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Serous surface papillary borderline ovarian tumor (SSPBOT) is a distinct subtype of serous borderline ovarian tumor characterized by solid tissue deposition confined to the ovarian surface. Because SSPBOT is rare, there are few published reports on the ultrasonographic features of this condition. In this retrospective study, we investigated 12 cases of SSPBOT. Ultrasound imaging of SSPBOT showed grossly normal ovaries that were encased partially or wholly by tumor deposits that were confined to the surface, with clear demarcation between normal ovarian tissue and surrounding tumors. Color Doppler imaging demonstrated the 'fireworks sign' in all cases of SSPBOT, corresponding to an intratumoral vascular bundle originating from the ovarian vessels and supplying hierarchical branching blood flow to the surrounding tumor. No patient with ovarian high‐grade serous carcinoma showed these morphological and Doppler features. In our series, the fireworks sign appeared to be a characteristic feature of SSPBOT that could facilitate correct identification of this tumor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to predict platinum sensitivity using routine baseline multimodal magnetic resonance imaging (MRI) and established clinical data in a radiomics framework. Methods: We evaluated 96 patients with ovarian cancer who underwent multimodal MRI and routine laboratory tests between January 2016 and December 2020. The patients underwent diffusion-weighted, contrast-enhanced T1-weighted, and T2-weighted MRI. Subsequently, 293 radiomic features were extracted by manually identifying tumor regions of interest. The features were subjected to the least absolute shrinkage and selection operators, leaving only a few selected features. We built the first prediction model with a tree-based classifier using selected radiomics features. A second prediction model was built by combining the selected radiomic features with four established clinical factors: age, disease stage, initial tumor marker level, and treatment course. Both models were built and tested using a five-fold cross-validation. Results: Our radiomics model predicted platinum sensitivity with an AUC of 0.65 using a few radiomics features related to heterogeneity. The second combined model had an AUC of 0.77, confirming the incremental benefits of the radiomics model in addition to models using established clinical factors. Conclusion: Our combined radiomics-clinical data model was effective in predicting platinum sensitivity in patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Differential expression of programmed death-1 ligand (PD-L1) and its clinical significance in primary and metastatic ovarian high-grade serous carcinoma (HGSC) have not been defined. Thus, we investigated the PD-L1 expression of paired ovarian primary and omental metastatic HGSC and its correlation with CD8 + tumor-infiltrating lymphocyte (TILs) and patient survival. A total of 212 cases of ovarian HGSCs with matched primary ovarian and metastatic omental tumors accessioned between 2003 and 2018 were selected for further analysis. Using immunohistochemistry, we evaluated the density of CD8 + TILs and expression of PD-L1 on whole tissue sections. Applying tumor proportion score (TPS, cutoff 1%) and combined positive score (CPS, cutoff 1), the prevalence of PD-L1 expression was similar but with significant discordance in ovarian and omental tumor. Using TPS, patients with PD-L1-positive tumors demonstrated significantly worse recurrence free survival (RFS) and overall survival (OS) than patients with PD-L1-negative tumors. Using CPS, patients with PD-L1-positive ovarian tumors demonstrated significantly worse OS while no significant difference in RFS was found. Patients with PD-L1-positive omental tumors demonstrated significantly worse RFS and OS. Patients with omental PD-L1-positive tumors (TPS) were associated with poorer RFS and OS, while patients with ovarian PD-L1-positive tumors (TPS) were associated with OS not RFS, in COX multivariant analysis. Nonetheless, ovarian and omental high CD8 TILs density was not associated with worse OS in univariant and COX multivariant analysis. PD-L1 expression in ovarian and omental tumor associated with an increased CD8 + TILs density. PD-L1 expression by TPS was better correlated with survival than by CPS, and PD-L1 expression in omental tumors was a stronger prognostic indicator than that in ovarian tumors. [ABSTRACT FROM AUTHOR]

Detecting cell types from histopathological images is essential for various digital pathology applications. However, large number of cells in whole-slide images (WSIs) necessitates automated analysis pipelines for efficient cell type detection. Herein, we present hematoxylin and eosin (H&E) Image Processing pipeline (HEIP) for automatied analysis of scanned H&E-stained slides. HEIP is a flexible and modular open-source software that performs preprocessing, instance segmentation, and nuclei feature extraction. To evaluate the performance of HEIP, we applied it to extract cell types from ovarian high-grade serous carcinoma (HGSC) patient WSIs. HEIP showed high precision in instance segmentation, particularly for neoplastic and epithelial cells. We also show that there is a significant correlation between genomic ploidy values and morphological features, such as major axis of the nucleus. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of this study was to evaluate the clinicopathological factors and prognosis of mucinous carcinoma (MC) with infiltrative invasion, MC with expansile invasion, and high-grade serous carcinoma (HGSC). Methods Cases of MC and HGSC between 1984 and 2019 were identified. The clinicopathological factors and prognosis of MC with infiltrative invasion or expansile invasion and HGSC were retrospectively compared. Although our present study included cases in our previous studies, we extended observational period when analysis was performed. Accordingly, our study added increased cases and survival analysis was newly conducted. Results After pathological review, 27 cases of MC with infiltrative invasion, 25 cases of MC with expansile invasion, and 219 cases of HGSC were included. MC had a better prognosis in terms of progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than HGSC for all International Federation of Gynecology and Obstetrics (FIGO) stages; however, multivariate analysis did not show statistical differences in PFS and OS. There were no statistically significant differences in PFS and OS for all FIGO stages between MC with infiltrative invasion and HGSC. However, in cases with FIGO stages II to IV, MC with infiltrative invasion had worse PFS (p < 0.01) and OS (p < 0.01) than HGSC. In univariate analysis, MC with infiltrative invasion was a worse prognostic factor for PFS (hazard ratio [HR] 2.83, p < 0.01) and OS (HR 3.83, p < 0.01) than HGSC. Compared with HGSC, MC with expansile invasion had better PFS (p < 0.01) and OS (p < 0.01). Multivariate analysis demonstrated that MC with expansile invasion was a better prognostic factor for PFS (HR 0.17, p < 0.01) and OS (HR 0.18, p = 0.03) than HGSC. Conclusions Compared to the prognosis of HGSC, that of MC was different according to the invasive pattern and FIGO stage. Therefore, future study may be needed to consider this association.

Detecting cell types from histopathological images is essential for various digital pathology applications. However, large number of cells in whole-slide images (WSIs) necessitates automated analysis pipelines for efficient cell type detection. Herein, we present hematoxylin and eosin (H&E) Image Processing pipeline (HEIP) for automatied analysis of scanned H&E-stained slides. HEIP is a flexible and modular open-source software that performs preprocessing, instance segmentation, and nuclei feature extraction. To evaluate the performance of HEIP, we applied it to extract cell types from ovarian high-grade serous carcinoma (HGSC) patient WSIs. HEIP showed high precision in instance segmentation, particularly for neoplastic and epithelial cells. We also show that there is a significant correlation between genomic ploidy values and morphological features, such as major axis of the nucleus.

Background: The aim of this study was to evaluate the clinicopathological factors and prognosis of mucinous carcinoma (MC) with infiltrative invasion, MC with expansile invasion, and high-grade serous carcinoma (HGSC). Methods: Cases of MC and HGSC between 1984 and 2019 were identified. The clinicopathological factors and prognosis of MC with infiltrative invasion or expansile invasion and HGSC were retrospectively compared. Although our present study included cases in our previous studies, we extended observational period when analysis was performed. Accordingly, our study added increased cases and survival analysis was newly conducted. Results: After pathological review, 27 cases of MC with infiltrative invasion, 25 cases of MC with expansile invasion, and 219 cases of HGSC were included. MC had a better prognosis in terms of progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than HGSC for all International Federation of Gynecology and Obstetrics (FIGO) stages; however, multivariate analysis did not show statistical differences in PFS and OS. There were no statistically significant differences in PFS and OS for all FIGO stages between MC with infiltrative invasion and HGSC. However, in cases with FIGO stages II to IV, MC with infiltrative invasion had worse PFS (p < 0.01) and OS (p < 0.01) than HGSC. In univariate analysis, MC with infiltrative invasion was a worse prognostic factor for PFS (hazard ratio [HR] 2.83, p < 0.01) and OS (HR 3.83, p < 0.01) than HGSC. Compared with HGSC, MC with expansile invasion had better PFS (p < 0.01) and OS (p < 0.01). Multivariate analysis demonstrated that MC with expansile invasion was a better prognostic factor for PFS (HR 0.17, p < 0.01) and OS (HR 0.18, p = 0.03) than HGSC. Conclusions: Compared to the prognosis of HGSC, that of MC was different according to the invasive pattern and FIGO stage. Therefore, future study may be needed to consider this association. [ABSTRACT FROM AUTHOR]

