The morbidity and toxicity associated with current intensive treatment protocols for acute lymphoblastic leukemia in childhood become even more important as the vast majority of children can be cured and become long-term survivors. Osteonecrosis is one of the most common therapy-related and debilitating side effects of anti-leukemic treatment and can adversely affect long-term quality of life. Incidence and risk factors vary substantially between study groups and therapeutic regimens. We therefore analyzed 22 clinical trials of childhood acute lymphoblastic leukemia in terms of osteonecrosis incidence and risk factors. Adolescent age is the most significant risk factor, with patients >10 years old at the highest risk. Uncritical modification or even significant reduction of glucocorticoid dosage cannot be recommended at this stage. A novel and innovative approach to reduce osteonecrosis-associated morbidity might be systematic early screening for osteonecrosis by serial magnetic resonance images. However, discriminating patients at risk of functional impairment and debilitating progressive joint disease from asymptomatic patients still remains challenging.

Summary: Relapse remains the major cause of treatment failure in children with high‐risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem‐cell transplantation (allo‐SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo‐SCT enrolled in the Berlin‐Frankfurt‐Munster (BFM) ALL‐SCT‐BFM 2003 and ALL‐SCT‐BFM international 2007 studies. Median time from allo‐SCT to relapse was 7·7 months; median follow‐up from relapse after allo‐SCT until last follow‐up was 3·4 years. The 3‐year event‐free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo‐SCT, 26% of the children underwent a second allo‐SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo‐SCT hold promise to improve outcome in children with post allo‐SCT relapse.

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.

The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology.