Ovarian Tumors Research Articles

Histopathological insights into ovarian tumors: A case series perspective

: Ovarian cancer stands as the third most prevalent cancer among women in India and contributes to 6% of cancer-related facilities emphasizing its significant impact on mortality. Usually, it manifests with nonspecific symptoms in correlation with age, leading to a frequent oversight in early diagnosis causing more advanced stages when intervention becomes challenging.Case records of six patientsshed light on the diverse spectrum of ovarian neoplasms encountered in clinical practice, highlighting the complexity and heterogeneity within this disease entity of different age groups. In our case series, we found that the overall burden of ovarian cancer was heaviest in the age group 20–45, while the increase was the largest in the age group 50 years and above. Given their asymptomatic nature, late onset of symptoms, and lack of effective screening facilities, ovarian cancers are known as the “silent killer”. Hence, histopathological examination plays a prime role in diagnosis and for primary optimum treatment management. Tumor markers such as AFP, LDH, and beta hCG serve as supplementary tools in the initial diagnostic process, monitoring treatment response, and post-treatment surveillance. Proactive measures targeting diverse risk factors are essential for effective prevention and treatment strategies. This case series underscores the critical importance of timely diagnosis of ovarian tumors, particularly in young females. Heightened vigilance is warranted given the potential for diverse presentations, therefore precise categorization into specific histological types is crucial for clinicians to devise timely management strategies for affected patients.

EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.

A case of struma ovarii with coexistent Brenner tumor presenting with thyrotoxicosis

ABSTRACT Struma ovarii is an ovarian tumor, characterized by the presence of thyroid tissue comprising >50% of the overall mass. Although struma ovarii does not usually secrete thyroid hormones, there are cases in which it produces thyroid hormones, which results in hyperthyroidism. Here, we report the case of a 73-year-old female who presented with a right ovarian mass and symptoms suggestive of thyrotoxicosis. Her thyroid function test showed suppressed thyroid-stimulating hormone and elevated T3 and T4 levels. We suspected thyroiditis initially. Later, in view of persistent thyrotoxicosis, she was started on antithyroid drugs. Tc99 pertechnetate thyroid uptake scan showed absent uptake in the neck. A possibility of struma ovarii was considered. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Histopathology revealed >80% thyroid tissue suggestive of struma ovarii with a coexistent Brenner tumor. Postoperatively, her thyrotoxicosis got resolved. To conclude, in any case of thyrotoxicosis that is persisting and with absent uptake in the neck, rare cases such as struma ovarii should be considered. Struma ovarii with a coexistent Brenner tumor is a very rare finding.

Presentation of a Locally Advanced Cervical Cancer with Hydrometrocolpos: A Case Report

Introduction: Early stages of cervical cancer remain asymptomatic. Its common symptoms are postcoital bleeding, postmenopausal bleeding, heavy menstrual flow and foul smelling blood stained discharge. Presentation of locally advanced cervical cancer with hydrometrocolpos is unusual. Case report: An 83-year-old woman who presented with a large abdomino-pelvic mass was diagnosed as benign bilateral ovarian tumour with left sided hydroureteronephrosis. During laparotomy, the mass was confirmed to be a hydrometrocolpos with left hydroureteronephrosis secondary to a locally advanced cervical cancer (FIGO IIIB). Histology confirmed the diagnosis of invasive squamous cell carcinoma of the cervix. Conclusion: Besides thorough evaluation via symptoms and signs, radiologists have an important role in guiding surgeons to the most probable diagnosis. In an elderly woman with a stenosed vagina and a pelvic mass with hydroureteronephrosis, gynecologists need to be aware of the possibility of locally advanced cervical cancer, and perform relevant preoperative assessments and plan management.

MR imaging diagnosis of small-cell carcinoma of the ovary, hypercalcemic type: A case report and literature review.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive gynecological tumor. We retrospectively analyzed the clinical manifestations and imaging findings of this patient and analyzed the relevant literature, with the aim of improving the ability of radiologists to differentiate SCCOHT from other ovarian tumors. We report a case of 36-year-old woman who was diagnosed with SCCOHT. MRI suggested a malignant tumor of the left ovary. The immunohistochemical markers shows SMARCA4 negativity. Notably, hypercalcemia was not detected. Microscopically, it was consistent with the large-cell variants. Despite its rarity, SCCOHT should still be considered in the differential diagnosis of ovarian malignancies. When a young female patient presents with a large unilateral tumor on MRI with a predominant solid component and significant enhancement on the contrast enhanced scans, along with hypercalcemia, SCCOHT should be considered.