Abstract Background Epithelial ovarian carcinomas encompass a heterogeneous group of diseases with a poor 5-year survival rate. Serous carcinoma is the most common type. Most FDA-approved serum tumor markers are glycoproteins. These glycoproteins on cell surface or shed into the bloodstream could serve as therapeutic targets as well as surrogates of tumor. In addition to glycoprotein expressions, the analysis of protein glycosylation occupancy could be important for the understanding of cancer biology as well as the identification of potential glycoprotein changes in cancer. In this study, we used an integrated proteomics and glycoproteomics approach to analyze global glycoprotein abundance and glycosylation occupancy for proteins from high-grade ovarian serous carcinoma (HGSC) and serous cystadenoma, a benign epithelial ovarian tumor, by using LC–MS/MS-based technique. Methods Fresh-frozen ovarian HGSC tissues and benign serous cystadenoma cases were quantitatively analyzed using isobaric tags for relative and absolute quantitation for both global and glycoproteomic analyses by two dimensional fractionation followed by LC–MS/MS analysis using a Orbitrap Velos mass spectrometer. Results Proteins and N-linked glycosite-containing peptides were identified and quantified using the integrated global proteomic and glycoproteomic approach. Among the identified N-linked glycosite-containing peptides, the relative abundances of glycosite-containing peptide and the glycoprotein levels were compared using glycoproteomic and proteomic data. The glycosite-containing peptides with unique changes in glycosylation occupancies rather than the protein expression levels were identified. Conclusion In this study, we presented an integrated proteomics and glycoproteomics approach to identify changes of glycoproteins in protein expression and glycosylation occupancy in HGSC and serous cystadenoma and determined the changes of glycosylation occupancy that are associated with malignant and benign tumor tissues. Specific changes in glycoprotein expression or glycosylation occupancy have the potential to be used in the discrimination between benign and malignant epithelial ovarian tumors and to improve our understanding of ovarian cancer biology.

Introduction: We aimed to predict platinum sensitivity using routine baseline multimodal magnetic resonance imaging (MRI) and established clinical data in a radiomics framework., Methods: We evaluated 96 patients with ovarian cancer who underwent multimodal MRI and routine laboratory tests between January 2016 and December 2020. The patients underwent diffusion-weighted, contrast-enhanced T1-weighted, and T2-weighted MRI. Subsequently, 293 radiomic features were extracted by manually identifying tumor regions of interest. The features were subjected to the least absolute shrinkage and selection operators, leaving only a few selected features. We built the first prediction model with a tree-based classifier using selected radiomics features. A second prediction model was built by combining the selected radiomic features with four established clinical factors: age, disease stage, initial tumor marker level, and treatment course. Both models were built and tested using a five-fold cross-validation., Results: Our radiomics model predicted platinum sensitivity with an AUC of 0.65 using a few radiomics features related to heterogeneity. The second combined model had an AUC of 0.77, confirming the incremental benefits of the radiomics model in addition to models using established clinical factors., Conclusion: Our combined radiomics-clinical data model was effective in predicting platinum sensitivity in patients with advanced ovarian cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Na, Noh, Kim, Lee and Park.)

Background: Visualization is an indispensable facet of genomic data analysis. Despite the abundance of specialized visualization tools, there remains a distinct need for tailored solutions. However, their implementation typically requires extensive programming expertise from bioinformaticians and software developers, especially when building interactive applications. Toolkits based on visualization grammars offer a more accessible, declarative way to author new visualizations. Yet, current grammar-based solutions fall short in adequately supporting the interactive analysis of large datasets with extensive sample collections, a pivotal task often encountered in cancer research., Findings: We present GenomeSpy, a grammar-based toolkit for authoring tailored, interactive visualizations for genomic data analysis. By using combinatorial building blocks and a declarative language, users can implement new visualization designs easily and embed them in web pages or end-user-oriented applications. A distinctive element of GenomeSpy's architecture is its effective use of the graphics processing unit in all rendering, enabling a high frame rate and smoothly animated interactions, such as navigation within a genome. We demonstrate the utility of GenomeSpy by characterizing the genomic landscape of 753 ovarian cancer samples from patients in the DECIDER clinical trial. Our results expand the understanding of the genomic architecture in ovarian cancer, particularly the diversity of chromosomal instability., Conclusions: GenomeSpy is a visualization toolkit applicable to a wide range of tasks pertinent to genome analysis. It offers high flexibility and exceptional performance in interactive analysis. The toolkit is open source with an MIT license, implemented in JavaScript, and available at https://genomespy.app/., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC. [Display omitted] • RBM39 regulates mRNA splicing of DNA damage repair genes such as ATM and BRCA1 • RBM39 depletion through indisulam synergizes with cisplatin and PARP inhibitors • Olaparib-induced activation of ATM, Chk2, and Chk1 is suppressed by indisulam • Indisulam improves response to olaparib treatment in a murine HGSC model Xu et al. show that RBM39 modulates correct splicing of various DNA damage repair factors in ovarian cancer cells. Depletion of RBM39 through molecular glues such as indisulam leads to RNA splicing defects in these genes and improves PARP inhibitor response in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best‐known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP‐ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next‐generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high‐grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome‐wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

• A case of pulmonary tumor thrombotic microangiopathy (PTTM) diagnosed postmortem. • Patient with a past medical history of ovarian high-grade serous carcinoma. • Main manifestation of progressive respiratory failure and pulmonary hypertension. • Imagining findings on chest computerized tomography (CT) were non-specific. • Tumor emboli in the arterioles, small arteries, and capillaries of bilateral lungs. Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare entity with poor prognosis, and often diagnosed postmortem. PTTM is resulting from tumor emboli induced activation of coagulation cascade, fibrin clot formation and fibrocellular intimal proliferation in pulmonary microvasculature. The patient was a 65-year-old female, with past medical history of ovarian high-grade serous carcinoma, presented with chest pain and shortness of breath. The chest computed tomography (CT) revealed innumerable new lung nodules as well as small hazy and patchy opacities compared to the chest CT 2 months before current presentation. She developed progressive respiratory failure and expired. A lung-restricted autopsy showed diffuse subcentimetric nodules in bilateral lungs grossly. Microscopic examination revealed the lung parenchyma demonstrated numerous tumor emboli consisting of pleomorphic tumor cells with varying degrees of fibrin deposition and fibrocellular intimal proliferation in the pulmonary arterioles, small arteries, and capillaries in the alveolar septa. Immunohistochemistry confirmed the ovarian origin of the tumor cells. The findings were consistent with PTTM secondary to metastasis of ovarian high-grade serous carcinoma. Literature review of PTTM caused by ovarian cancer was conducted. PTTM is a fatal entity with rare association with primary ovarian malignancy. This case study demonstrates the clinicopathological features of PTTM associated with high-grade serous carcinoma, and it will be the second case of PTTM with this association in the literature. [ABSTRACT FROM AUTHOR]

