Different approach to medical decision-making in difficult circumstances: Kittay's Ethics of Care.

The onset of the COVID-19 pandemic has necessitated advances in bioethical approaches to medical decision-making. This paper develops an alternative method for rationing care during periods of resource scarcity. Typical approaches to triaging rely on utilitarian calculations; however, this approach introduces a problematic antihumanist sentiment, inviting the proposition of alternative schemata. As such, we suggest a feminist approach to medical decision-making, founded in and expanding upon the framework of Eva Kittay's Ethics of Care. We suggest that this new structure addresses the issue of medical decision-making during times of resource scarcity just as well as pure utilitarian approaches while better attending to their significant theoretical concerns, forming a coherent alternative to the current bioethical consensus.

Clinical Validation of a Cell-Free DNA Gene Panel.

The use of liquid biopsies to identify driver mutations in patients with solid tumors holds great promise for performing targeted therapy selection, monitoring disease progression, and detecting treatment resistance mechanisms. We describe herein the development and clinical validation of a 28-gene cell-free DNA panel that targets the most common genetic alterations in solid tumors. Bioinformatic and variant filtering solutions were developed to improve test sensitivity and specificity. The panel and these tools were used to analyze commercially available controls, allowing establishment of a limit of detection allele fraction cutoff of 0.25%, with 100% (95% CI, 81.5%-100%) specificity and 89.8% (95% CI, 81.0%-94.9%) sensitivity. In addition, we analyzed a total of 163 blood samples from patients with metastatic cancer (n = 123) and demonstrated a >90% sensitivity for detecting previously identified expected mutations. Longitudinal monitoring of patients revealed a strong correlation of variant allele frequency changes and clinical outcome. Additional clinically relevant information included identification of resistance mutations in patients receiving targeted treatment and detection of complex patterns of mutational heterogeneity. Achieving lower limits of detection will require additional improvements to molecular barcoding; however, these data strongly support clinical implementation of cell-free DNA panels in advanced cancer patients.

DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.

Genotype-targeted local therapy of glioma.

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

Draft Genome Sequences of Four Genetically Distinct Human Isolates of Streptococcus dysgalactiae subsp. equisimilis.

ß-Hemolytic group C and group G streptococci (GCS-GGS; Streptococcus dysgalactiae subsp. equisimilis) emerged as human pathogens in the late 1970s. We report here the draft genome sequences of four genetically distinct human strains of GCS-GGS isolated between the 1960s and 1980s. Comparative analysis of these genomes may provide a deeper understanding of GCS-GGS genome and virulence evolution.