Primary extrauterine endometrial stromal sarcoma: response to hormone therapy

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Primary extrauterine endometrial stromal sarcoma

Cervical cancer complicating pelvic organ prolapse, and use of a pessary to restore anatomy for optimal radiation: A case report

Cervical cancer is the most common gynecologic malignancy worldwide and the third most common gynecologic cancer in the USA. Improved screening methods such as liquid-based cytology accompanied by Human Papilloma Virus (HPV) co-testing have contributed to a declining incidence of cervical cancer. There are approximately 13,000 new cases per year in the United States, accounting for 4200 deaths (Siegel et al., 2011). Pelvic organ prolapse increases with age, obesity and parity. In the absence of bothersome urinary, gastrointestinal or pressure symptoms, patients may choose conservative management options.The index patient was a 72 year old woman with a known history of pelvic organ prolapse who had been managed by her primary physician for 7 years until she developed new-onset vaginal bleeding. One month following worsening prolapse and increased vaginal bleeding she presented to the emergency department and was evaluated. On physical examination the cervix appeared as an 8 cm exophytic fungating mass extruding from the vagina and bled easily from areas of apparent necrosis. Multiple biopsies confirmed an invasive squamous cell carcinoma. The patient underwent the insertion of a Gelhorn pessary and perineorrhaphy to reduce her procidentia, cystocele and enterocele. Chemotherapy with Cisplatin and radiation therapy in the form of brachytherapy and external beam radiation therapy were then administered with curative intent.Cervical cancer complicating a uterine procidentia in an elderly patient is a rare occurrence in the United States and requires a multidisciplinary approach involving a urogynecologist, a gynecologic oncologist and a radiation oncologist. Nonetheless, in carefully selected patients, the outcome can be successful. Keywords: Cervical cancer, Pelvic organ prolapse, Procidentia, Pessar

Enhanced Ovarian Cancer Tumorigenesis and Metastasis by the Macrophage Colony-Stimulating Factor1

Coexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) in metastatic ovarian cancer specimens is a predictor of poor outcome in epithelial ovarian cancer. This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype. Our current work sought to validate this autocrine stimulation model using stable transfection of a 4-kb CSF-1 construct into otherwise nonvirulent Bix3 ovarian cancer cells. A representative clone, Bix3T8.2, produced a 72-fold increase in CSF-1 gene transcription rate (by nuclear run-off assays) and a 57-fold increase in secreted CSF-1 protein (by sandwich ELISA), compared to parent cells. Comparison of Bix3T8.2 invasion, adhesion, and motility in vitro and metastasis in vivo were made to parental and transfectant controls. Up to 12-fold higher invasiveness was seen with Bix3T8.2 and 2- and 6-fold higher adhesion and motility, respectively, over controls in vitro. In nude mice, i.p. injection of Bix3T8.2 produced a wide array of visceral, nodal, and distant metastasis with a degree of enhanced tumor burden not seen in any of the 10 mice inoculated with transfectant control cells. Complete absence of tumor take distinguished 40% of mice implanted with transfectant control cells. Disruption of this autocrine loop using antisense oligomer therapy against CSF-1R and 3′ untranslated region knockdown of CSF-1 protein resulted in reversal of in vitro and in vivo tumor phenotypes. This CSF-1 feedback loop offers a model by which novel biologic therapies can potentially target multiple levels of this pathway

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old