Citations

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]

Background Crouzon syndrome is associated with severe respiratory impairment of the upper airway due in part to midfacial dysmorphology. We calculated the distinctive nasal diameter and pharyngeal airway volume in patients with Crouzon syndrome and compared them with age-matched control subjects. Methods Children with computed tomography scans in the absence of surgical intervention were included. Computed tomography scans were digitized and manipulated using Surgicase CMF (Materialise). Craniometric data relating to the midface and airway were collected. For all linear measurements, mean percent increases or decreases were calculated relative to the size of control subjects, and volumetric assessment of the airway was tabulated. Statistical analysis was performed using t test. Results Twenty-six computed tomography scans were included (control n = 17, Crouzon n = 9). All children were in early mixed dentition. Pharyngeal airway volume was decreased in patients with Crouzon syndrome relative to control subjects by 46% (P = 0.003). The distance from the posterior tongue to the posterior pharyngeal wall decreased 31% when comparing the Crouzon group versus the control (P = 0.04). Conclusions Three-dimensional analysis revealed notably decreased pharyngeal and nasal airway volumes in patients with Crouzon syndrome, but nasal bone tissue and soft tissue measurements showed very little change between patients and control subjects.