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Microvesicle proteomics of 187 utero-tubal lavage samples for early diagnosis of HGOC.• Machine learning-based classification of a 9-protein signature with high predictive power.• Signature has 70% sensitivity and 76.2% specificity, predicting stage I lesions.

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Nuclear translocation of transmembrane proteins was reported in high-grade serous ovarian cancer (HGSOC), a highly aggressive gynecological malignancy. Although the membrane receptor αvβ3 integrin is amply expressed in HGSOC and involved in disease progression, its nuclear localization was never demonstrated. Nuclear αvβ3 was explored in HGSOC cells (OVCAR3, KURAMOCHI, and JHOS4), nuclear localization signal (NLS) modified β3 OVCAR3, Chinese hamster ovaries (CHO-K1) and human embryonic kidney (HEK293) before/after transfections with β3/β1 integrins. We used the ImageStream technology, Western blots (WB), co immunoprecipitations (Co-IP), confocal immunofluorescence (IF) microscopy, flow cytometry for cell counts and cell cycle, wound healing assays and proteomics analyses. Fresh/archived tumor tissues were collected from nine HGSOC patients and normal ovarian and fallopian tube (FT) tissues from eight nononcological patients and assessed for nuclear αvβ3 by WB, confocal IF microscopy and immunohistochemistry (IHC). We identified nuclear αvβ3 in HGSOC cells and tissues, but not in normal ovaries and FTs. The nuclear integrin was Tyr 759 phosphorylated and functionally active. Nuclear αvβ3 enriched OVCAR3 cells demonstrated induced proliferation and oncogenic signaling, intact colony formation ability and inhibited migration. Proteomics analyses revealed a network of nuclear αvβ3-bound proteins, many of which with key cancer-relevant activities. Identification of atypical nuclear localization of the αvβ3 integrin in HGSOC challenges the prevalent conception that the setting in which this receptor exerts its pleiotropic actions is exclusively at the cell membrane. This discovery proposes αvβ3 moonlighting functions and may improve our understanding of the molecular basis of ovarian cancer pathogenesis.

BackgroundA prolonged latent phase is independently associated with an increased incidence of subsequent labor abnormalities. We aimed to compare between oxytocin augmentation, amniotomy and a combination of both on the duration of labor among women with a prolonged latent phase.MethodsWomen with a singleton fetus in cephalic presentation who have a prolonged latent phase, were randomly allocated to amniotomy (group 1), oxytocin (group 2) or both (group 3). A group of women who progressed spontaneously without intervention composed the control group (group 4). The primary outcome was the duration of time from initiation of augmentation until delivery.ResultsA total of 213 women were consented and randomized to group 1 (70 women), group 2 (72 women) and group 3 (71 women). Group 4 was composed from additional 70 women. A mean reduction of 120 minutes in labor duration was observed among group 3 compared to group 1 (p = 0.08) and 180 minutes compared to group 2 and 4 (p = 0.001). Women in group 3 had a shorter length of time from augmentation until the beginning of the active phase and a shorter first stage of labor than group 1 (p = 0.03), group 2 (p = 0.001) and group 4 (p = 0.001). Satisfaction was greater among group 3 and 4. Mode of delivery and neonatal outcome were comparable between the groups.ConclusionLabor augmentation by combined amniotomy and oxytocin among women with a prolonged latent phase at term seems superior compared to either of them alone.

Although not significant, BRCA mutation carriers tended to have more advanced disease at diagnosis. However, the survival was similar irrespective of the BRCA status in this small group. Further research is needed to confirm these findings in a larger cohort.

Objective. BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy-associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation. Mateials and Methods. A retrospective cohort study of patients with EOC receiving first-line platinum-based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony-stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers.Results. A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia <1500 per mL: 6% vs. 0%, p = .12; thrombocytopenia <100,000 per mL: 23% vs. 9%, p = .07), but these differences were not statistically significant. Similarly, no significant differences were found in surrogates of bone marrow toxicity such as blood transfusions, use of gCSF, episodes of febrile neutropenia, or treatment delays. Conclusion. BRCA mutation carriers and noncarriers receiving first-line platinum-based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations. The Oncologist 2019;24:e1471-e1475 Implications for Practice: Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first-line platinum-based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule.