Caries Lesion Assessment Using 3D Virtual Models by Examiners with Different Degrees of Clinical Experience.

Background and Objectives: Dental caries is a preventable, reversible disease in its early stages. This study evaluated the intra-rater agreement of International Caries Assessment and Detection System (ICDAS) scores with Medit i500® and Omnicam® scanners versus traditional clinical examinations and the inter-rater agreement using the Omnicam® among senior dentists and dental students and between these two groups. Materials and Methods: A total of 24 patients aged between 21 and 34 years, randomly selected from dental students and interns, underwent four examinations (three intraoral scans and one clinical examination), and the corresponding ICDAS scores were recorded by a randomly selected rater out of the 31 available examiners. The examination team consisted of dental students, dentists with less than 3 years, and dentists with more than 5 years of clinical experience. The following inter- and intra-rater agreement tests for the ordinal data were chosen: Fleiss' kappa coefficient, Cohen's weighted kappa, and inter-class correlations. Results: For all examination techniques, there was statistically significant agreement for the experienced raters (p < 0.05). The highest positive interclass correlation was obtained for inter-rater agreement tests of 288 observations recorded by senior dentists: ICC = 0.969 (95% CI 0.949-0.981). Conclusions: Intra-rater reliability was excellent for Omnicam compared to clinical exams conducted by senior dentists but moderate for Medit i500. Although inter-rater agreement using Omnicam was poor between students and between senior dentists and students, it was excellent among senior dentists.

Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer.

: Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F in vitro at high drug concentrations. ALCL xenografts selected in vivo showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations. Interestingly, intracellular localization of NPM/ALKN1178H skewed toward the cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of resistant cells showed significant alteration of PI3K/AKT and RAS/MAPK pathways. Functional validation by small-molecule inhibitors confirmed the involvement of these pathways in resistance to lorlatinib. NSCLC cells exposed in vitro to lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and proteomic profiling of lorlatinib-resistant cells revealed a truncating NF1 mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive characterization of resistance mechanisms that may arise in different ALK-positive cancers following lorlatinib treatment. SIGNIFICANCE: High-throughput genomic, transcriptomic, and proteomic profiling reveals various mechanisms by which multiple tumor types acquire resistance to the third-generation ALK inhibitor lorlatinib.