Epithelial Ovarian Cancer Patients Research Articles

Randomised Controlled Trial Evaluating the Impact of Intravenous Iron (ferric carboxymaltose) Supplementation Among Epithelial Ovarian Cancer Patients with Anemia

Randomised Controlled Trial Evaluating the Impact of Intravenous Iron (ferric carboxymaltose) Supplementation Among Epithelial Ovarian Cancer Patients with Anemia

Immunological impact of intraperitoneal and intravenous chemotherapy in ovarian cancer, translational analyses of the Phase 3 iPocc trial

BackgroundThe iPocc trial, a randomized, global phase 3 study that compared intraperitoneal (IP) and intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients, demonstrated improved progression-free survival in patients who received IP chemotherapy. The present study aimed to investigate the role of preexisting tumor immunity in the clinical outcomes of patients receiving IP chemotherapy. MethodsThis study involved analyzing patient data from the iPocc trial, selectively of those whose tumor specimens were preserved at the time of primary surgery. A total of 116 cases ((IP; n = 59), (IV; n = 57)) were subjected to microarray analysis. Single-sample gene set enrichment analyses were performed to evaluate the tumor immune microenvironment. ResultsPatients with enhanced tumor infiltration of T cells, natural killer (NK) cells, and cytotoxic lymphocytes in the IP group had a longer overall survival (OS) than those in the IV group, but not in the group with low infiltration. IP therapy improved the OS of patients with high expression of immune-related genes such as CD8A and FOXP3. In patients' subdivided into “immune Hot” and “immune Cold” groups based on hierarchical clustering analysis using four parameters representing “Innate immunity,” “T cells,” “IFNG response” and “Inhibitory molecules,” IP therapy significantly improved prognosis in the “immune Hot” group, but not in the “immune Cold” group compared to that of IV therapy. ConclusionsIP chemotherapy enhances the survival rates of patients with EOC with an immune-Hot phenotype in the tumor microenvironment prior to treatment.(Japan Registry of Clinical Trials number, jRCTs031180141.)

Integrated proteomics and scRNA-seq analyses of ovarian cancer reveal molecular subtype-associated cell landscapes and immunotherapy targets.

Epithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, yet understanding the connections between its molecular subtypes and their therapeutic implications remains incomplete. We conducted mass spectrometry-based proteomics analyses of 154 EOC tumour samples and 29 normal fallopian tubes, and single-cell RNA sequencing (scRNA-seq) analyses of an additional eight EOC tumours to classify proteomic subtypes and assess their cellular ecosystems and clinical significance. The efficacy of identified therapeutic targets was evaluated in patient-derived xenograft (PDX) and orthotopic mouse models. We identified four proteomic subtypes with distinct clinical relevance: malignant proliferative (C1), immune infiltrating (C2), Fallopian-like (C3) and differentiated (C4) subtypes. C2 subtype was characterized by lymphocyte infiltration, notably an increased presence of GZMK CD8+ T cells and phagocytosis-like MRC+ macrophages. Additionally, we identified CD40 as a specific prognostic factor for C2 subtype. The interaction between CD40+ phagocytosis-like macrophages and CD40RL+ IL17R CD4+ T cells was correlated with a favourable prognosis. Finally, we established a druggable landscape for non-immune EOC patients and verified a TYMP inhibitor as a promising therapeutic strategy. Our study refines the current immune subtype for EOC, highlighting CD40 agonists as promising therapies for C2 subtype patients and targeting TYMP for non-immune patients.

The Diagnostic Value of 3.0 T Magnetic Resonance Imaging Combined with Carbohydrate Antigen 125 and Human Epididymis Protein 4 in Epithelial Ovarian Cancer

Background: Epithelial ovarian cancer (EOC) is among the top 5 causes of cancer-associated death in women. We explored the diagnostic value of 3.0 T magnetic resonance imaging (MRI) combined with carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) on EOC. Methods: Among 380 ovarian space-occupying patients in this retrospective analysis, 344 were included, 59 were excluded, 25 had incomplete clinical data, and 260 were finally included as the subjects. Patients were classified into the EOC (110 patients with EOC) and N-EOC (150 patients without EOC) groups. The levels of interleukin-6 (IL-6), C-reactive protein (CRP), follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), CA125, and HE4 were determined. The apparent diffusion coefficient (ADC) value and the clinical diagnostic value of MRI, CA125, HE4, and their combination were analyzed. Results: There were significant differences in tumor family history, gravidity, parity, IL-6, CRP, FSH, LH, AMH, and ADC value between EOC and N-EOC patients (all p < 0.05). EOC patients exhibited highly-expressed CA125 and HE4 (p < 0.01). CA125/HE4 expression was correlated with the clinicopathological features of EOC, while the ADC value was correlated with the EOC tumor diameter (all p < 0.05). MRI [area under the curve (AUC) = 0.77], CA125 (AUC = 0.85) and HE4 (AUC = 0.90) had certain diagnostic value for EOC (all p < 0.05). Conclusions: The prevalence of EOC in ovarian space-occupying patients with highly-expressed CA125 and HE4 is higher. MRI combined with CA125 and HE4 has high clinical diagnostic value for EOC.

LKB1 and STRADα Promote Epithelial Ovarian Cancer Spheroid Cell Invasion.

Late-stage epithelial ovarian cancer (EOC) involves the widespread dissemination of malignant disease throughout the peritoneal cavity, often accompanied by ascites. EOC metastasis relies on the formation of multicellular aggregates, called spheroids. Given that Liver Kinase B1 (LKB1) is required for EOC spheroid viability and LKB1 loss in EOC cells decreases tumor burden in mice, we investigated whether the LKB1 complex controls the invasive properties of human EOC spheroids. LKB1 signalling was antagonized through the CRISPR/Cas9 genetic knockout of LKB1 and/or the RNAi-dependent targeting of STE20-related kinase adaptor protein (STRAD, an LKB1 activator). EOC spheroids expressing nuclear GFP (green) or mKate2 (red) constructs were embedded in Matrigel for real-time live-cell invasion monitoring. Migration and invasion were also assessed in spheroid culture using Transwell chambers, spheroid reattachment, and mesothelial clearance assays. The loss of LKB1 and STRAD signalling decreased cell invasion through Matrigel and Transwell membranes, as well as mesothelial cell clearance. In the absence of LKB1, zymographic assays identified a loss of matrix metalloproteinase (MMP) activity, whereas spheroid reattachment assays found that coating plates with fibronectin restored their invasive potential. A three-dimensional EOC organoid model demonstrated that organoid area was greatly reduced by LKB1 loss. Overall, our data indicated that LKB1 and STRAD facilitated EOC metastasis by promoting MMP activity and fibronectin expression. Given that LKB1 and STRAD are crucial for EOC metastasis, targeting LKB1 and/or STRAD could disrupt the dissemination of EOC, making inhibitors of the LKB1 pathway an alternative therapeutic strategy for EOC patients.

Characterization of the female reproductive tract microbiome in epithelial ovarian cancer patients

Characterization of the female reproductive tract microbiome in epithelial ovarian cancer patients

Artificial intelligence-assisted classification of epithelial ovarian cancer patients using machine learning clustering to determine the rate of platinum sensitivity and disease recurrence

Artificial intelligence-assisted classification of epithelial ovarian cancer patients using machine learning clustering to determine the rate of platinum sensitivity and disease recurrence

A phase II study evaluating carboplatin/paclitaxel/pembrolizumab among newly diagnosed stage III/IV epithelial ovarian cancer patients receiving neoadjuvant chemotherapy followed by olaparib/pembrolizumab maintenance

A phase II study evaluating carboplatin/paclitaxel/pembrolizumab among newly diagnosed stage III/IV epithelial ovarian cancer patients receiving neoadjuvant chemotherapy followed by olaparib/pembrolizumab maintenance

Keratin-15 high expression links with lymph node metastasis and poor survival prognosis in epithelial ovarian cancer patients

BackgroundKeratin-15 (KRT15) involves in the progression and owns prognostic values in several solid cancers, whose clinical role in epithelial ovarian cancer (EOC) is rarely reported. This study aimed to identify the association of KRT15 expression with tumor features and survival of surgical EOC patients.MethodsFormalin-fixed paraffin-embedded tumor tissues of 140 EOC patients who underwent tumor resection were retrieved for KRT15 determination using immunohistochemistry (IHC) assay.ResultsThe median (interquartile range) KRT15 IHC score was 0.0 (0.0–1.0), ranging from 0.0 to 12.0. Among all, 36.4% of patients had positive KRT15 expression (IHC score > 0) and 15.0% of patients had high KRT15 expression (IHC score > 3). KRT15 was positively related to lymph node metastasis incidence (P = 0.027), and showed a tendency to correlate to FIGO stage but without statistical significance (P = 0.052), while it was not correlated with age, other tumor features, and tumor markers. Positive KRT15 expression was linked with poor disease-free survival (DFS) (P = 0.009) and overall survival (OS) (P = 0.032). Notably, high KRT15 expression showed an even stronger relationship with worse DFS (P = 0.001) and OS (P < 0.001). After adjustment of multivariable Cox’s regression, high KRT15 expression was independently correlated with unfavorable DFS (hazard ratio (HR): 2.241, P = 0.007).ConclusionEven though KRT15 is insufficiently expressed in EOC tissues generally, its positive expression or high expression can predict the lymph node metastasis and poor survival prognosis in EOC patients who undergo tumor resection.

LncRNA LINC00261 associates with chemoresistance and clinical prognosis in patients with epithelial ovarian cancer.

The purpose of this experiment is to explore the role of long intergenic noncoding RNA 261 (LINC00261) gene in the chemoresistance and clinical prognosis of epithelial ovarian cancer (EOC). We used matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry to detect the methylation levels of the LINC00261 promoter region in EOC patient specimens. The expression levels of LINC00261, miR-545-3p, and MT1M in EOC patients were evaluated by quantitative real-time reverse transcriptase PCR (RT-qPCR). Spearman's correlation analysis was used for relevance analyses and clinical prognosis was counted by Kaplan-Meier analysis. Stable overexpressed LINC00261 SKOV3 cells were established to test the influence of LINC00261 on proliferation, platinum sensitivity, migration, and invasion. The promoter region methylation level of the LINC00261 was hypermethylated and LINC00261 was significantly downregulated in platinum-resistant EOC tissues. The methylation level of LINC00261was significantly negative correlated with its RNA expression in EOC. Moreover, hypermethylation and lower expression of LINC00261 in EOC patients were related to shorter progression-free survival (PFS) and overall survival (OS). Furthermore, Spearman's correlation analysis showed that the expression of miR-545-3p had a negative relevance with LINC00261. According to the website prediction, MT1M might be the downstream target gene of LINC00261. Expression of MT1M was negatively correlated with miR-545-3p and positively with LINC00261 in EOC tissues. And lower MT1M mRNA expression was correlated with chemotherapy resistance and worse prognosis. In vitro, overexpression of LINC00261 could inhibit cisplatin resistance, proliferation, and suppression of migration and invasion in SKOV3 cells. This research indicates that the aberrant hypermethylation and low expression of LINC00261 were associated with platinum resistance and adverse outcomes in EOC patients.

A Retrospective Analysis of Epidemiology and Clinical Outcomes of Patients with Epithelial Ovarian Tumors Treated in Ain Shams Clinical Oncology Department in the Period from 2017 Till 2020. Ain Shams Clinical Oncology Registry (ASCOR)

Abstract Background OC is the 3rd most commonly diagnosed gynecological malignancy and ranked 2nd most common cause of gynecological malignancies deaths. In our study we reviewed medical records of 97 patients including demographic data and clinico-pathological factors; which include age, performance status, histological subtypes, histological grading, optimal surgery, CA 125 level at presentation and relation with macroscopic residual, number, types, setting and lines of chemotherapy, survival rates were calculated to evaluate them as prognostic factors. Aim of the Work to analyze Retrospectively Epidemiological, Risk factors and Clinical Outcomes of Epithelial Ovarian Cancer Patients Treated in Ain Shams University Hospitals in Egypt in the Period From 2017 till 2020. Patients and Methods At the department of clinical oncology and nuclear medicine, Ain Shams University teaching hospitals, patients with a histologically confirmed diagnosis of epithelial ovarian cancer, in the period from January 2017 to December 2020, were included in this retrospective analysis. Results Our results showed that ECOG status had a statistically significant correlation with OS and PFS, the better the performance the longer the OS and PFS (p = 0.000, 0.000 respectively). Our study population showed similar results were Platinum sensitive patients showed strong correlation to PFS &amp; OS period with the best in the group platinum sensitive and minimum difference in groups showed no response to platinum or were resistant (p value = 0.000). Conclusion our study shows prognostic effects for age, performance status, histological grade, stage, optimal surgery, number of chemotherapy cycles, and platinum sensitivity furthermore after adjustment for different cofounder, high score of age adjusted charleson index &amp;gt;2, stage, ECOG status, platinum sensitivity and optimal cytoreduction were independent prognostic factors affecting OS.

Interplay of microRNAs and circRNAs in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) with its high death incidence rate is generally detected at advanced stages. During its progression, EOC often develops peritoneal metastasis aggravating the outcomes of EOC patients. Studies on non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and circular RNAs (circRNAs), have analyzed the impact of miRNAs and circRNAs, along with their interaction among each other, on cancer cells. MiRNAs can act as oncogenes or tumor suppressors modulating post-transcriptional gene expression. There is accumulating evidence that circRNAs apply their stable, covalently closed, continuous circular structures to competitively inhibit miRNA function, and so act as competing endogenous RNAs (ceRNAs). This interplay between both ncRNAs participates in the malignity of a variety of cancer types, including EOC. In the current review, I describe the characteristics of miRNAs and circRNAs, and discuss their interplay with each other in the development, progression, and drug resistance of EOC. Sponging of miRNAs by circRNAs may be used as a biomarker and therapeutic target in EOC.

Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

Circulating exosomal protein EFEMP1 and SERPINC1 as diagnostic biomarkers for epithelial ovarian cancer

ObjectivesCaner-derived exosomes, containing diverse nucleic acids and proteins, are being exploited in diagnostic biomarker development. This study aims to screen and identify the altered exosomal proteins between epithelial ovarian cancer (EOC) patient and healthy volunteers, and to evaluate their diagnostic accuracy for EOC. MethodsExosomes were separate by ultracentrifugation, and then subjected to TEM, qNano, and western blot for identification. Exosomal EFEMP1 and SERPINC1 were selected by MS/MS analysis, validated by ELISA in a cohort with 163 healthy donors, 183 EOC patients and 30 patients with benign ovarian tumors. ResultsMS/MS analyses identified a total of 207 differential exosomal proteins, including the 122 up-regulated and 85 down-regulated. Exosomal EFEMP1 and SERPINC1 were significantly upregulated in EOC patients compared with those in healthy donors as well as in the benign patients, possessing favorable diagnostic efficiency. The area under the curves (AUCs) were 0.8071, 0.8211, respectively. They also exerted rather high early diagnostic efficiency, as well as the potential to distinguish the malignant patients from the benign individuals. Besides, exosomal SERPINC1 was associated with coagulation index and LE-DVT (lower extremity deep venous thrombosis) in EOC patients. ConclusionsExosomal EFEMP1 and SERPINC1 are upregulated and serve as the promising diagnostic biomarkers for EOC.

Postoperative Complications of Upfront Ovarian Cancer Surgery and Their Effects on Chemotherapy Delay.

Extensive surgery on advanced-stage epithelial ovarian cancer is associated with increased postoperative morbidity, which may cause a delay in or omission of chemotherapy. We examined postoperative complications and their effects on adjuvant treatment in patients undergoing primary debulking surgery (PDS). Stage IIIC-IV epithelial ovarian cancer patients who underwent PDS between January 2013 and December 2020 were included. Patients were divided into two groups according to the radicality of the operation, i.e., extensive or standard surgery, and their outcomes were compared. In total, 172 patients were included; 119 underwent extensive surgery, and 53 had standard surgery. Clavien-Dindo grade 3-5 (CDC 3+) complications were detected in 41.2% of patients after extensive operations and in 17% after standard surgery (p = 0.002). The most common CDC 3+ complication was pleural effusion. Despite the difference in the complication rates, the delay in chemotherapy did not differ between the extensive and standard groups (p = 0.98). Complications are common after PDS. Extensive surgery increases the complication rate, but most complications can be treated effectively; therefore, a delay in adjuvant treatment is rare.

Human papillomavirus infection of the fallopian tube as a potential risk factor for epithelial ovarian cancer

Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV’s 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.

Predicting prognosis for epithelial ovarian cancer patients receiving bevacizumab treatment with CT-based deep learning

Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model’s performance was evaluated using Harrell’s C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P < 0.001) and 8.16 in the internal test set (95% CI: 2.5, 26.8; P < 0.001). The multimodal model demonstrated a C-index of 0.76 in the internal test set and a C-index of 0.64 in the external test set. Comparative analysis against FIGO staging revealed an NRI of 0.06 (P < 0.001) for the multimodal model. The model presents opportunities for prognostic assessment, treatment strategizing, and ongoing patient monitoring.

A multicenter retrospective study to assess feasibility, safety and efficacy of first-line carboplatin-paclitaxel versus carboplatin monotherapy in a frail, elderly epithelial ovarian cancer population

ObjectiveUnderrepresentation of elderly ovarian cancer patients in clinical trials has led to lack of clarity regarding optimal first-line chemotherapy in this cohort. The Elderly Women with Ovarian Cancer (EWOC)-1 trial...

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer.

The TGF-β superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-βA and INHBB/ Inhibin-βB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-βA) is significantly elevated in EOC patient ascites. INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.

1582P Pregnancy and miscarriage in epithelial ovarian cancer (EOC) patients harboring mutational signature of homologous recombination deficiency (HRD)

1582P Pregnancy and miscarriage in epithelial ovarian cancer (EOC) patients harboring mutational signature of homologous recombination deficiency (HRD)