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Visual outcome is one of the main issues in the treatment of optic pathway glioma in childhood. Although the prognostic factors of low vision have been discussed extensively, no reliable indicators for visual loss exist. Therefore, we aimed to define initial and evolving factors associated with long-term vision loss. We conducted a multicenter historical cohort study of children treated in France with up-front BB-SFOP chemotherapy between 1990 and 2004. Visual acuity performed at the long-term follow-up visit or within 6 months prior was analyzed. Logistic regression analysis was used to estimate the effects of clinical and radiological factors on long-term visual outcome. Of the 180 patients in the cohort, long-term visual acuity data were available for 132 (73.3%) patients (median follow-up: 14.2 years; range: 6.1-25.6). At the last follow-up, 61/132 patients (46.2%) had impaired vision, and 35 of these patients (57.3%) were partially sighted or blind. Multivariate analysis showed that factors associated with a worse prognosis for long-term visual acuity were an age at diagnosis of < 1 year (OR 3.5 [95% CI: 1.1-11.2], p = 0.04), tumor extent (OR 4.7 [95% CI: 1.2-19.9], p = 0.03), intracranial hypertension requiring one or more surgical procedures (OR 5.6 [95% CI: 1.8-18.4], p = 0.003), and the need for additional treatment after initial BB-SFOP chemotherapy (OR 3.5 [95% CI: 1.1-11.9], p = 0.04). NF1 status did not appear as a prognostic factor, but in non-NF1 patients, a decrease in tumor volume with contrast enhancement after BB-SFOP chemotherapy was directly associated with a better visual prognosis (OR 0.8 [95% CI: 0.8-0.9], p = 0.04). Our study confirms that a large proportion of children with optic pathway glioma have poor long-term outcomes of visual acuity. These data suggest new prognostic factors for visual acuity, but these results need to be confirmed further by large- and international-scale studies.

Background Treatment summaries and a personalized survivorship care plans based on internationally approved, organ-specific follow-up care recommendations are essential in preserving the health and quality of life for cancer survivors. Cohorts made up of survivors of childhood cancer have made significant contributions to the understanding of early mortality, somatic late complications, and psychosocial outcomes among former patients. New treatment protocols are needed to enhance survival and reduce the potential risk and severity of late effects, and working with treatment databases is crucial in doing so. Construction and content In the GOCE (Grand Ouest Cancer de l’Enfant [Western Region Childhood Cancer]) network, in a participative approach, we developed the LOG-after medical tool, on which health data are registered and can be extracted for analysis. Its name emphasizes the tool’s goal, referring to ‘logiciel’ (the French word for software) that focuses on the period “after” the acute phase. This tool is hosted on a certified health data server. Several interfaces have been developed that can be used depending on the user’s profile. Here we present this innovative co-constructed tool that takes national aspects into account, including the results of the feasibility/satisfaction study and its perspective. Utility and discussion The database contains data relating to 2558 patients, with samples from 1702 of these (66.54%) being held in a tumor bank. The average year in which treatment started was 2015 (ranging from December 1967 to November 2022: 118 patients were treated before 2012 and registered retrospectively when seen in long-term follow-up consultations or for another cancer since November 2021). A short questionnaire was distributed to healthcare professionals using the tool (physicians and research associates or technicians, n  = 14), of whom 11 answered and were all satisfied. Access to the patient interface is currently open to 124 former patients. This was initially offered to 30 former patients who were over 15 years old, affected by the disease within the last 5 years, and had agreed to test it. Their opinions were collected by their doctor by e-mail, telephone, or during a consultation in an open-ended question and a non-directive interview. All patients were satisfied with the tool, with interest in testing it in the long term. Some former patients found that the tool provided them with some ease of mind; one, for instance, commented: \"I feel lighter. I allow myself to forget. I know I will get a notification when the time comes.\" Conclusions Freely available to all users, LOG-after: (1) provides help with determining personalized survivorship care plans for follow-up; (2) builds links with general practitioners; (3) empowers the patient; and (4) enables health data to be exported for analysis. Database URL for presentation: https://youtu.be/2Ga64iausJE

The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of gene-disease relationship and have been performed on adult but not pediatric cancers. We performed a deep multi-layer understanding of pan-cancer transcriptome data selected from the Treehouse Childhood Cancer Initiative through a co-expression network analysis. We identified six modules strongly associated with pediatric tumor histotypes that were functionally linked to developmental processes. Topological analyses highlighted that pediatric cancer predisposition genes and potential therapeutic targets were central regulators of cancer-histotype specific modules. A module was related to multiple pediatric malignancies with functions involved in DNA repair and cell cycle regulation. This canonical oncogenic module gathered most of the childhood cancer predisposition genes and clinically actionable genes. In pediatric acute leukemias, the driver genes were co-expressed in a module related to epigenetic and post-transcriptional processes, suggesting a critical role of these pathways in the progression of hematologic malignancies. This integrative pan-cancer study provides a thorough characterization of pediatric tumor-associated modules and paves the way for investigating novel candidate genes involved in childhood tumorigenesis.

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4–6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).

Background To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. Methods A cross‐sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long‐term follow‐up program, was conducted, and education‐related data were obtained via self‐report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. Results A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long‐term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. Conclusion Although the results are reassuring, socioeconomic and cancer‐related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long‐term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system.

T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B‐ALL, T‐ALL in this young population remains poorly characterized due to limited data and lacks evidence‐based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T‐ALL cases from a French national cohort, utilizing high‐throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of TLX1/3 dysregulation. Instead, we identified a significant prevalence of NKX2 rearrangements (n = 9, 33%), co‐occurring with MYB alterations (n = 5/9) or chromothripsis‐like events (n = 3/9). Additional findings included TAL1/‐like anomalies (30%), STAG2::LMO2 (15%), ETS rearrangements (15%), and rarely, KMT2A rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5‐year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), p = 0.86. Notably, alterations in NKX2, KMT2A, and STAG2::LMO2 delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with TAL1 or ETS dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T‐ALL in infants/toddlers. Large‐scale collaborative studies remain essential to confirm these findings and refine treatment strategies.

Background Childhood cancer confront the whole family with a traumatic event. Because brothers and sisters may encounter emotional problems that can remain for a long time and that only few studies have assessed their long‐term outcome, our present objectives were to describe the long‐term quality of life (QoL) of childhood leukemia survivors' siblings and to explore its determinant. Methods Brothers and sisters (from 8‐year‐old) of survivors included in the French LEA Cohort completed a QoL questionnaire (according to their age). Scores were compared with those reported by age‐ and gender‐matched French general population and by survivors. Using a clustering method, siblings were categorized into 3 groups depending on their level of QoL's scores and factors likely to be linked with these clusters were explored with multivariate analyses. Results We included 689 brothers and sisters (313 minors, 376 adults) and the mean time from diagnosis was 13.2 ± 6.6 years. Minor siblings reported higher QoL scores than general population (p < 0.001), but a lower score for relationship with family than survivors (p < 0.001). In adult siblings, Mental Component Summary score was lower than general population (p < 0.001). Level of siblings' QoL was linked with female gender, but no association was found with cancer‐related factors. Conclusion Brothers and sisters expressed a divergent perception of their long‐term QoL depending on their age. To minimize the impact from childhood to adulthood, long‐term attention should also be paid to siblings, often referred as “forgotten children”. Years after diagnosis, brothers and sisters reported a different perception of their Quality of Life (QoL) according to their age, suggesting a deterioration in adulthood compared to their peers. Being female was associated with the lowest QoL level, but no association was found with cancer‐related factors.

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)–derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamk acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.