Targeting homologous recombination deficiency in uterine leiomyosarcoma.

BACKGROUND: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. METHODS: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. RESULTS: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs. CONCLUSIONS: Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

Changed ophthalmic workload following introduction of digital retinal photography for retinopathy of prematurity screening.

BACKGROUND: ROP screening is vital in care of premature infants but is considered burdensome, difficult and time consuming for ophthalmologists. This study assessed the reduction in workload following the introduction of nurse-led WFDRI to a large neonatal nursery. METHODS: We report a retrospective audit of 628 infants screened for ROP in the years 2010, 2013 and 2019 at the Royal Women's Hospital, Victoria. The last complete year of screening for ROP using binocular indirect ophthalmoscopy (BIO) alone (2010) was compared with two subsequent years after the introduction of nurse-led WFDRI. The main outcome measures were the time taken to report and document WFDRI and the time taken to undertake BIO examination of a premature infant and document the results. RESULTS: The ophthalmologist's time taken to conduct BIO, review images and document the results per 100 patient examinations was reduced from 16.7 hours before introduction of WFDRI to 3.7 hours. Similarly, the weekly time spent on this component of ROP screening fell from 2.3 hours per week to 0.8 and 1.0 hours per week after introduction of WFDRI. CONCLUSIONS: The introduction of nurse-led WFDRI has resulted in a dramatic and sustained reduction in ophthalmologist workload involved in ROP screening in a large Australian neonatal nursery. This may result in improved retention of the ophthalmic workforce required to undertake ROP screening.