Mechanisms of Cell Death Induced by Erastin in Human Ovarian Tumor Cells.

Erastin (ER) induces cell death through the formation of reactive oxygen species (ROS), resulting in ferroptosis. Ferroptosis is characterized by an accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. ER-induced ferroptosis may have potential as an alternative for ovarian cancers that have become resistant due to the presence of Ras mutation or multi-drug resistance1 (MDR1) gene expression. We used K-Ras mutant human ovarian tumor OVCAR-8 and NCI/ADR-RES, P-glycoprotein-expressing cells, to study the mechanisms of ER-induced cell death. We used these cell lines as NCI/ADR-RES cells also overexpresses superoxide dismutase, catalase, glutathione peroxidase, and transferase compared to OVCAR-8 cells, leading to the detoxification of reactive oxygen species. We found that ER was similarly cytotoxic to both cells. Ferrostatin, an inhibitor of ferroptosis, reduced ER cytotoxicity. In contrast, RSL3 (RAS-Selective Ligand3), an inducer of ferroptosis, markedly enhanced ER cytotoxicity in both cells. More ROS was detected in OVCAR-8 cells than NCI/ADR-RES cells, causing more malondialdehyde (MDA) formation in OVCAR-8 cells than in NCI/ADR-RES cells. RSL3, which was more cytotoxic to NCI/ADR-RES cells, significantly enhanced MDA formation in both cells, suggesting that glutathione peroxidase 4 (GPX4) was involved in ER-mediated ferroptosis. ER treatment modulated several ferroptosis-related genes (e.g., CHAC1, GSR, and HMOX1/OX1) in both cells. Our study indicates that ER-induced ferroptotic cell death may be mediated similarly in both NCI/ADR-RES and OVCAR-8 cells. Additionally, our results indicate that ER is not a substrate of P-gp and that combinations of ER and RSL3 may hold promise as more effective treatment routes for ovarian cancers, including those that are resistant to other current therapeutic agents.

Amplified Cell Cycle Genes Identified in High-Grade Serous Ovarian Cancer.

The objective of this study was to identify differentially expressed genes and their potential influence on the carcinogenesis of serous-type ovarian cancer tumors. Serous cancer is an epithelial ovarian cancer subtype and is the most common type of ovarian cancer. Transcriptomic profiles of serous cancer and non-cancerous datasets were obtained from the Gene Expression Omnibus (GEO-NCBI). Differentially expressed genes were then derived from those profiles; the identified genes were consistently upregulated in three or more transcriptomic profiles. These genes were considered as the serous ovarian cancer gene set for further study. The serous gene set derived from the transcriptomic profiles was then evaluated for ontological functional analysis using the Molecular Signatures Database. Next, we examined the mutational impact of this serous gene set on the transcriptomic profile of high-grade serous ovarian (HGSO) adenocarcinoma using the cBioPortal database. Results from OncoPrint revealed that 26 genes were amplified in more than 5% of HGSO cancer patients. Interestingly, several of these genes are involved in cell cycle processes, including genes ATPase family AAA domain containing 2 (ATAD2), recQ-like helicase 4 (RECQL4), cyclin E1 (CCNE1), anti-silencing function 1B histone chaperone (ASF1B), ribonuclease H2 subunit A (RNASEH2A), structural maintenance of chromosome 4 (SMC4), cell division cycle associated 20 (CDC20), and cell division cycle associated 8 (CDCA8). The receiver operating characteristic (ROC) curve results also revealed higher specificity and sensitivity for this subtype of tumors. Furthermore, these genes may affect the recurrence of serous ovarian carcinogenesis. Overall, our analytical study identifies cell cycle-related genes that can potentially be targeted as diagnostic and prognostic markers for serous ovarian cancer.

Unique features of KGN granulosa-like tumour cells in the regulation of steroidogenic and antioxidant genes.

