RESUMO
Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy.
RESUMO
Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.
Assuntos
Adenocarcinoma in Situ , Carcinoma in Situ , Carcinoma , Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Feminino , Humanos , Proteína BRCA1 , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Neoplasias Ovarianas/patologia , Antígeno Ki-67 , Proteína Supressora de Tumor p53/genética , Proteína BRCA2 , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , DNARESUMO
PURPOSE: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. EXPERIMENTAL DESIGN: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. RESULTS: We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. CONCLUSIONS: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.