Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway

PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient (HRP) EOC is limited. Thus, new therapeutic strategy for HRP EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HRP cases. These data suggested that anti-angiogenic agents might potentiate the response to PARP inhibitors in EOC cells. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HRP EOC cells by suppressing HR activity. Most of the γ-H2AX foci were co-localized with RAD51 foci in control cells. However, most of the RAD51 were decreased in the bevacizumab-treated cells. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. CRY1 is one of the transcriptional coregulators associated with circadian rhythm and has recently been reported to regulate the expression of genes required for HR in cancer cells. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/VEGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC

CA-125 early dynamics to predict overall survival in women with newly diagnosed advanced ovarian cancer based on meta-analysis data

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients’ monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy

Copy Number Analysis Identifies Novel Interactions Between Genomic Loci in Ovarian Cancer

Ovarian cancer is a heterogeneous disease displaying complex genomic alterations, and consequently, it has been difficult to determine the most relevant copy number alterations with the scale of studies to date. We obtained genome-wide copy number alteration (CNA) data from four different SNP array platforms, with a final data set of 398 ovarian tumours, mostly of the serous histological subtype. Frequent CNA aberrations targeted many thousands of genes. However, high-level amplicons and homozygous deletions enabled filtering of this list to the most relevant. The large data set enabled refinement of minimal regions and identification of rare amplicons such as at 1p34 and 20q11. We performed a novel co-occurrence analysis to assess cooperation and exclusivity of CNAs and analysed their relationship to patient outcome. Positive associations were identified between gains on 19 and 20q, gain of 20q and loss of X, and between several regions of loss, particularly 17q. We found weak correlations of CNA at genomic loci such as 19q12 with clinical outcome. We also assessed genomic instability measures and found a correlation of the number of higher amplitude gains with poorer overall survival. By assembling the largest collection of ovarian copy number data to date, we have been able to identify the most frequent aberrations and their interactions

Feasibility of reduced port surgery applying Higuchi's transverse incision

Objective: Higuchi's transverse incision is made at a lower position than the Pfannenstiel transverse incision and is superior in terms of cosmetic outcomes. The purpose of this study was to examine the safety and efficacy of novel forms of reduced port surgery for ovarian cysts and uterine fibroids applying Higuchi's transverse incision. Methods: In 33 patients with ovarian cysts who underwent low-position single-incision laparoscopic surgery (L-SILS)-modified single-port laparoscopy placed in the 2–3-cm Higuchi's incision above the pubis, patient's characteristics and perioperative outcomes were compared with those of patients who underwent multiport laparoscopy (n=53). In addition, 18 patients with uterine fibroids who underwent dual-port laparoscopically assisted myomectomy without using power morcellators and conventional four-port laparoscopically assisted myomectomy were investigated. Results: There were no significant differences between L-SILS and multiport laparoscopy in tumor diameter, bleeding, hospital stay, or postoperative pain. However, the L-SILS group demonstrated significantly shorter operative and pneumoperitoneum times (p<0.01 and p<0.01). In comparison with cases of uterine fibroids, no significant differences were found in maximum fibroid diameter, operative time, pneumoperitoneum time, or bleeding. However, the dual-port laparoscopically assisted myomectomy group demonstrated a significantly shorter length of hospital stay than the conventional laparoscopically assisted myomectomy group (p<0.05). Conclusion: We reported novel forms of reduced port surgery applying Higuchi's transverse incision. It was suggested that these procedures are relatively simple, but ensure the same safety and efficacy as conventional methods. We intend to increase the number of cases and examine safety, efficacy, and patient satisfaction for these procedures

Laparoscopic conservative surgery for massive ovarian edema with torsion

Massive ovarian edema is a rare condition in which intermittent torsion of the ovary at its pedicle obstructs venous and lymphatic drainage and results in the development of edema in the ovarian stroma. Massive ovarian edema occurs in young women, and most women undergo oophorectomy or wedge resection of the ovary to verify the presence of a neoplasm. We report a case of massive ovarian edema with torsion in a patient who underwent laparoscopic surgery with preserved ovarian function. It is clinically important to make a diagnosis appropriately and rapidly to prevent unnecessary oophorectomy and preserve ovarian function

MicroRNA Gene Expression Signature Driven by <i>miR-9</i> Overexpression in Ovarian Clear Cell Carcinoma

<div><p>Previous studies have identified microRNA (miRNA) involvement in human cancers. This study aimed to elucidate potential clinical and biological associations of ovarian cancer-related miRNA gene expression profiles in high-grade serous carcinoma (HGSC) and ovarian clear cell carcinoma (OCCC). Accordingly, we investigated 27 patients with ovarian cancer (12 HGSC and 15 OCCC cases) using quantitative real-time reverse transcription polymerase chain reaction to determine the cancer-related miRNA expressions. Gene Cluster 3.0 was used for hierarchical clustering analysis, and differentially expressed miRNAs between HGSC and OCCC were identified by the class comparison analysis using BRB-ArrayTools. An unsupervised hierarchical clustering analysis identified two distinct miRNA expression clusters, with histological subtype-related significant differences in the associations between clusters and clinicopathological features. A comparison of miRNA expression in HGSCs and OCCCs identified five miRNAs (<i>miR-132</i>, <i>miR-9</i>, <i>miR-126</i>, <i>miR-34a</i>, and <i>miR-21</i>), with OCCCs demonstrating a statistically higher expression. Further investigation of the biological significance of <i>miR-9</i> overexpression in OCCC revealed that <i>miR-9</i> inhibition reduced the cell invasion ability and upregulated E-cadherin expression. Using a luciferase reporter assay, we further demonstrated the direct binding of <i>miR-9</i> to E-cadherin. Global cancer-related miRNA expression analysis identified statistically unique profiles that could discriminate ovarian cancer histotypes. In OCCC, <i>miR-9</i> overexpression may affect pathogenesis by targeting E-cadherin, thereby inducing an epithelial–mesenchymal transition. Therefore, <i>miR-9</i> may be a promising therapeutic target strategy for OCCC.</p></div

Clinicopathological Characteristics of Patients with Ovarian Cancer.

<p>Clinicopathological Characteristics of Patients with Ovarian Cancer.</p

Cancer-related miRNA expression profiles of 27 patients with ovarian cancer.

<p>An unsupervised hierarchical clustering analysis of 87 miRNA expression in 27 patients with ovarian cancer, including the calculated centered correlation distances and average linkages, identified two main clusters, A and B.</p

Differentially Expressed miRNAs in OCCC <i>vs</i>. HGSC.

<p>Differentially Expressed miRNAs in OCCC <i>vs</i>. HGSC.</p

Validating original data by individual real-time RT-PCR analysis for both cohorts.

<p>Individual Taqman MicroRNA assays were used to analyze the relative expression of <i>miR-9</i> (A), <i>miR-132</i> (B), <i>miR-126</i> (C), and <i>miR-34a</i> (D) in the original 27 and additional 23 cases. Horizontal lines inside dots represent the median values.</p