The ovarian KGN granulosa-like tumour cell line is commonly used as a model for human granulosa cells, especially since it produces steroid hormones. To explore this further, we identified genes that were differentially expressed by KGN cells compared to primary human granulosa cells using three public RNA sequence datasets. Of significance, we identified that the expression of the antioxidant gene TXNRD1 (thioredoxin reductase 1) was extremely high in KGN cells. This is ominous since cytochrome P450 enzymes leak electrons and produce reactive oxygen species during the biosynthesis of steroid hormones. Gene Ontology (GO) analysis identified steroid biosynthetic and cholesterol metabolic processes were more active in primary granulosa cells, whilst in KGN cells, DNA processing, chromosome segregation and kinetochore pathways were more prominent. Expression of cytochrome P450 cholesterol side-chain cleavage (CYP11A1) and cytochrome P450 aromatase (CYP19A1), which are important for the biosynthesis of the steroid hormones progesterone and oestrogen, plus their electron transport chain members (FDXR, FDX1, POR) were measured in cultured KGN cells. KGN cells were treated with 1 mM dibutyryl cAMP (dbcAMP) or 10 μM forskolin, with or without siRNA knockdown of TXNRD1. We also examined expression of antioxidant genes, H2O2 production by Amplex Red assay and DNA damage by γH2Ax staining. Significant increases in CYP11A1 and CYP19A1 were observed by either dbcAMP or forskolin treatments. However, no significant changes in H2O2 levels or DNA damage were found. Knockdown of expression of TXNRD1 by siRNA blocked the stimulation of expression of CYP11A1 and CYP19A1 by dbcAMP. Thus, with TXNRD1 playing such a pivotal role in steroidogenesis in the KGN cells and it being so highly overexpressed, we conclude that KGN cells might not be the most appropriate model of primary granulosa cells for studying the interplay between ovarian steroidogenesis, reactive oxygen species and antioxidants.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ∼50% of treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

Ovarian-adnexal reporting and data system ultrasound evaluation and pathological characteristics of ovarian collision tumor.

Collision tumor are neoplasms, including two histologically distinct tumors that coexist in the same mass without histological admixture. The incidence of collision tumor is low and is rare clinically. To investigate ultrasound images and application of ovarian-adnexal reporting and data system (O-RADS) to evaluate the risk and pathological characteristics of ovarian collision tumor. This study retrospectively analyzed 17 cases of ovarian collision tumor diagnosed pathologically from January 2020 to December 2023. All clinical features, ultrasound images and histopathological features were collected and analyzed. The O-RADS score was used for classification. The O-RADS score was determined by two senior doctors in the gynecological ultrasound group. Lesions with O-RADS score of 1-3 were classified as benign tumors, and lesions with O-RADS score of 4 or 5 were classified as malignant tumors. There were 17 collision tumors detected in 16 of 6274 patients who underwent gynecological surgery. The average age of 17 women with ovarian collision tumor was 36.7 years (range 20-68 years), in whom, one occurred bilaterally and the rest occurred unilaterally. The average tumor diameter was 10 cm, of which three were 2-5 cm, 11 were 5-10 cm, and three were > 10 cm. Five (29.4%) tumors with O-RADS score 3 were endometriotic cysts with fibroma/serous cystadenoma, and unilocular or multilocular cysts contained a small number of parenchymal components. Eleven (64.7%) tumors had an O-RADS score of 4, including two in category 4A, six in category 4B, and three in category 4C; all of which were multilocular cystic tumors with solid components or multiple papillary components. One (5.9%) tumor had an O-RADS score of 5. This case was a solid mass, and a small amount of pelvic effusion was detected under ultrasound. The pathology was high-grade serous cystic cancer combined with cystic mature teratoma. There were nine (52.9%) tumors with elevated serum carbohydrate antigen (CA)125 and two (11.8%) with elevated serum CA19-9. Histological and pathological results showed that epithelial-cell-derived tumors combined with other tumors were the most common, which was different from previous results. The ultrasound images of ovarian collision tumor have certain specificity, but diagnosis by preoperative ultrasound is difficult. The combination of epithelial and mesenchymal cell tumors is one of the most common types of ovarian collision tumor. The O-RADS score of ovarian collision tumor is mostly ≥ 4, which can sensitively detect malignant tumors.

Dual Primary Endometrial and Ovarian Tumors - A Case Report

Dual Primary Endometrial and Ovarian Tumors - A Case Report

Learning curve of ovarian cystectomy by vaginal natural orifice transluminal endoscopic surgery: a cumulative sum analysis.

To identify the learning curve in ovarian cystectomy by vaginal natural orifice transluminal endoscopic surgery. Data consist of consecutively ordered patients who underwent ovarian cystectomy via vaginal natural orifice transluminal endoscopic surgery between May 2020 and June 2023. The learning curve of ovarian cystectomy via vaginal natural orifice transluminal endoscopic surgery was measured in terms of the operating time adjusted by multivariate linear regression. A cumulative sum analysis was performed to establish the learning curve. Patients' characteristics and surgical outcomes were compared based on the inflection points of this curve. The learning curve was divided into two unique phases: phase 1 (1-26 patients), and phase 2 (27-40 patients). The expected operating time in phase 2 was shorter than in phase 1 (86.4 ± 11.2 min vs. 102.0 ± 22.7 min, p = 0.021). The time to first postoperative flatus was shorter in phase 2 compared with phase 1 (14.6 ± 6.5 h vs. 20.6 ± 6.3 h, respectively, p = 0.008). No significant differences were observed in terms of patient's age, BMI, tumor size, parity, bilateral ovarian tumor, pathological diagnoses, estimated blood loss, postoperative pain score, or perioperative complications between the two phases. Proficiency in ovarian cystectomy by vaginal natural orifice transluminal endoscopic surgery was achieved after 26 surgeries based on cumulative sum analysis. These findings may provide insight for structured training programs of ovarian cystectomy via vaginal natural orifice transluminal endoscopic surgery.

Personalized approach to malignant struma ovarii: Insights from a web-based machine learning tool.

Malignant struma ovarii (MSO) is a rare ovarian tumor characterized by mature thyroid tissue. The diverse symptoms and uncommon nature of MSO can create difficulties in its diagnosis and treatment. This study aimed to analyze data and use machine learning methods to understand the prognostic factors and potential management strategies for MSO. In this retrospective cohort, the Surveillance, Epidemiology, and End Results (SEER) database provided the data used for this study's analysis. To identify the prognostic variables, we conducted Cox regression analysis and constructed prognostic models using five machine learning algorithms to predict the 5-year survival. A validation method incorporating the area under the curve of the receiver operating characteristic curve was used to validate the accuracy and reliability of the machine learning models. We also investigated the role of multiple therapeutic options using the Kaplan-Meier survival analysis. The study population comprised 329 patients. Multivariate Cox regression analysis revealed that older age, unmarried status, chemotherapy, and the total number of tumors in patients were poor prognostic factors. Machine learning models revealed that the multilayer perceptron accurately predicted outcomes, followed by the random forest classifier, gradient boosting classifier, K-nearest neighbors, and logistic regression models. The factors that contributed the most were age, marital status, and the total number of tumors in the patients. The present study offers a comprehensive approach for the treatment and prognosis assessment of patients with MSO. The machine learning models we have developed serve as a practical, personalized tool to aid in clinical decision-making processes.

The molecular prognostic score, a classifier for risk stratification of high-grade serous ovarian cancer

BackgroundThe clinicopathological parameters such as residual tumor, grade, the International Federation of Gynecology and Obstetrics (FIGO) score are often used to predict the survival of ovarian cancer patients, but the 5-year survival of high grade serous ovarian cancer (HGSOC) still remains around 30%. Hence, the relentless pursuit of enhanced prognostic tools for HGSOC, this study introduces an unprecedented gene expression-based molecular prognostic score (mPS). Derived from a novel 20-gene signature through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression, the mPS stands out for its predictive prowess.ResultsValidation across diverse datasets, including training and test sets (n = 491 each) and a large HGSOC patient cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium (n = 7542), consistently shows an area-under-curve (AUC) around 0.7 for predicting 5-year overall survival. The mPS’s impact on prognosis resonates profoundly, yielding an adjusted hazard-ratio (HR) of 6.1 (95% CI: 3.65–10.3; p < 0.001), overshadowing conventional parameters—FIGO score, residual disease, and age. Molecular insights gleaned from mPS stratification uncover intriguing pathways, with focal-adhesion, Wnt, and Notch signaling upregulated, and antigen processing and presentation downregulated (p < 0.001) in high-risk HGSOC cohorts.ConclusionPositioned as a robust prognostic marker, the 20-gene signature-derived mPS emerges as a potential game-changer in clinical settings. Beyond its role in predicting overall survival, its implications extend to guiding alternative therapies, especially targeting Wnt/Notch signaling pathways and immune evasion—a promising avenue for improving outcomes in high-risk HGSOC patients.

Quality of life among borderline ovarian tumor survivors: A comparison with survivors of early-stage ovarian cancer and a cancer-free population: A cross-sectional population-based PROFILES study

ObjectiveThis study assessed the health-related quality of life (HRQo) of women surviving a borderline ovarian tumor (BOT) in comparison with early-stage ovarian cancer survivors treated surgically alone and with a matched cancer-free population. MethodsSurvivors of BOT and ovarian cancer were invited in two Dutch cross-sectional, population-based studies. Ovarian cancer survivors with tumor stage I who were treated surgically only were included. A random sample from the cancer-free population was matched on sex, age and education to the sample of BOT survivors. The EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 were completed by the cancer-free population and the BOT and ovarian cancer survivors in study 1 and 2. The Hospital Anxiety and Depression Scale (HADS) was only completed by the cancer-free population and the survivors of BOT and ovarian cancer in study 1. BOT survivors were compared to early-stage ovarian cancer survivors and the general population using linear regression analyses and effect sizes regarding clinical importance. Results83 BOT (42%), 88 early-stage ovarian cancer survivors (52%), and 82 women from the general population were included. In most HRQoL domains, BOT survivors were not significantly different from early-stage ovarian cancer survivors and the cancer-free population, except that BOT survivors reported significantly less insomnia than early-stage ovarian cancer survivors and more dyspnea than the cancer-free population (small clinical difference). ConclusionIn general, BOT survivors' HRQoL lies between the HRQoL of early-stage ovarian cancer survivors and of the cancer-free population, but clinical effect sizes between the groups were mostly only trivial.

Primary Ovarian Leiomyoma in a Post-Menopausal Woman: A Rare Ovarian Tumor

Primary Ovarian Leiomyoma in a Post-Menopausal Woman: A Rare Ovarian Tumor

Diagnostic Efficacy of Ultrasound-Based International Ovarian Tumor Analysis Simple Rules and Assessment of the Different Neoplasias in the Adnexa Model in Malignancy Prediction Among Women With Adnexal Masses: A Systematic Review.

Transvaginal ultrasonography (USG) is most commonly used before surgery to accurately diagnosebenign and malignant ovarian massesfor effectivetreatment, avoid unnecessary interventions,improve the prognosis of patients,and preserve fertility in patients with benigntumors. Therefore, the objective of the present systematic review was to assess the diagnostic efficacy of ultrasound-based International Ovarian Tumor Analysis (IOTA) Simple Rules (SR) and Assessment of Different NEoplasias in the adneXa (ADNEX) model in predicting malignancy among women with adnexal masses. A systematic literature search was carried out on electronic databases consisting of Science Direct, PubMed, and Google Scholar. The keywords utilized to perform the literature search and include relevant articles consisted of "Diagnostic Efficacy", AND "Ultrasound-Based International Ovarian Tumor Analysis Simple Rules", AND "International Ovarian Tumor Analysis ADNEX Model", AND "Adnexal masses", AND "Ovarian tumors". Based on the selection criteria, a total of five studies were included. The study concluded that both the models showed high diagnostic efficacy for malignancy prediction; however, in comparison to the IOTA SR, the IOTA ADNEX model demonstrated good diagnostic efficacy.

