SUMMARY Tuberculosis associated with systemic lupus erythematosus (SLE) was studied in a cohort of 311 patients seen between 1963 to 1979. There were 16 such patients, giving rise to a prevalence rate of 5 %. The characteristics of SLE-associated tuberculosis include a high incidence of miliary and far-advanced pulmonary disease, delay in establishing diagnosis, especially the extrapulmonary form, and tendency to attribute symptoms like fever, malaise, and weight loss to the lupus process. Treatment was successful in 9 patients. Of the 7 deaths 5 were attributed directly to the mycobacterial infection and 2 to complications of SLE.
The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.
Primary myelofibrosis is a chronic clonal stem cell disorder that results in a build-up of marrow fibrosis and dysfunction, hypermetabolic states, and myeloid metaplasia. The clinical and radiological consequences can be quite diverse and range from the manifestations of osteosclerosis and extramedullary haematopoiesis to thrombohaemorrhagic complications from haemostatic dysfunction. In addition, there is the challenge of identifying less well-recognised sites of extramedullary haematopoiesis and their site-specific complications. The intent of this article is to illustrate the spectrum of primary myelofibrosis as declared though multimodality imaging, with examples of both common and rarer disease manifestations.
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.
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