RESUMEN
We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses showed that most keratinocytes in normal skin had lower mutation burdens than melanocytes and fibroblasts, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens, suggesting that these mutations prime keratinocytes for transformation by increasing their mutation rate. Mutational profiling and spatial transcriptomics on squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study documents key events during the evolution of cutaneous squamous cell carcinoma.
RESUMEN
BACKGROUND: Skeletal maturity estimation is central in the management of scoliosis and lower-limb deformity. Utilizing demographic characteristics and modern computing, we sought to create a reliable, rapid, and accurate method for measuring skeletal maturity on an elbow radiograph. METHODS: Utilizing the Bolton-Brush Collection, 4 parameters from the modified Sauvegrain method and 7 novel parameters were screened. Ten parameters were evaluated on serial peripubertal elbow radiographs, using Greulich and Pyle (GP) skeletal age from corresponding hand radiographs as a comparison. Stepwise linear regression and generalized estimating equations were used to identify radiographic and demographic parameters for estimating skeletal maturity based on 90% of final height. The elbow system was compared with GP only; olecranon apophysis only; age, sex, and GP; age, sex, and olecranon apophysis; age, sex, and elbow system with anteroposterior and lateral parameters; age, sex, and elbow system with anteroposterior parameters; and age, sex, and elbow system with lateral parameters. RESULTS: In this study, 367 radiographs from 77 patients (40 girls and 37 boys) were included. Following stepwise linear regression, 4 radiographic parameters were included in the anteroposterior and lateral elbow system; 3 were included in the anteroposterior elbow system; and 4 were included in the lateral elbow system. The lateral elbow system predicted skeletal maturity with a mean discrepancy of 0.41 year and produced similar mean discrepancies to GP with age and sex (0.42; p = 0.93), and it trended toward better performance than the olecranon apophysis system with age and sex (0.43; p = 0.06). The lateral elbow system had the lowest percent of outlier predictions >1 year discrepant from the skeletal maturity reference (4.6%), although it was only significantly better than the GP-only group (29.4%) and the olecranon apophysis-only group (21.0%) (p < 0.001 for both). CONCLUSIONS: We systematically developed a lateral elbow system that performed equivalently to GP using 4 simple parameters and trended toward outperforming the olecranon apophysis systems in skeletal maturity estimation. Future clinical validation will be necessary to understand the utility of this system. CLINICAL RELEVANCE: The lateral elbow system may be a more accurate prediction of skeletal maturity compared with the previously described olecranon apophysis system and can be used to guide the management of many pediatric orthopaedic conditions.