Real-world evaluation of safety and effectiveness of dydrogesterone in the management of threatened abortion

Background: Threatened abortion is a relatively common complication during pregnancy. Inadequate production of endogenous progesterone is implicated as a risk factor for miscarriages. Thus, supplementation of external progesterone can be used as a preventive strategy in these women. Dydrogesterone a stereoisomer of progesterone has a good safety and tolerability profile and is known to effectively prevent pregnancy loss in women with threatened miscarriage, however, real-world data safety and effectiveness analysis of dydrogesterone in Indian patients was lacking. Therefore, this real-world retrospective analysis of the case reports was done to evaluate the safety, effectiveness, compliance, and tolerability of oral dydrogesterone in the treatment of women with threatened abortion.Methods: Data was collected from 194 obstetricians and gynaecologists in India, on the use of oral dydrogesterone in women presenting with threatened abortion in the first trimester of pregnancy.Results: Completed case report forms of patients who met the eligibility criteria (n = 617) were considered for the analysis. The main presenting symptom was vaginal bleeding/spotting with an additional symptom of abdominal cramp/pelvic pain/low back pain in 364 (69.07%) patients. Miscarriage was reported in 45 (7.29%) patients and 23 (3.98%) patients needed surgical intervention before 20 weeks of gestation with dydrogesterone treatment. The median time for relief of symptoms from the start of dydrogesterone tablets was 3.32 days for low back pain, 3.9 days for abdominal pain, and 4.37 days for the establishment of hemostasis. Treatment with dydrogesterone was found to be well-tolerated and adverse events were reported in 3.72% of the patients.Conclusions: This retrospective analysis suggests that dydrogesterone is safe and effective in reducing the incidence of pregnancy loss in women with threatened abortion

Integrated mutational landscape analysis of uterine leiomyosarcomas

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or on-cogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being po-tentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothrip-sis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-62 6510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring de-rangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/ or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and sug-gest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs