Factors affecting the long-term prognosis of patients in the AYA generation with epithelial ovarian cancer: A multicenter propensity score matching analysis.

OBJECTIVE: Ovarian carcinoma (OvCa) is more common in the elderly, but also affects the adolescent and young adult (AYA) generation, which refers to those aged 15-39 years. Although the characteristics of OvCa may differ between AYAs and non-AYAs, limited information is currently available on differences in prognostic factors. Therefore, we herein investigated prognostic factors for and the prognosis of OvCa in AYAs. We also examined the prognostic impact of fertility-sparing surgery in a subgroup analysis. METHODS: We retrospectively collected data on 4897 patients with OvCa from the databases of multiple institutions and ultimately included 1161 patients with epithelial ovarian cancer (EOC). We performed a survival analysis to compare AYAs and non-AYAs with backgrounds that conformed to those of AYAs using the propensity score (PS) matching method. A Cox regression analysis was also conducted to evaluate each predictor of recurrence-free survival (RFS) and overall survival (OS) in the original population. As a subgroup analysis, a multivariate analysis stratified by the AYA and non-AYA generations was performed. RESULTS: In total, 119 AYA patients were included in this study. After PS adjustments, no significant differences were observed in RFS or OS between AYAs and non-AYAs. Prognostic factors differed between AYAs and non-AYAs, particularly in histology and cytology. A multivariate analysis stratified by the AYA and non-AYA generations described that uterine-preserving surgery (UPS) did not have a significant impact on the prognosis of AYAs or non-AYAs. In cases with recurrence, no significant differences were observed in RFS and recurrent sites in the two groups. CONCLUSION: Characteristic prognostic factors for EOC in AYAs were identified. The present results indicate the limited prognostic impact of UPS for EOC in AYAs.

Tumor-associated fibrosis: a unique mechanism promoting ovarian cancer metastasis and peritoneal dissemination.

Epithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.

Chondroitin Sulfate Proteoglycan 4 Provides New Treatment Approach to Preventing Peritoneal Dissemination in Ovarian Cancer.

Most epithelial ovarian cancer (EOC) patients are diagnosed with peritoneal dissemination. Cellular interactions are an important aspect of EOC cells when they detach from the primary site of the ovary. However, the mechanism remains underexplored. Our study aimed to reveal the role of chondroitin sulfate proteoglycan 4 (CSPG4) in EOC with a major focus on cell-cell interactions. We examined the expression of CSPG4 in clinical samples and cell lines of EOC. The proliferation, migration, and invasion abilities of the CSPG4 knockdown cells were assessed. We also assessed the role of CSPG4 in spheroid formation and peritoneal metastasis in an in vivo model using sh-CSPG4 EOC cell lines. Of the clinical samples, 23 (44.2%) samples expressed CSPG4. CSPG4 was associated with a worse prognosis in patients with advanced EOC. Among the EOC cell lines, aggressive cell lines, including ES2, expressed CSPG4. When CSPG4 was knocked down using siRNA or shRNA, the cell proliferation, migration, and invasion abilities were significantly decreased compared to the control cells. Proteomic analyses showed changes in the expression of proteins related to the cell movement pathways. Spheroid formation was significantly inhibited when CSPG4 was inhibited. The number of nodules and the tumor burden of the omentum were significantly decreased in the sh-CSPG4 mouse models. In the peritoneal wash fluid from mice injected with sh-CSPG4 EOC cells, significantly fewer spheroids were present. Reduced CSPG4 expression was observed in lymphoid enhancer-binding factor 1-inhibited cells. CSPG4 is associated with aggressive features of EOC and poor prognosis. CSPG4 could be a new treatment target for blocking peritoneal metastasis by inhibiting spheroid formation.

9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins.

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25-50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

Ovarian cancer: Novel mechanisms and therapeutic targets regarding the microenvironment in the abdominal cavity.

Ovarian cancer is an intractable disease that is mostly diagnosed at an advanced stage and has a high recurrence rate. The early development of characteristic peritoneal dissemination via ascites contributes to a poor prognosis. Based on the "seed and soil" theory, ovarian cancer is considered to form a disseminated tumor that interacts with the peritoneum; superficial mesothelial cells are structurally important. Thus far, we have reported that peritoneal mesothelial cells, which originally are ecological defenses, transform into ovarian cancer-associated mesothelial cells, which are allies of cancer. They are found to be actively involved in the formation of a friendly "soil" that promotes the survival of "seeds" of ovarian cancer cells. We also demonstrated that the progression of ovarian cancer and the induction of its refractory nature are partially mediated through competition and cooperation between ovarian cancer and mesothelial cells. We believe that it is necessary to shift the aim of treatment strategies from solely targeting cancer cells to focusing on the crosstalk between the surrounding environment and ovarian cancer, an approach that ultimately aims to achieve "coexistence" with cancer through disease control.

