The sublingual cavity (SC) has been shown to play an important role in shaping the spectra of consonants, potentially distinguishing /s/ from /∫/. This work reports on acoustic-articulatory experiments using MRI and mechanical modeling designed to investigate the details of how the SC acts as an acoustic filter and whether it also affects the aeroacoustic source in fricative production. Five American English subjects were imaged while producing fricatives in various vowel contexts. Two subjects that show opposite patterns were studied in detail. In M1, the /s/-/∫/ distinction is mainly carried by SC presence and lip protrusion in /∫/ versus absence in /s/, resulting in marked spectral differences. M2 exhibits significant variability in SC shape and size, and tongue and lip position, in both fricatives; the acoustic spectra likewise vary. Mechanical model experiments show that the noise generation changes as the sublingual cavity is filled in. The main resonance frequency does not necessarily change. It seems thus that the sublingual cavity is just one of many articulatory variables available to the speaker and may not be the principal cause of observed acoustic differences in all subjects. [Work supported by NIH NIDCD DC 006705 to Haskins, NIH NIDCD T32 DC00038 to MIT-SHBT.]

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16 Background: African American (AA) men have higher prostate cancer (PC) incidence and PC-specific mortality than non-AA men. Socioeconomic/healthcare access and environmental factors contribute to the disparity in clinical outcomes. Moreover, AA PC exhibits increased inflammatory and immune response signaling, which may contribute to its aggressive behavior, but also allow for therapeutic intervention. Microsatellite instability (MSI) is a tissue-agnostic biomarker predictive of response to immune-checkpoint inhibition (pembrolizumab) that can be assessed by NGS testing of tumor tissue or circulating tumor DNA (ctDNA, liquid biopsy). The latter is particularly relevant for patients with PC, a disease which frequently metastasizes to bone and other deep sites, making conventional tissue biopsies invasive, painful and potentially risky. Methods: We retrospectively analyzed NGS results obtained via Tempus|xT tissue assay and/or Tempus|xF liquid biopsy assay for MSI, as well as clinical data (response to pembrolizumab), from 100 PC patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic disease at Ben Taub Hospital (BTH, a safety net hospital in Houston serving a patient population of which 91% are racial/ethnic minorities). We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC patients (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: MSI-High status (MSI-H) was detected using xT and/or xF assays in 4/100 (4%) of patients in the BTH cohort and in 62/2090 (3%) of metastatic PC patients in the nationwide Tempus Labs cohort. Specifically, within the AA PC patient population, MSI-H was detected in 2/53 (3.7%) in the BTH cohort and in 8/225 (3.6%) in the nationwide Tempus Labs cohort. For those patients who had both tissue and liquid biopsy testing, there was 100% concordance in MSI-H detection between the two assays. Genomically-driven treatment of two MSI-H AA CRPC patients with pembrolizumab resulted in prompt and durable clinical, biochemical and molecular responses, with precipitous decline in PSA levels to below detection limit, complete radiographic response of metastatic lymphadenopathy, radiographic non-progression of visceral disease (per iRECIST and PC Working Group 3 criteria) and disappearance of PC-derived ctDNA mutations in the liquid biopsy. Conclusions: MSI-H status is present in advanced AA PC at a frequency comparable to non-AA PC. Liquid biopsy (xF assay) is a minimally invasive tool that allows detection of MSI-H in PC patients, as well as longitudinal monitoring of response to treatment with pembrolizumab. Liquid biopsy conversion from positive to negative may provide reassurance that any residual lesions seen on imaging represent treated/inactive disease.

14 Background: The largest US cancer health disparity exists in prostate cancer (PC), with African American (AA) men having: ~1.6-1.8-fold higher risk of developing PC; younger age and more advanced stage at diagnosis; increased risk of recurrence after radical prostatectomy; and up to 2.5-fold higher mortality rate relative to men of other ancestries. Access to healthcare and other socioeconomic and environmental factors contribute to the disparity in clinical outcomes. However, genetic factors may also be involved, and their role and prevalence need to be better defined, especially in real-world clinical settings, as the high cost of next-generation sequencing (NGS) may have resulted in underrepresentation of uninsured and minority patients in prior studies. Methods: We retrospectively analyzed NGS data obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations detected in 100 patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic PC at Ben Taub Hospital (BTH), a safety net hospital in Harris County/Houston serving a patient population of which 91% are racial/ethnic minorities. For confirmation, we analyzed de-identified NGS data from a nationwide cohort of 1,211 metastatic PC patients (213 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: We found higher frequencies of AR (18.9%), TP53 (41.5%), SPOP (20.7%) and homologous recombination repair (HRR) pathway gene mutations, in particular BRCA2 (17%), in our AA BTH cohort, as compared to PC patients of other races/ethnicities. The latter finding was confirmed in the nationwide Tempus Labs cohort, with 91/213 (42.7%) AA patients exhibiting mutation in at least one of 14 HRR pathway genes associated with PC sensitivity to PARP inhibitors, compared to 347/998 (34.7%) non-AA patients (P < 0.05). This difference was mainly driven by higher frequency of BRCA2 (16.9%), CDK12 (8%) and PALB2 (5.2%) mutations in AA patients. In both cohorts, TMPRSS2 fusions were much less common in AA PC patients. Conclusions: The observed high frequency of mutations in key PC drivers in AA patients may reflect differences in disease biology between racial/ethnic groups or the more advanced disease presentation of AA patients due to socioeconomic factors delaying access to healthcare. Our study provides a real-world snapshot of the genomic landscape of advanced PC in a safety net hospital serving large racial/ethnic minority populations and highlights the role that NGS testing can play to improve their access to treatment with novel targeted therapies and to biomarker-based Precision Oncology clinical trials.