Increased Human Chorionic Gonadotropin Level in a Nonsexually Active Young Female

BackgroundQuantitative and qualitative human chorionic gonadotropin (hCG) tests are obtained in the emergency department (ED) to determine if a female of child-bearing age is pregnant. A positive hCG result is commonly assumed to indicate an intrauterine or other form of pregnancy. However, elevated hCG levels can also result from various other conditions, such as ovarian tumors, pituitary tumors, and thyroid disorders. Intracranial germ cell tumors, rare central nervous system tumors capable of secreting hCG, primarily affect adolescent and young adult females. Case ReportA 16-year-old female student without significant past medical history presented to our ED with a complaint of intermittent bilateral frontal headache for two days. Last menstrual period started two days prior to presentation. The headache was associated with phonophobia, photophobia, nausea, and vomiting. Serum quantitative hCG was elevated. She denied history of sexual activity or sexual assault. Transabdominal ultrasound was negative for intrauterine pregnancy. Obstetrics and gynecology as well as pediatric oncology were consulted. Subsequent investigations, including brain imaging, revealed a 3.5 cm mass in the right caudate nucleus and corpus callosum. The patient was diagnosed with an intracranial nongerminomatous germ cell tumor, necessitating hospitalization and prompt initiation of chemotherapy. Why Should an Emergency Physician Be Aware of This?An elevated quantitative hCG is not always indicative of pregnancy, especially in a young patient without sexual history. In the case of a nonrevealing transabdominal ultrasound, obstetrics and gynecology should be consulted for discussion of further testing and imaging. Emergency physicians should include malignancy high on their differential since prompt initiation of chemotherapy, evaluation by surgical services, and family planning will be required.

Correlation of PD-L1 expression with different clinico-pathological and immunohistochemical features of ovarian surface epithelial tumors.

Primary carcinoma of the ovary (OCs) are responsible for a significant number of deaths related to cancer, and have the highest rate of death related to cancers of the female reproductive organs. Programmed cell death 1 (PD1) protein, acts as an immune checkpoint, and has an important role in the down-regulation of the immune system by preventing the activation of T-cells, which will weaken the autoimmunity and increases self-tolerance. This study aimed at the evaluation of the immunohistochemical (IHC) expression of PD-L1 in various primary surface ovarian epithelial tumours and to test its correlation with different clinicopathological parameters together with the expression of a panel of P53, ER and PR. A set of 102 cases of primary ovarian surface epithelial neoplasms (benign, borderline and malignant) were collected to construct Tissue Microarray (TMA) using 3 tissue cores from each case. IHC for PD-L1, p53, PR and ER was performed. The expression of PD-L1 was evaluated in relation to some clinicopathological parameters and to the expression patterns of other markers. Expression of PD-L1 was detected in about 51% (n = 36) of malignant tumours. The malignant group significantly showed PD-L1 positivity compared to borderline and benign groups. The malignant tumours significantly showed PD-L1 and total p53 positivity in comparison to borderline group. Also, malignant tumours significantly showed higher combined positivity of PD-L1 and either PR or ER compared to borderline and benign lesions. No significant correlation was appreciated between PD-L1 expression and with any of the studied clinicopathological parameters. This study showed a significant PD-L1 expression in malignant primary surface epithelial tumours. Construction of a panel of IHC markers, including PD-L1, could have a potential value to define patients those would benefit from the addition of immunotherapy to the treatment plan.

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

Chronic inflammation contributes to the progression of isoproterenol (ISO)-induced heart failure (HF). Caspase-associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO-driven cardiac remodelling is little explored. This study utilized Card9-/- mice and reconstituted C57BL/6 mice with either Card9-/- or Otud1-/- marrow-derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK-293T cells. Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole-body CARD9 knockout or myeloid-specific CARD9 deletion inhibited ISO-driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO-induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33-linked ubiquitin from CARD9 to promote the assembly of the CARD9-BCL10-MALT1 (CBM) complex, without affecting CARD9 stability. The ISO-activated CBM complex results in NF-κB activation and macrophage-based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid-specific OTUD1 deletion also attenuated ISO-induced murine cardiac inflammation and remodelling. These results suggested that the OTUD1-CARD9 axis is a new pro-inflammatory signal in ISO-challenged macrophages and targeting this axis has a protective effect against ISO-induced HF. Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration. Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling. ISO promoted the assembly of CBM complex and then activated NF-κB signaling in macrophages through OTUD1-mediated deubiquitinating modification. OTUD1 deletion in myeloid cells protected hearts from ISO-induced injuries in mice.