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Another patient had an interruption of the treatment with blinatumomab because of hyperammonemia on the second cycle, but this patient had a portocaval shunt. Only one other patient had blast after treatment with blinatumomab, but this patient did not have myelogram before treatment with blinatumomab and had a prolonged interruption of treatment. Only one patient had >5% medullary blasts, 15 patients (65%) had negative MRD and 7 (30%) patients had detectable MRD. [Extracted from the article]

SACHA-France (NCT04477681) is a prospective real-world study that collects clinical safety and efficacy data of novel anticancer therapies prescribed off-label or on compassionate use to patients <25 years. From March 2020 until February 2024, 640 patients with solid tumors or lymphomas were included, with 176 (28%) reported objective tumor responses. Centralized medical monitoring of local radiological/functional imaging reports by the SACHA coordinating investigator led to response modification in 45 out of 176 cases (26%), highlighting the relevance of the medical review of study data. We suggest this pragmatic approach for improving clinical trial data when centralized radiological review is not performed., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1-18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m 2 /day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m 2 /day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76-1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75-1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28-1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group ( p  = 0.012). The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Background: Adult- and adolescent-onset neuroblastomas are rare, with no established therapy. In addition, rare pheochromocytomas may harbor neuroblastic components. This study was designed to collect epidemiological, diagnostic and therapeutic data in order to better define the characteristics of malignant peripheral neuroblastic tumors (MPNT) and composite pheochromocytomas (CP) with MPNT., Procedure: Fifty-nine adults and adolescents (aged over 15 years) diagnosed with a peripheral or composite neuroblastic tumor, who were treated in one of 17 institutions between 2000 and 2020, were retrospectively studied., Results: Eighteen patients with neuroblastoma (NB) or ganglioneuroblastoma (GNB) had locoregional disease, and 28 patients had metastatic stage 4 NB. Among the 13 patients with CP, 12 had locoregional disease. Fifty-eight percent of the population were adolescents and young adults under 24 years of age. The probability of 5-year event-free survival (EFS) was 40% (confidence interval: 27%-53%)., Conclusions: Outcomes were better for patients with localized tumor than for patients with metastases. For patients with localized tumor, in terms of survival, surgical treatment was the best therapeutic option. Multimodal treatment with chemotherapy, surgery, radiotherapy, and immunotherapy-based maintenance allowed long-term survival for some patients. Adolescent- and adult-onset neuroblastoma appeared to have specific characteristics associated with poorer outcomes compared to pediatric neuroblastoma. Nevertheless, complete disease control improved survival. The presence of a neuroblastic component in pheochromocytoma should be considered when making therapeutic management decisions. The development of specific tools/resources (Tumor Referral Board, Registry, biology, and trials with new agents or strategies) may help to improve outcomes for patients., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Refractory chronic immune thrombocytopenia (r-cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r-cITP is inconsistently defined in literature, contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r-cITP including five pediatric definitions in 886 patients with cITP (median [min-max] follow-up 5.3 [1.0-29.3] years). The pediatric definitions identified overlapping groups of various sizes (4%-20%) but with similar characteristics (higher proportion of immunopathological manifestations [IM] and systemic lupus erythematosus [SLE]), suggesting that they adequately captured the population of interest. Based on the 79 patients with r-cITP (median follow-up 3.1 [0-18.2] years) according to the CEREVANCE definition (≥3 second-line treatments), we showed that r-cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r-cITP. One patient (1%) experienced two grade five bleeding events after meeting r-cITP criteria and while not receiving second-line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r-cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48-19.84, p = 7.8 × 10 -4 ). In sum, children with cITP may be diagnosed with r-cITP at any time point of the follow-up and are at increased risk of IM and SLE. Second-line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE)., Methods: Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use., Results: Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%)., Conclusion: Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Pablo Berlanga reported an advisory role (institutional funding) for EUSA Pharma and grants and drugs for trials from Bayer outside the submitted work. No other disclosures were reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Autoimmune cytopenia (AIC) in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS'CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer ≥1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk [RR], 3.67; 95% confidence interval [CI], 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period. This trial was registered at www.ClinicalTrials.gov as #NCT05937828., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

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)., (© 2024. The Author(s).)

