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We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management., (© 2022. The Author(s).)

To characterize latent classes of diagnostic and/or treatment procedures among hospitalized U.S. adults, 18-64 years, with primary diagnosis of TBI from 2004-2014 Nationwide Inpatient Samples, latent class analysis (LCA) was applied to 10 procedure groups and differences between latent classes on injury, patient, hospital and healthcare utilization outcome characteristics were modeled using multivariable regression. Using 266,586 eligible records, LCA resulted in two classes of hospitalizations, namely, class I (n = 217,988) (mostly non-surgical) and class II (n = 48,598) (mostly surgical). Whereas orthopedic procedures were equally likely among latent classes, skin-related, physical medicine and rehabilitation procedures as well as behavioral health procedures were more likely among class I, and other types of procedures were more likely among class II. Class II patients were more likely to have moderate-to-severe TBI, to be admitted on weekends, to urban, medium-to-large hospitals in Midwestern, Southern or Western regions, and less likely to be > 30 years, female or non-White. Class II patients were also less likely to be discharged home and necessitated longer hospital stays and greater hospitalization charges. Surgery appears to distinguish two classes of hospitalized patients with TBI with divergent healthcare needs, informing the planning of healthcare services in this target population.

Bone marrow stromal cells isolated from a model of osteogenesis imperfecta (oim) mice, were transduced with a retrovirus (BAG) carrying the LacZ and neor genes after passage 21. The transduced cells retained the ability to express alkaline phosphatase activity in vitro when treated with recombinant human bone morphogenetic protein two (rhBMP-2), formed cartilage in vitro in aggregate cultures and formed bone in ceramic cubes after 6 weeks of implantation in nude mice. X-gal staining of ceramic cubes seeded with the transduced cells demonstrated the presence of LacZ-positive cells on the edges of bone and also in the lacunae of the newly formed bone 6 weeks after implantation. After infusion into femurs of oim mice, the transduced cells were detected in the marrow cavity and on the edges of the trabecular bone of the injected and contralateral femurs by X-gal staining and PCR analysis at 4, 10, 20, 30 and 40 days after injection. The LacZ gene was also detected in the lung and liver of the recipient mice at 4 and 10 days after injection but not at later time-periods. The present findings suggest that long-term cultured bone marrow stromal cells from osteogenesis imperfecta (OI) animals have the potential to traffic through the circulatory system, home to bone, form bone and continue to express exogenous genes. These findings open the possibility of using these cells as vehicles to deliver normal genes to bone as an alternative approach for the treatment of some forms of OI and certain other bone acquired and genetic diseases.