Differential expression of programmed death-1 ligand (PD-L1) and its clinical significance in primary and metastatic ovarian high-grade serous carcinoma (HGSC) have not been defined. Thus, we investigated the PD-L1 expression of paired ovarian primary and omental metastatic HGSC and its correlation with CD8 + tumor-infiltrating lymphocyte (TILs) and patient survival. A total of 212 cases of ovarian HGSCs with matched primary ovarian and metastatic omental tumors accessioned between 2003 and 2018 were selected for further analysis. Using immunohistochemistry, we evaluated the density of CD8 + TILs and expression of PD-L1 on whole tissue sections. Applying tumor proportion score (TPS, cutoff 1%) and combined positive score (CPS, cutoff 1), the prevalence of PD-L1 expression was similar but with significant discordance in ovarian and omental tumor. Using TPS, patients with PD-L1-positive tumors demonstrated significantly worse recurrence free survival (RFS) and overall survival (OS) than patients with PD-L1-negative tumors. Using CPS, patients with PD-L1-positive ovarian tumors demonstrated significantly worse OS while no significant difference in RFS was found. Patients with PD-L1-positive omental tumors demonstrated significantly worse RFS and OS. Patients with omental PD-L1-positive tumors (TPS) were associated with poorer RFS and OS, while patients with ovarian PD-L1-positive tumors (TPS) were associated with OS not RFS, in COX multivariant analysis. Nonetheless, ovarian and omental high CD8 TILs density was not associated with worse OS in univariant and COX multivariant analysis. PD-L1 expression in ovarian and omental tumor associated with an increased CD8 + TILs density. PD-L1 expression by TPS was better correlated with survival than by CPS, and PD-L1 expression in omental tumors was a stronger prognostic indicator than that in ovarian tumors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Simple Summary: Ovarian high-grade serous carcinoma is the deadliest ovarian cancer. Cancer cells develop resistance to anti-cancer regimens leading to poor prognosis. Previous studies showed that the progesterone receptor was associated with better rates of survival of ovarian cancer patients. We aimed to investigate the association between the progesterone receptor and its isoform-B and platinum sensitivity of ovarian high-grade serous carcinoma. We found that strong progesterone receptor-B expression was associated with better platinum sensitivity and better survival in high-grade serous ovarian cancer patients. Our clinical data also showed that a high expression of progesterone receptor-B and optimal debulking were the independent factors associated with better platinum sensitivity. In a cell model, enhancing progesterone receptor-B expression and progesterone treatment increased platinum sensitivity and platinum-related apoptosis of the ovarian cancer cells. These might be potential therapeutic targets of ovarian high-grade serous carcinoma. Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms' expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson's correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated. [ABSTRACT FROM AUTHOR]

Background: Whether patients with advanced tubo-ovarian high-grade serous cancer (HGSC) fare better after upfront debulking surgery (UDS) or neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) remains controversial., Methods: We studied patients with HGSC who underwent UDS or NACT-IDS between July 2000 and December 2015, with peritonectomy procedures combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Clinical reports were included peritoneal cancer index (PCI), NACT responses, surgical complexity score (SCS), completeness of cytoreduction (CC), complete follow-up with timing, site, and treatment of recurrence. Outcome measures were morbidity, progression-free survival (PFS), PFS2, and overall survival during a mean 5-year follow-up., Results: A total of 34 patients (23.6%) underwent UDS and 110 (76.4%) NACT-IDS both combined with HIPEC. At a median 66.3-month follow-up, patients who underwent UDS or NACT-IDS had similar outcomes. NACT subgroup responses correlated with PCI, SCS, morbidity, and CC. Patients who underwent UDS had lower recurrence rates than those who responded partly or poorly to NACT (PFS, P < .04; PFS2, P < .01). Despite HIPEC, the peritoneal disease recurred in 42.5% of the overall patients., Conclusion: In patients with primary HGSC who undergo UDS or NACT-IDS, despite similar outcomes, peritonectomy procedures combined with HIPEC seem unable to prevent peritoneal recurrence., (© 2019 Wiley Periodicals, Inc.)