The prognostic impact of limited-staging surgery in patients with stage IA epithelial ovarian cancer: a multi-center study with a propensity score-adjusted analysis.

OBJECTIVE: Complete-staging surgery is recommended for stage IA ovarian cancer, but may be omitted for various reasons, including the preservation of fertility and an advanced age. We herein investigated the prognostic impact of limited-staging surgery in patients with stage IA epithelial ovarian cancer. METHODS: We retrospectively collected data on 4730 patients with malignant ovarian tumors from the databases of multiple institutions and ultimately included 293 with stage IA epithelial ovarian cancer. Limited-staging surgery was defined as one that did not involve hysterectomy, systematic retroperitoneal lymphadenectomy or the collection of ascites cytology. We used an inverse probability of treatment weighting analysis with propensity scores and estimated the hazard ratios of recurrence and death with limited-staging surgery. RESULTS: In total, 176 out of 293 patients (39.9%) were assigned to the limited-staging surgery group. After propensity score adjustments, no significant differences were observed in recurrence-free survival or overall survival between the limited- and complete-staging surgery groups. Even in the subgroup analysis with age stratification, recurrence-free survival and overall survival were similar in the limited- and complete-staging surgery groups. CONCLUSIONS: The present results indicate the limited prognostic impact of limited-staging surgery for stage IA epithelial ovarian cancer.

Obesity contributes to the stealth peritoneal dissemination of ovarian cancer: a multi-institutional retrospective cohort study.

OBJECTIVE: The clinical significance of a higher BMI on the prognosis of ovarian cancer remains controversial; therefore, a more detailed analysis is demanded. This study investigated the impact of BMI on peritoneum-specific recurrence to clarify the involvement of adipose tissue in the proliferation of cancer cells at sites of peritoneal dissemination. METHODS: Among 4,730 patients with malignant ovarian tumors, 280 diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIC epithelial ovarian cancer and who underwent complete resection in the primary surgery were included in the present study. RESULTS: There were 42, 201, and 37 women in the low, normal, and high BMI groups, respectively. Peritoneum-specific recurrence-free survival and overall survival were both significantly shorter in patients with a high BMI than in those with a normal BMI (p = 0.028 and 0.018, respectively). No significant differences were observed in the distribution of sites of recurrence between these two groups. A multivariate analysis identified obesity as an independent prognostic factor in addition to pT3 tumor staging and positive ascites cytology. CONCLUSIONS: Patients with a high BMI had a significantly worse prognosis than those with a normal BMI, and peritoneal adipose tissue may have contributed to this difference.

Who are the long-term survivors of recurrent ovarian carcinoma?: a retrospective analysis of a multicenter study.

BACKGROUND: The aim of the present study was to investigate the incidence and hallmarks of long-term survivors of recurrent ovarian carcinoma (LTSROC) in a large-scale retrospective cohort of patients from a multicenter study group. METHODS: We performed a regional multicenter retrospective study between January 1986 and September 2021 using clinical data collected under the central pathological review system. Patients who underwent surgery for primary OC at diagnosis and developed recurrent tumors after the initial treatment were included. We defined LTSROC as patients who survived for 5 years or longer after initial tumor recurrence and examined factors affecting the long-term survival of ROC and outcomes of LTSROC. RESULTS: We collected information on patients with malignant ovarian tumors and finally 657 of them that developed ROC were included in the study population. Sixty-eight (10.4%) patients were LTSROC while 399 (60.7%) were short-term survivors of recurrent ovarian carcinoma. In a multivariate logistic regression analysis, negative ascites cytology [odds ratio (OR) 1.865; 95% CI 1.026-3.393; p = 0.041] and a recurrence-free interval (RFI) of 1 year or longer (OR 2.896; 95% CI 1.546-5.425; p < 0.001) were identified as independent factors associated with LTSROC. Approximately 80% of LTSROC presented with solitary recurrent tumors. Furthermore, more than 50% of LTSROC underwent tumor debulking surgery for the first recurrent tumor with or without chemotherapy. CONCLUSION: RFI of 1 year or longer and negative ascites cytology in the initial surgery were identified as independent predictive factors for LTSROC.