Background: Long-term musculoskeletal complications represent a growing burden for survivors of childhood acute lymphoblastic leukemia (cALL). This study aimed to describe impairments, activity limitations, and participation restrictions of survivors of cALL at highest risk for late morbidity (PETALE cohort). Procedure: This retrospective study, using cross-sectional observational data from the PETALE cohort, included a subgroup of survivors who presented extreme phenotypes of late effects. Participants completed bilateral hip magnetic resonance imaging (MRI), assessment of maximal isometric muscle strength (MIMS), range of motion (ROM), Near Tandem Balance (NTB), 6-Minute Walk Test (6MWT), Five Time Sit-to-Stand Test (FTSST)), and quality of life (QOL). Descriptive statistics and regression analyses were performed. Results: 97 survivors were included in this study. The selected survivors (24.2 ± 6.7 years old) trended toward lower scores for most outcomes compared to available expected values referenced from a healthy population except for QOL. Thirteen participants (14.6%, 18 hips) had hip ON (53.8% male). Female survivors had hip ON with higher severity score (66.7% female vs. 22.2% male). Survivors with hip ON had reduced hip external rotation ROM compared to those without (p<0.05). Relationships were found between MIMS and ROM outcomes, and with 6MWT. Our multiple linear regression model explained 27.6% of the variance of the 6MWT. Conclusions: Although they reported QOL in the range of healthy peers, long-term cALL survivors at highest risk for late morbidity had clinically significant impairments and activity limitations. These data are in keeping with the frailty phenotype described in childhood cancer survivors.

Platelet-Derived Growth Factor Receptor Beta (PDGFRB) is critically implicated in development. Germline pathogenic variants (GPVs) in PDGFRB result in several distinct inherited syndromes including primary familial brain calcifications (PFBC) and infantile myofibromatosis. To date, GPVs in PDGFRB have not been identified in children with brain tumors. Here, we describe the clinicopathological features of a 9-year-old male with a medulloblastoma and an 11-year-old female with a glioma. Sequencing of the blood and tumor samples revealed the same PDGFRB c.2959C>T (p. Arg987Trp) GPV in both children. Additional fusion genes DCTN1-ALK and TRIM24-MET were also identified in the patients’ tumors through RNAseq.

Background T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on pediatric T-LBL are scarce and, therefore, its molecular landscape has not been fully elucidated yet. Procedure To characterize the genetic and molecular heterogeneity of paediatric T-LBL, 33 patients were analyzed using an integrated approach, including targeted next generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. Results Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ to that described in T-ALL in terms of mutation incidence and global genomic complexity level but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the latter being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favorable outcome. Conclusions In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.