Background: We aimed to study adherence to cardiac screening in long-term childhood cancer survivors (CCS) at high risk of cardiomyopathy., Methods: This study involved 976 5-year CCS at high risk for cardiomyopathy from the French Childhood Cancer Survivor Study. Determinants of adherence to recommended surveillance were studied using multivariable logistic regression models. Association of attendance to a long-term follow-up (LTFU) visit with completion of an echocardiogram was estimated using a Cox regression model., Results: Among participants, 32% had an echocardiogram within the 5 previous years. Males (adjusted RR [aRR] 0.71, 95% CI 0.58-0.86), survivors aged 36-49 (aRR 0.79, 95% CI 0.64-0.98), Neuroblastoma (aRR 0.53, 95% CI 0.30-0.91) and CNS tumour survivors (aRR 0.43, 95% CI 0.21-0.89) were less likely to adhere to recommended surveillance. Attendance to an LTFU visit was associated with completion of an echocardiogram in patients who were not previously adherent to recommendations (HR 8.20, 95% CI 5.64-11.93)., Conclusions: The majority of long-term survivors at high risk of cardiomyopathy did not adhere to the recommended surveillance. Attendance to an LTFU visit greatly enhanced the completion of echocardiograms, but further interventions need to be developed to reach more survivors., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Cancer treatments of the last decades improve the survival rate of children and adolescents. However, chemo- and radiotherapy result in gonadal damage, leading to acute ovarian failure and sterility. The preservation of fertility is now an integral part of care of children requiring gonadotoxic treatments. Ovarian tissue cryopreservation (OTC) is an effective fertility preservation option that allows long-term storage of primordial follicles, subsequent transplantation, and restoration of endocrine function and fertility. The efficacy of this technique is well-demonstrated in adults but the data are scarce for pediatric patients. Currently, OTC represents the only possibility of preserving the potential fertility in prepubertal girls., Procedure: This is a retrospective study of OTC practice of two French centers from January 2004 to May 2020. A total of 72 patients from pediatric units underwent cryopreservation of ovarian tissue before gonadotoxic therapy for malignant or non-malignant diseases. The ovarian cortex was cut into fragments and the number of follicles per square millimeter was evaluated histologically. The long-term follow-up includes survival rate and hormonal and fertility status., Results: The mean age of patients at OTC was 9.3 years [0.2-17] and 29.2% were postpubertal; 51 had malignant diseases and 21 had non-malignant diseases. The most frequent diagnoses included acute leukemia, hemoglobinopathies, and neuroblastoma. Indication for OTC was stem cell transplantation for 81.9% ( n  = 59) of the patients. A third of each ovary was collected for 62.5% ( n  = 45) of the patients, a whole ovary for 33.3% ( n  = 24) of the patients, and a third of one ovary for 4.2% ( n  = 3) of the patients. An average of 17 fragments [5-35] per patient was cryoconserved. A correlation was found between the age of the patients and the number of fragments ( p  < 0.001). More fragments were obtained from partial bilateral harvesting than from whole ovary harvesting ( p  < 0.05). Histological analysis of ovarian tissue showed a median of 6.0 primordial follicles/mm 2 [0.0-106.5] and no malignant cells were identified. A negative correlation was found between age and follicular density ( p  < 0.001). Median post-harvest follow-up was 92 months [1-188]. A total of 15 girls had died, 11 were still under treatment for their pathology, and 46 were in complete remission. Of all patients, 29 (40.2%) were subjected to a hormonal status evaluation and 26 were diagnosed with premature ovarian insufficiency (POI) ( p  < 0.001). One patient had undergone thawed ovarian tissue transplantation., Conclusion: OTC should be proposed to all girls with high risk of developing POI following gonadotoxic therapies in order to give them the possibility of fertility and endocrine restoration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Grellet-Grün, Delepine, Le Van Quyen, Avérous, Durlach, Greze, Ladureau-Fritsch, Lichtblau, Canepa, Liné, Paillard, Pluchart, Pirrello, Rongieres, Harika, Becmeur and Teletin.)

Importance: Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected., Objectives: To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines., Design, Setting, and Participants: This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022., Exposures: All patients treated in a French Society of Pediatric Oncology (SFCE) center., Main Outcomes and Measures: Collection of adverse drug reactions and anticancer activity attributable to the treatment., Results: A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population., Conclusions and Relevance: This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.

Objective: The aim of this study was to identify risk factors for obesity in childhood cancer survivors (CCSs)., Methods: The study included 3199 patients of the French Childhood Cancer Survivor Study cohort, with 303 patients with obesity who had returned the self-questionnaire. Analyses were adjusted for social deprivation index and sex., Results: CCSs were less likely to have obesity (9.5%; 95% CI: 8.5%-10.5%) than expected from the general French population rates (12.5%; p = 0.0001). Nevertheless, brain tumor survivors were significantly more likely to develop obesity than the general French population (p = 0.0001). Compared with patients who did not receive radiotherapy to the pituitary gland, those who received a dose >5 Gy had an increased risk of obesity: relative risk 1.9 (95% CI: 1.2-3.1), 2.5 (95% CI: 1.7-3.7), and 2.6 (95% CI: 1.6-4.3), respectively, for participants with 6 to 20 Gy, 20 to 40 Gy, and ≥40 Gy of radiation. Etoposide administration significantly increased the risk of obesity (relative risk 1.7; 95% CI: 1.1-2.6). High social deprivation index was also a risk factor, just like BMI at diagnosis., Conclusions: Long-term follow-up of CCSs should include weight follow-up during adulthood., (© 2023 The Obesity Society.)

Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second-line treatment use, association with clinical and/or biological immunopathological manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex, or IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex, and IMs on cITP outcomes. We included 886 patients with a median (min-max) follow-up duration of 5.3 (1.0-29.3) years. We identified an age cutoff that dichotomized the risk of the outcomes and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four-fold higher risk of grade ≥3 bleeding, second-line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, second-line treatment use, and SLE diagnosis, respectively. The combination of these three risk factors defined outcome-specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long-term outcomes of pediatric cITP. We defined risk groups for each outcome, which will help clinical management and further studies., (© 2023 Wiley Periodicals LLC.)

Background: The HIT-SKK protocol is used for low/standard-risk medulloblastomas in young children with the aim to eliminate cranial irradiation and its neuropsychological (NP) sequelae. This therapy includes IV and intraventricular (ITV) methotrexate (MTX) potentially responsible for leukoencephalopathy (LE) and neurocognitive disorders. This study describes the risk factors and course of LE, and investigates its correlation with neurocognitive impact., Methods: A retrospective, multicenter study was conducted in 35 children under 5 years old, with a median follow-up of 72 months (range 14 to 130). The main analysis was performed in 30 patients who received cumulative doses of MTX as per-protocol (group 1). Five patients who received higher cumulative doses of MTX were analyzed separately. All follow-up MRIs and NP assessments were centrally reviewed by experts., Results: Twenty patients in group 1 developed LE, grade 2 and 3 abnormalities did not correlate with higher cumulative doses of ITV-MTX (p = 0.698). Considering the most recent NP evaluation, the Full-Scale IQ (FSIQ) and Wechsler indices were in the average to lower average range. The FSIQ was deficient in 6/17 evaluable patients. Cumulative dose of ITV-MTX was almost associated with decreased processing speed competence (p = 0.055) which was the most frequently impaired neurocognitive domain. Neuropsychological assessment scores were not statistically lower in patients with persistent grade 2 LE at the end of follow-up., Conclusion: This study described that the use of cumulative dose of MTX (IV and ITV) according to the HIT-SKK protocol resulted in LE that tented to decrease over time, without significant correlation with a decline in neuro-intellectual skills., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

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., (© 2022 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006-2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval [CI] 2.46-2.52) and the RBDR was 3.49 (95% CI 3.46-3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio [RR] 1.62, 95% CI 1.53-1.70), radiotherapy (RR 2.11, 95% CI 1.99-2.24) or both (RR 2.59, 95% CI 2.46-2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS., (© 2022. The Author(s).)

Splenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS'CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10-7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes., (© 2022 by The American Society of Hematology.)

Purpose: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers., Methods and Materials: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy., Results: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy., Conclusions: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Childhood cancer survivors (CCS) may require lifelong medical care due to late effects of cancer treatments. Little is known about of their healthcare utilization and expenditures at long-term especially in publicly funded health care system. We aim to estimate and describe the health care expenditures among long-term CCS in France., Methods: A total of 5319 five-year solid CCS diagnosed before the age of 21 between 1945 and 2000 in France were identified in the French Childhood Cancer Survivors Study cohort (FCCSS) and the French cancer registry. Information about health care expenditure was taken from the French national health data system between 2011 and 2016, and was described according to survivors' characteristics. Generalized linear models were used to determine associations between health care expenditures and survivors' characteristics., Results: Mean annual amount of healthcare expenditures was € 4,255. Expenditures on hospitalizations and pharmacy represents 60% of total expenditures. Mean annual of healthcare expenditures were higher at increasing age, among women survivors (€ 4,795 vs € 3,814 in men) and in central nervous system (CNS) tumor survivors (€ 7,116 vs € 3,366 in lymphoma and € 3,363 in other solid tumor survivors)., Conclusions: Childhood cancer survivorship is associated with a substantial economic burden in France. We found that female gender and CNS primary cancer were associated with increased healthcare expenditures., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aim of this study was to examine whether texture analysis features on pretreatment contrast-enhanced CT images could predict adequate response (AR) or inadequate response (IR) after two cycles of chemotherapy in pediatric Hodgkin's lymphoma (PHL)., Materials and Methods: This retrospective single-center study included 32 children and adolescents with HL. Texture analysis was independently performed by two radiologists using pretreatment CT scans. The mean gray level, standard deviation, entropy, kurtosis, and skewness were derived from pixel distribution histograms before and after spatial filtration ranging from two (fine texture) to six (coarse texture). Interobserver reliability was studied using interobserver correlation coefficients (ICCs) to select texture parameters. Relationships between early response assessment (ERA) to induction therapy and associated factors were studied using Student's t -tests and a lasso penalized logistic regression analysis., Results: Of the 32 patients, IR was observed in 13 and AR in 19. Inter-reader agreement was good to excellent (ICC > 0.75) for all parameters except skewness and kurtosis without filtration and at spatial scale filtration (SSF) = 2. These parameters were excluded from the analysis. The t -test identified only entropy at SSF = 2 ( p value = 0.039) as a potential predictor of ERA. No parameters were significantly associated with ERA, according to a lasso penalized logistic regression., Conclusion: No textural parameters were identified as predictors of ERA after two cycles of chemotherapy in PHL., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Background: In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia., Methods: We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio., Findings: The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795., Interpretation: The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings., Funding: Ligue Nationale Contre le Cancer., Competing Interests: Declaration of interests AM declares paid appointments for lectures, consultancy, or advice, and invitations to European Society for Paediatric Infectious Diseases meetings from GlaxoSmithKline and Pfizer. FD received expenses from Sanofi-Pasteur and Takeda for scientific experts' meetings in 2020 and 2021. MD, FG, HB, AT, HS-B, AL, SA, SP, ST-D, IP, LM, CPi, CPa, LB, ET, DP, PB, PSc, CG, PSi, CD, HP, MLM, CPl, CV, GP, and AD declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Since the introduction of tyrosine kinase inhibitors (TKIs), the profile of pediatric relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has changed. However, the management of pediatric Ph + ALL relapses is not currently standardized., Procedure: We retrospectively analyzed the therapeutic strategies and outcomes of pediatric Ph + ALL patients in first relapse who were initially treated with a TKI-containing regimen in one of the French pediatric hematology centers from 2004 to 2019., Results: Twenty-seven children experienced a Ph + ALL relapse: 24 (89%) had an overt relapse and three a molecular relapse. Eight involved the central nervous system. A second complete remission (CR2) was obtained for 26 patients (96%). Induction consisted of nonintensive chemotherapy for 13 patients (48%) and intensive chemotherapy for 14 (52%). Thirteen patients (48%) received consolidation. Allogenic hematopoietic stem cell transplantation (alloHSCT) was performed for 21 patients (78%). The TKI was changed for 23 patients (88%), mainly with dasatinib (n = 15). T315I was the most common mutation at relapse (4/7). The 4-year event-free survival and survival rates were 60.9% and 76.1%, respectively. Survival was positively associated with alloHSCT in CR2., Conclusion: We show that pediatric first-relapse Ph + ALL reinduces well with a second course of TKI exposure, despite the use of different therapeutic approaches. The main prognostic factor for survival was alloHSCT in CR2. Because of the small size of the cohort, we could not draw any conclusions about the respective impact of TKIs, but the predominance of the T315I mutation should encourage careful consideration of the TKI choice., (© 2021 Wiley Periodicals LLC.)