Accumulating evidence has indicated that microRNAs play a critical role in the pathogenesis of human cancers. microRNA-34a ( miR-34a ) has been shown to be a key regulator of tumor suppression by targeting several cancer-related signals, including the interleukin-6 receptor (IL-6R)/Signal Transducers and Activator of Transcription 3 (STAT3) signaling pathway. Previously, we determined that miR-34a expression was frequently reduced in high-grade serous carcinoma (HGSC), the major subtype of epithelial ovarian cancer (EOC). Considering that the IL-6R/STAT3 signaling pathway is upregulated and believed to be a potential therapeutic target in EOC, we investigated the biological significance of reduced miR-34a expression in HGSC with regard to IL-6R signaling. Additionally, we evaluated the viability of miR-34a as a therapeutic application for HGSC both in vitro and in vivo . Accordingly, we found that the ectopic expression of miR-34a significantly reduced tumor proliferation and invasion through downregulation of IL-6R expression, suggesting that reduced miR-34a expression might play an important role in the malignant potential of HGSC through upregulation of the IL-6R/STAT3 signaling pathway. Moreover, we demonstrated that replacement of miR-34a reduced tumorigenicity of HGSC in vivo . Therefore, this study may provide the rationale for miR-34a replacement as a promising therapeutic strategy for HGSC., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Background: The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF., Methods: From two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized., Findings: In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities., Interpretation: This study revealed that the FF-IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions. FUND: The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01)., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aim: The purpose of this study was to compare the clinical behavior of several grades of endometrioid carcinoma (EC) compared to high-grade serous carcinoma (HGSC), based on World Health Organization 2014 criteria., Materials and Methods: Clinicopathological features were compared between all grades of EC and HGSC, and between HGSC and either grade 1/2 or grade 3 EC., Results: Sixty-five patients with EC and 214 with HGSC were identified. Among patients with EC, 56 displayed 1/2 EC and nine had grade 3 EC. The progression-free (PFS) and overall (OS) survival of patients with grade 1/2 EC were better than of those of patients with HGSC; however, PFS and OS did not statistically differ between patients with grade 3 EC and those with HGSC. Grade 1/2 EC, but not grade 3, was a better prognostic factor compared with HGSC., Conclusion: A grading system for EC would be beneficial for the accurate prognosis of ovarian cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Epithelial ovarian carcinomas encompass a heterogeneous group of diseases with a poor 5-year survival rate. Serous carcinoma is the most common type. Most FDA-approved serum tumor markers are glycoproteins. These glycoproteins on cell surface or shed into the bloodstream could serve as therapeutic targets as well as surrogates of tumor. In addition to glycoprotein expressions, the analysis of protein glycosylation occupancy could be important for the understanding of cancer biology as well as the identification of potential glycoprotein changes in cancer. In this study, we used an integrated proteomics and glycoproteomics approach to analyze global glycoprotein abundance and glycosylation occupancy for proteins from high-grade ovarian serous carcinoma (HGSC) and serous cystadenoma, a benign epithelial ovarian tumor, by using LC-MS/MS-based technique., Methods: Fresh-frozen ovarian HGSC tissues and benign serous cystadenoma cases were quantitatively analyzed using isobaric tags for relative and absolute quantitation for both global and glycoproteomic analyses by two dimensional fractionation followed by LC-MS/MS analysis using a Orbitrap Velos mass spectrometer., Results: Proteins and N -linked glycosite-containing peptides were identified and quantified using the integrated global proteomic and glycoproteomic approach. Among the identified N -linked glycosite-containing peptides, the relative abundances of glycosite-containing peptide and the glycoprotein levels were compared using glycoproteomic and proteomic data. The glycosite-containing peptides with unique changes in glycosylation occupancies rather than the protein expression levels were identified., Conclusion: In this study, we presented an integrated proteomics and glycoproteomics approach to identify changes of glycoproteins in protein expression and glycosylation occupancy in HGSC and serous cystadenoma and determined the changes of glycosylation occupancy that are associated with malignant and benign tumor tissues. Specific changes in glycoprotein expression or glycosylation occupancy have the potential to be used in the discrimination between benign and malignant epithelial ovarian tumors and to improve our understanding of ovarian cancer biology.

Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT., (Copyright © 2015 Elsevier Inc. All rights reserved.)