treatment leads to higher dose of anthracyclines and an increased theoretical risk of cardiac toxicity. Conclusion: In conclusion, age did not appear as a significant prognostic factor in outcome of children treated for a low risk B-cell ALL. Moreover, among children aged 10 years and older, therapeutic intensification in standard risk group did not lead to a significant gain in outcome. However, results are not significant, partly due to a low number of patients, and larger studies should be performed to evaluate whether these children could benefit from a less intensive treatment. Disclosures No relevant conflicts of interest to declare.

Background Cranial radiotherapy (CRT) is associated with early and late side effects. Intrathecal (IT) and systemic chemotherapy could successfully replace CRT in most protocols for standard risk ALL. However, in medium and high risk ALL patients (pts) its omission is still debatable. Aim We investigated the long-term outcome, the occurrence of second malignant neoplasms (SMN) and the incidence of late toxicities in pts randomized for receiving or not CRT in the EORTC 58832 study. Methods From 1983 to 1989, ALL children under 18 years (yrs) were included in EORTC Children Leukemia Group BFM-oriented studies, either 58831, for standard risk pts (Riehm-Langerman Risk Factor (RF) < 1.2), or 58832, for medium risk (RF 1.2-1.69) and high risk pts (RF ≥1.7). Pts with central nervous system (CNS) involvement at diagnosis were ineligible. The present report focusses on pts included in the 58832 trial (randomized for receiving or not prophylactic CRT). Prophylactic CNS therapy consisted of 4 high-dose methotrexate (HD-MTX) injections (2500 mg/m2) during consolidation and 7 IT MTX injections scheduled during the treatment period. Pts still in complete remission (CR) after the end of late intensification were randomized for receiving prophylactic CRT (standard arm) or not (experimental arm) before the start of continuation therapy. Dose of CRT was age dependent: 24 Gy (> 2 yrs), 20 Gy (1-2 yrs) and 16 Gy (< 1 yr). Endpoints were: disease-free survival (DFS) (event: relapse, death in CR), incidence of SMN, event-free survival (EFS) (event: relapse, death in CR, SMN), incidence of late toxicities, and overall survival (OS) from randomization. Results 788 pts were included in the 58831/58832 study. Among them, 189 were randomized in the 58832 study to receive CRT (n=93) or No CRT (n=96). A total of 6 pts did not meet eligibility criteria, 2 had an early relapse, 3 had an early protocol violation and 2 refused allocated treatment. Finally, 176 randomized pts were included in the analyses: 84 in the CRT group and 92 in the No CRT group. The median follow-up was 20 yrs (range 4-32 yrs). Omission of CRT did not increase the 25-yr incidence of isolated CNS relapse, any CNS relapse or non-CNS relapse (4.8 vs 6.5; 11.9 vs 8.7 and 16.7 vs 21.8 in the CRT vs No CRT arms, respectively). No relapses occurred after 10 yrs. The 25-yr DFS rates were similar in both arms: 70.2% with CRT and 67.4% without CRT; No CRT vs CRT hazard ratio (HR)=1.08, 95% CI (0.63, 1.83). CRT was associated with an increase of the 25-yr SMN incidence: 13.2% with CRT and 3.9% without CRT. In the CRT arm, 9 pts (10.7%) developed SMN: 2 acute myeloid leukemias (AML), 1 non-Hodgkin lymphoma, 1 thyroid carcinoma, 4 meningiomas and 1 malignant histiocytosis. One SMN (meningioma) occurred after a CNS combined relapse. Three pts developed second SMN (meningiomas): 1 after an AML and 2 after a first meningioma. In the No CRT arm, 3 pts (3.3%) had SMN: 1 pleomorphic xanthoastrocytoma, 1 melanoma and 1 adenocarcinoma of the ileum. One SMN occurred after a bone marrow (BM) relapse. The 25-yr EFS rates were similar in both arms: 60.3% with CRT and 63.2% without CRT, HR=0.90, 95% CI (0.55, 1.46). CRT was also associated with an increase of late CNS and endocrine toxicities. Five pts (19.2% of the pts with available data) developed leukoencephalopathy in the CRT arm, versus 2 pts (8.7%) in the No CRT arm. Noteworthy, 1 of those 2 pts received CRT for a BM relapse, while the other received total body irradiation for a CNS relapse. Stroke was observed in 2 pts (7.7%) who received CRT. In contrast, there was no clear increase of the incidence of cognitive disturbance after CRT: 33.3% in the CRT arm vs 25.0% in the No CRT arm. Regarding endocrine toxicities, GH deficiency, hypothyroidism and precocious puberty were more frequent in the CRT arm: 53.1% vs 29.6%, 27.8% vs 0% and 29.4% vs 0%, respectively. Finally, the 25-yr OS rates were similar in both arms: 78.5% with CRT and 78.1% without CRT, HR=1.00, 95% CI (0.53, 1.88). Conclusion In medium and high risk pts without CNS involvement at diagnosis and treated with HD-MTX in the EORTC trial 58832 (1983-1989), omission of CRT did not increase the risk of CNS or non-CNS relapse. On long-term evaluation, CRT was associated with a higher incidence of SMN, late CNS and endocrine toxicities. These long-term results indicate that prophylactic CRT can be safely omitted in childhood medium and high risk ALL pts receiving IT and systemic chemotherapy (including HD-MTX) as CNS prophylaxis. Table Table. Disclosures No relevant conflicts of interest to declare.

Background In childhood BCP-ALL, the presence of t(12;21)/ETV6 -RUNX1 defines one of the most prevalent oncogenic subgroup and is usually associated with a favorable outcome. Nevertheless, an excellent prognosis has not been reported by all collaborative groups, suggesting that the outcome of ETV6 -RUNX1 patients (pts) could be influenced by the treatment. To address this issue, the long-term outcome of ETV6 -RUNX1 pts was investigated into the EORTC 58881 and 58951 studies, with particular attention to the effect of the randomized treatments. Methods The 58881 study (1989-1998) used a BFM backbone without cranial irradiation, and aimed to compare E-Coli (Medac®) Asparaginase (A'ase) with Erwinia A'ase and to assess the value of 6-Mercaptopurine (6-MP) i.v. (1 g/m²/month) when added to classic maintenance. The subsequent 58951 study (1999-2008) used the best arm of the trial 58881, i.e. E-Coli A'ase and classic maintenance. The aims of this study were to compare dexamethasone (Dexa) (6 mg/m²/day) with prednisone (Pred) (60 mg/m²/day) during induction and maintenance; to evaluate increased number of A'ase administrations (24 vs 12) for non-very high risk pts; and to assess the value of vincristine/corticosteroid pulses during maintenance for average risk pts. Detection of ETV6 -RUNX1 by FISH and/or RT-PCR was centralized. Pts less than 1 year (yr) or with t(9;22)/BCR-ABL were excluded from the analysis. Results An ETV6 -RUNX1 was evidenced in 104/363 (28%) and 380/1493 (27%) newly diagnosed BCP-ALL pts enrolled in the 58881 and 58951 trial respectively. A majority of ETV6-RUNX1 pts were below the age of 10 yrs (93.3% in 58881 and 91.3% in 58951). The median follow-up was 11.8 yrs for the 58881 and 6.7 yrs for the 58951. In both studies, the 10-yr event-free-survival (EFS) rate was significantly higher for ETV6 -RUNX1 pts than for all BCP-ALL pts (82.5% vs 74.9% in 58881 and 90.8% vs 82.7% in 58951), and was similar to the 10-yr EFS of hyperdiploid pts. Noteworthy, very few EFS events were observed during treatment period or after 6 yrs from diagnosis. The main prognostic factors of the ETV6-RUNX1 subgroup in both studies were the white blood cell count (WBC) and the response to prephase. As shown in the table below, the analysis of the relationship between treatment modalities and outcome revealed that the in vivo drug sensitivity of ETV6-RUNX1 ALL was distinct from that of other BCP-ALL. In this subgroup, the benefit of a more potent A'ase (58881) or of intensified A'ase administrations (58951) was less pronounced as compared to other pts, and 6-MP i.v. during maintenance was particularly deleterious. Moreover, the overall benefit of vincristine/corticosteroid pulses was not observed in ETV6-RUNX1 average risk group pts, who already had an outstanding outcome. By contrast, the use of Dexa in place of Pred significantly improved the 10-yr EFS of ETV6-RUNX1 pts (95.0% vs 87.2%, hazard ratio (HR)=0.44, 95% CI 0.20-0.96) whereas no difference was observed in the remaining population (HR=1.01, 95% CI 0.77-1.33) (test for interaction: p=0.04). Table.5888158951All (n=363)ETV6-RUNX1 (n=104)Hyperdiploid (n=102)Others1 (n=155)All (n=1493)ETV6-RUNX1 (n=380)Hyperdiploid (n=484)Others1 (n=619)10-yr EFS ratesAll pts74.9%82.5%83.3%65.2%82.7%90.8%88.4%73.2%Pred ² (n=745)81.8%87.2%88.8%73.0%Dexa ² (n=748)83.6%95.0%88.0%73.5%Medac A'ase 2,3 (n=320)76.6%83.2%88.6%65.7%Other A'ase 2,3 (n=43)62.8%78.6%50.0%60.0%10-yr disease-free-survival ratesShort A'ase 4 (n=607)83.5%91.2%90.1%72.4%Long A'ase 4 (n=622)87.0%94.8%88.2%80.7%No 6-MP iv 2,5 (n=96)85.4%100%90.9%72.5%6-MP iv 2,5 (n=94)72.3%70.6%78.6%68.8%No Pulse 5,6 (n=148)87.5%96.1%88.5%71.1%Pulse 5,6 (n=153)82.8%95.1%91.3%82.3%1Others, MLL rearrangements excluded 2All risk groups 3Pts randomized or not for A'ase 4Non-very high risk pts 5Pts who started maintenance 6Average risk pts Conclusions Within the EORTC 58881 and 58951 trials, the use of Dexa rather than Pred allowed to further improved the long-term outcome for ETV6-RUNX1 pts. Our data also show that this excellent outcome can be jeopardized by slight changes in therapy, such as the addition of 6-MP i.v. to classic maintenance. Together, these results stress the importance of analyzing homogeneous oncogenetic subgroups when comparing different therapeutic schemes, to unmask specific drug effects that could be hidden when analyzing the whole group of patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.