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.

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)., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT)., Study Design: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units., Results: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10 -4 ) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents., Conclusions: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.

In paediatric acute lymphoblastic leukaemia (ALL), focus has shifted towards preventing treatment-related complications, including venous thromboembolism, the cause of significant mortality and morbidity. To better understand thrombogenic mechanisms during induction treatment, we studied the number, origin and procoagulant activity of extracellular vesicles (EVs) and P-selectin level throughout the induction course in 24 paediatric patients. EVs were mainly of platelet origin. We observed a significant increase in EV number, in platelet EV number and P-selectin level throughout the induction course. There was a correlation between higher EV and platelet EV number, P-selectin level, higher platelet count and leucocyte count. We also observed a correlation between higher EV procoagulant activity and higher platelet count and leucocyte count and higher P-selectin level. Older age and T phenotype were associated with a higher EV procoagulant activity. Platelet EV generation may play a role in thrombogenic complications in ALL patients and could serve as a biomarker to identify patients with a high risk of thrombosis. As a marker of platelet activation, P-selectin may be another relevant marker with the advantage of being easier to analyse in clinical practice.

Background: Childhood or adolescent cancer survivors are at increased risks of subsequent primary neoplasms (SPN) of the central nervous system (CNS) after cranial irradiation. In a large multicentric cohort, we investigated clinical and therapeutic factors associated with the long-term risk of CNS SPN, and quantified the dose-response relationships., Methods: We selected all CNS SPN cases diagnosed up to 2016 among members of the French Childhood Cancer Survivor Study at least 5 years after first cancer diagnosis in 1946-2000. Four controls per case were randomly selected within the cohort and matched by sex, year of/age at first cancer diagnosis, and follow-up time. On the basis of medical and radiological reports, cumulative radiation doses received to the SPN or matched location were retrospectively estimated using mathematical phantoms. We computed conditional logistic regression models., Results: Meningioma risk significantly increased with higher radiation doses [excess OR per Gy (EOR/Gy) = 1.377; P < 0.001; 86 cases; median latency time = 30 years], after adjustment for reported genetic syndromes and first CNS tumor. It was higher among youngest individuals at first cancer diagnosis, but did not vary with follow-up time. On the opposite, radiation-related glioma risk (EOR/Gy = 0.049; P = 0.11; 47 cases; median latency time = 17 years) decreased over time ( P for time effect = 0.05). There was a significant association between meningioma risk and cumulative doses of alkylating agents, but no association with growth hormone therapy., Conclusions: The surveillance of patients with cranial irradiation should continue beyond 30 years after treatment., Impact: The identified risk factors may inform long-term surveillance strategies., (©2020 American Association for Cancer Research.)

Purpose: The purpose of this work is to assess the clinical outcome of pediatric patients diagnosed with pheochromocytoma and paraganglioma (PPGL) detected in France since 2000., Methods: A retrospective multicenter study was conducted that included all patients younger than 18 years with PPGL diagnosed in France between 2000 and 2016. Patients were identified from 4 different sources: the National Registry of Childhood Solid Tumors, the French Pediatric Rare Tumors Database, the French registry of succinate dehydrogenase (SDH)-related hereditary paraganglioma, and the nationwide TenGen network., Results: Among 113 eligible patients, 81 children with available data were enrolled (41 with adrenal and 40 with extra-adrenal PPGL). At diagnosis, 11 had synchronous metastases. After a median follow-up of 53 months, 27 patients experienced a new event (n = 7 second PPGL, n = 1 second paraganglioma [PGL], n = 8 local recurrences, n = 10 metastatic relapses, n = 1 new tumor) and 2 patients died of their disease. The 3- and 10-year event-free survival rates were 80% (71%-90%) and 39% (20%-57%),respectively, whereas the overall survival rate was 97% (93%-100%)at 3 and 10 years. A germline mutation in one PPGL-susceptibility gene was identified in 53 of the 68 (77%) patients who underwent genetic testing ( SDHB [n = 25], VHL [n = 21], RET [n = 2], HIF2A [n = 2], SDHC [n = 1], SDHD [n = 1], NF1 [n = 1]). Incomplete resection and synchronous metastases were associated with higher risk of events ( P  = .011, P  = .004), but presence of a germline mutation was not ( P  = .11)., Conclusions: Most pediatric PPGLs are associated with germline mutations and require specific follow-up because of the high risk of tumor recurrence., (© Endocrine Society 2020.)

Background: Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery., Design/methods: All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed., Results: Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age., Conclusion: DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage., (© 2020 Wiley Periodicals, Inc.)

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., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Thromboembolic events are frequent and serious complications of acute lymphoblastic leukaemia treatment. The importance of chemotherapy in the pathogenesis of this increased risk is enhanced by the fact that thrombosis rarely occurs at diagnosis. Our study aims at investigating the effect of chemotherapy on pro-coagulant activity (PCA), phosphatidylserine (PS) exposure, tissue factor (TF) activity and derived extracellular vesicles (EV) of Jurkat cells. Jurkat cells were treated with two commonly used chemotherapeutics: Vincristine (VCR) or Daunorubicin (DNR), at relevant concentrations. PCA of cells and derived EV were evaluated using Thrombin generation Assay (TGA). Cells or EV were incubated with annexin V or anti TF antibodies to assess the respective contribution of TF and PS. PS exposure on cells was analysed by flow cytometry. Derived EV were evaluated in fluorescence microscopy and flow cytometry. Untreated Jurkat cells and EV support thrombin generation. Thrombin generation was abolished when PS activity was inhibited by annexin V. VCR treatment resulted in a time dependent increase of thrombin generation. After VCR exposure, TF activity increased as well as PS exposure increased on the cell surface. The increase in TF activity was abolished by annexin V indicating that PS was required. A spontaneous release of EV from Jurkat cells was observed and VCR treatment increased the number of generated EV. Our results indicate that VCR increased the PCA of Jurkat cells predominantly through PS exposure and increased EV generation. Lymphoid blasts derived EV could be biomarkers to determine high thrombotic risk ALL patients.