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ObjectiveUterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS.MethodsUCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells.ResultsThe expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected.ConclusionThese results suggest that the EMT plays an essential role in the pathogenesis of UCS.

Objective This study aims to clarify the incidence of Aurora kinase A (Aurora-A) protein expression and its correlation with clinical parameters in ovarian clear cell carcinoma (OCCC) tumor tissues. In addition, we assessed the efficacy of ENMD-2076, a novel selective Aurora-A inhibitor, in combination with chemotherapeutic agents for the treatment of OCCC. Methods/Materials Aurora-A protein expression was determined by immunohistochemical staining of OCCC specimens from 56 patients to evaluate its correlation with clinical outcomes in OCCC. In the in vitro study, 6 OCCC cell lines were exposed to ENMD-2076 in combination with cisplatin, SN38, doxorubicin, or paclitaxel, and cell proliferation, cell cycle distribution, and apoptosis were assessed. Results The 5-year survival rates of International Federation of Gynecology and Obstetrics stages IC3 to IV patients with intermediate or strong Aurora-A expression were significantly lower than those of patients with negative or weak Aurora-A expression. Increased Aurora-A expression was associated with significantly worse overall survival of International Federation of Gynecology and Obstetrics stages IC3 to IV patients (21% vs 77%). Multivariate analysis revealed that Aurora-A expression was an independent prognostic factor for stages IC3 to IV OCCC patients. Furthermore, synergistic effects were observed with ENMD-2076 in combination with cisplatin or SN-38 in 4 of the 6 tested cell lines. ENMD-2076 dramatically enhanced apoptosis and cell cycle arrest at the G2/M phase induced by cisplatin. Conclusions Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC. The results suggested that chemotherapy, including ENMD-2076 in combination with cisplatin, is a potential treatment modality for patients with OCCC.

Treatment beyond progressive disease (PD) is a concept that even after drugs become ineffective, their continued use is more beneficial for patients than their discontinuation. In recent years, a concept of bevacizumab beyond PD (BBP) has attracted attention in the treatment of various cancers, and the usefulness of this concept has been evaluated. BBP has been proven to prolong overall survival (OS) in recurrent colorectal cancer and progression-free survival (PFS) in recurrent breast and lung cancers. With regard to the treatment of ovarian cancer, the MITO16/MaNGO-OV2B study (the Multicenter Phase III Randomized Study with Second Line Chemotherapy Plus or Minus Bevacizumab in Patients with Platinum Sensitive Epithelial Ovarian Cancer Recurrence After a Bevacizumab/Chemotherapy First Line) was conducted in patients with platinum-sensitive recurrence and the JGOG3023 study (the Open-Label, Randomized, Phase II Trial Evaluating the Efficacy and Safety of Standard of Care with or Without Bevacizumab in Platinum-Resistant Ovarian Cancer Patients Previously Treated with Bevacizumab for Front-Line or Platinum-Sensitive Ovarian Cancer) was conducted in patients with platinum-resistant recurrence. The MITO16/MaNGO-OV2B study, reported in the 2018 annual meeting of the American Society of Clinical Oncology, showed that BBP achieved prolonged PFS. In the JGOG3023 study, enrollment of patients was completed in December 2018, and the follow-up period has been initiated. Proving the effectiveness of BBP in the treatment of ovarian cancer may provide a new therapeutic strategy and contribute to improved treatment outcomes in patients with poor prognosis and limited therapeutic options.

Recent studies have shown that cancer-associated fibroblasts (CAFs) and the epithelial-mesenchymal transition (EMT) contribute to invasive and metastatic abilities of ovarian cancer (OC) cells. In the present study, we attempted to identify the role of CAF- and EMT-related proteins in OCs, including serous carcinoma, mucinous carcinoma, endometrioid carcinoma and clear cell carcinoma using an immunohistochemical approach. The following CAF-related markers were used: CD10, podoplanin, fibroblast activating protein (FAP), platelet derived growth factor receptor (PDGFRα), PDGFRβ, S100A4 and α-smooth muscle actin (α-SMA). In addition, the following EMT-related markers were investigated: Slug, TWIST1 and ZEB1We performed hierarchical cluster analysis to group the samples according to their scoring. Subgroup 1 was characterized by high expression of CD10, podoplanin, α-SMA, Slug and ZEB1, whereas subgroup 2 was closely associated with high expression of podoplanin, PDGFRα, PDGFRβ, α-SMA, and Slug. In addition, marked expression of CD10 was observed in subgroup 3. High expression of α-SMA was a distinctive feature in subgroup 4, and expression of podoplanin and α-SMA characterized subgroup 5. Each subgroup was correlated with a histological type. The fact that different histological types were associated with different subgroups suggests the presence of distinct and heterogeneous subpopulations of CAFs in OC.

Cervical cancer is a malignant neoplastic disease that is the fourth most commonly occurring cancer in women worldwide. Since the introduction of angiogenesis inhibitors, treatments for recurrent and advanced cervical cancers have improved significantly in the past five years. However, the median overall survival in advanced cervical cancer is 16.8 months, with a 5-year overall survival rate of 68% for all stages, indicating that the effects of the treatment are still unsatisfactory. The development of a new treatment method is therefore imperative. Recently, in the clinical oncology field, remarkable progress has been made in immunotherapy. Immunotherapy is already established as standard therapy in some fields and in some types of cancers, and its clinical role in all areas, including the gynecology field, will change further based on the outcomes of currently ongoing clinical trials. This manuscript summarizes the results from previous clinical trials in cervical cancer and describes the ongoing clinical trials, as well as future directions.