How Progesterone Receptor Expression Impacts Platinum Sensitivity in Ovarian Clear Cell Carcinoma: Insights from Clinical and Experimental Perspectives.

Ovarian clear cell carcinoma (OCCC) is often considered a relatively platinum-resistant malignancy. The aim of this study was to explore the influence of progesterone receptor (PR) expression levels on platinum sensitivity and survival outcomes in people with OCCC. A retrospective analysis was conducted with 80 people with OCCC who underwent surgery followed by adjuvant chemotherapy. PR expression was assessed via immunohistochemical (IHC) staining and quantified using the H score. The platinum sensitivity and survival outcomes of patients with weak and strong PR expression were compared. Additionally, cisplatin viability and migration experiments were conducted with OCCC cell lines (ES-2 and TOV-21G) with varying PR isoform expressions. Among the 80 patients, 62 were classified as having platinum-sensitive disease, while 18 had platinum-resistant disease. The mean total PR H- score of platinum-sensitive tumors was significantly higher than that of platinum-resistant tumors (p = 0.002). Although no significant differences in progression-free and overall survival were observed between patients with high and low PR expression, those with high PR expression tended to have longer survival. While PR protein was only weakly detectable in ES-2 and TOV-21G cells, a transfection of the PR-A or PR-B gene resulted in a strong expression of PR-A or PR-B, which led to significantly reduced proliferation and migration in ES-2 and TOV-21G cells. Furthermore, overexpression of PR-A or PR-B enhanced cisplatin cytotoxicity in these cell lines. In conclusion, strong PR expression was associated with improved platinum sensitivity and survival outcomes, consistent with our experimental findings. The potential of PR as a tumor sensitizer to cisplatin in OCCC warrants further investigation.

A prospective study of endometrial histopathology in post-menopausal women in Jharkhand.

Introduction: Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal women. In the early menopausal years, endometrial hyperplasia, polyps and submucosal fibroids are common etiologies of post menopausal bleeding. The most common cause of postmenopausal bleeding is endometrial atrophy, comprises of 60-80%, while endometrial hyperplasia and endometrial cancer contribute to only 11% of Post menopausal bleeding. The aim of study is to analyses histomorphological pattern of endometrium in patients presenting with post-menopausal bleeding in Jharkhand. Materials and Methods: 103 postmenopausal women presenting to tertiary center of Jharkhand in 2020-22 with bleeding were subjected to endometrial curettage for histopathology. Analysis is based on morphological criteria to assess endometrium. Endometrial histology is of four categories: Proliferative, Secretory, premalignant and carcinoma. Results: The highest incidence of postmenopausal bleeding was noticed in age group of < 60 years and incidence of malignancy was higher after 57 years of age. The majority of patients had parity between 1 and 3 (78.6%). Malignant & premalignant lesions comprises about 22.3% among that 77.7% were due to benign causes. Among the benign causes of postmenopausal bleeding, proliferative endometrium was the commonest finding. Types of hyperplasia encountered were simple hyperplasia without atypia (6.8%), Complex hyperplasia without atypia (3.9%),Complex hyperplasia with atypia (4.8%) and Simple hyperplasia with atypia (4.8%). 21.4% of cases of postmenopausal bleeding were associated with atrophic endometrium. Secretory endometrium seen in 17.5% of women. Endometrial carcinoma accounted for 12.6% of cases of postmenopausal bleeding. Out of these 69.2% were of endometroid type of endometrial carcinoma, 15.3% were of papillary serous carcinoma and 15.3% had clear cell carcinoma. The mean age of patients with endometrium carcinoma was 62.3 years. All cases of endometrial carcinoma were associated with 1 or more risk factor like diabetes/hypertension/Nulligravida. Conclusion: Proliferative Endometrium was a major cause of postmenopausal bleeding. Among the malignant causes, endometrial adenocarcinoma of endometroid type was most frequent with a lower mean age at presentation than other high grade cancers like papillary serous carcinoma & clear cell carcinoma.

Lipid droplets: a candidate new research field for epithelial ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a histological subtype that constitutes approximately 20% of epithelial ovarian cancer cases in Asian countries, but has a relatively low incidence in Western countries. Meanwhile, clear cell renal cell carcinoma (ccRCC) is a major subtype of kidney cancer. OCCC and ccRCC resemble one another histologically and have clear cytoplasmic appearances. Studies have revealed some genetic similarities between OCCC and ccRCC. However, information regarding common biological background factors between these cancers remains scarce. For example, accumulation of cellular lipid droplets was shown to play a crucial role in ccRCC progression, while similar information is lacking for OCCC. In this perspective article, we propose that lipid droplets may be candidates for future exploration to better understand the common biological backgrounds between OCCC and ccRCC, potentially leading to subtype-specific treatment strategies. We further discuss the relationship between poly ADP-ribose polymerase inhibition treatment and lipid metabolism because this therapeutic strategy has attracted considerable attention as a treatment for epithelial ovarian cancer.

Research on molecular characteristics of ADME-related genes in kidney renal clear cell carcinoma.

Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are named ADME genes. However, the comprehensive role of ADME genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Using the clinical and gene expression data of KIRC patients downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and the Gene Expression Omnibus (GEO) databases, we cluster patients into two patterns, and the population with a relatively poor prognosis demonstrated higher level of immunosuppressive cell infiltration and higher proportion of glycolytic subtypes. Then, 17 ADME genes combination identified through the least absolute shrinkage and selection operator algorithm (LASSO, 1000 times) was utilized to calculate the ADME score. The ADME score was found to be an independent predictor of prognosis in KIRC and to be tightly associated with the infiltration level of immune cells, metabolic properties, tumor-related signaling pathways, genetic variation, and responses to chemotherapeutics. Our work revealed the characteristics of ADME in KIRC. Assessing the ADME profiles of individual patients can deepen our comprehension of tumor microenvironment (TME) features in KIRC and can aid in developing more personalized and effective therapeutic strategies.

EBP1 promotes the malignant biological behaviors of kidney renal clear cell carcinoma through activation of p38/HIF-1α signaling pathway.

BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is a common malignant tumor of the urinary system, and its incidence is increasing. ERBB3 binding protein (EBP1) is upregulated in various cancers. However, the connection between EBP1 and KIRC has not been reported. METHODS: The expression of EBP1 in normal kidney tissue and KIRC tissue was analyzed through database and tissue microarray. EBP1 was knocked down in KIRC cell lines, and its impact on KIRC proliferation was assessed through CCK-8, soft agar assay, and flow cytometry. Scratch and transwell assays were used to evaluate the influence of EBP1 on KIRC invasion and migration. Nude mice tumor experiment were conducted to examine the effect of EBP1 on tumor tissue. Database analysis explored potential pathways involving EBP1, and validation was performed through Western blot experiments and p38 inhibitor. RESULTS: EBP1 is upregulated in KIRC and significantly correlates with clinical staging, pathological grading, and lymph node metastasis in patients. The mechanism research showed that knocking down EBP1 inhibited KIRC proliferation, invasion, and migration and inhibited p38 phosphorylation and the expression of hypoxia-inducible factor-1α (HIF-1α) in KIRC. p-38 inhibitor (SB203580) inhibits p38 phosphorylation and HIF-1α expression and suppresses cell viability in a concentration-dependent manner, but has no effect on EBP1 expression. HEK 293T cells overexpressing EBP1 showed increased expression of phosphorylated p38 and HIF-1α and enhanced cell viability, however, SB203580 inhibited this effect of EBP1. CONCLUSION: EBP1 may promote the occurrence and development of KIRC by regulating the expression of p38/HIF-1α signaling pathway.

Comorbid thrombosis as an adverse prognostic factor in patients with ovarian clear cell carcinoma regardless of staging.

OBJECTIVE: Patients with ovarian clear cell carcinoma (OCCC) often present with thrombosis. While cancer patients with concomitant thrombosis were generally reported to have worse prognoses than those without, the association between thrombosis and prognosis has not been elucidated in OCCC. This study aimed to determine how the co-occurrence of thrombosis affects OCCC prognoses. METHODS: We retrospectively examined 115 patients with OCCC who were diagnosed and treated at the University of Tokyo Hospital between 2009 and 2019. RESULTS: Of 115 patients with OCCC, thrombosis was present in 12.5% of 80 patients and in 42.8% of 35 patients who had OCCC stage I/II and stage III/IV, respectively. In stage I/II, the 5-year progression-free survival was 20.6% and 91.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 50.0% and 94.1%. Therefore, the outcomes were significantly poorer among patients with thrombosis (p < 0.0001 and p < 0.0001, respectively). In stage III/IV, the 5-year progression-free survival was 26.7% and 52.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 32.0% and 62.2%. Similarly, the outcomes were significantly poorer among patients with thrombosis (p = 0.0139 and p = 0.369, respectively). CONCLUSION: We determined that thrombosis is more likely to develop in advanced OCCC stages than in early stages, and its co-occurrence is associated with a poor prognosis, regardless of disease stage.

Interesting Breast Tumours: A Tripod of Cases.

Knowledge regarding the lesser common breast tumours, including malignant papillary neoplasms and glycogen-rich clear cell carcinoma, is limited. Overall, cases of papillary carcinoma of the breast fare better than invasive breast carcinoma, from the data available in literature. Glycogen-rich clear cell carcinoma is characterized by the presence of clear cells, having mostly a poorer prognosis. We hereby present three such cases which would add to the existing available information. Case 1 is a 79-year-old female who presented with a left breast lump and bloody nipple discharge. Mammography suggested malignant lesion, with FNAC suspicious of malignancy. Surgery was done and histopathological examination showed irregular islands of tumour cells having papillary fronds with absence of myoepithelial layer. Immunohistochemically, the tumour was GATA3, CK7, ER, PR positive, HER2 negative, with Ki67 index 10%. The case was diagnosed as Solid papillary carcinoma. Case 2 is a 57-year-old female presenting with a left breast lump along with bloody nipple discharge. Mammography and FNAC were in favour of malignancy. Trucut biopsy was done, microscopy revealing a tumour having >90% papillary architecture with infiltrative pattern. Features were suggestive of Invasive breast carcinoma with papillaroid features. The tumour was GATA3, CK7, ER, PR positive, HER2 negative, with Ki67 index 15%. Case 3 is a 70-year-old female presenting with a right breast lump with nipple retraction. Mammography and FNAC were suggestive of malignancy. Trucut biopsy followed by microscopy revealed polygonal tumour cells with clear cytoplasm in nested pattern, showing positive staining for Periodic Acid Schiff. Immunostaining showed GATA3 positive, PAX8 negative, ER and PR positive, HER2 negative, and Ki67 index 20%. A diagnosis of Invasive breast carcinoma with Glycogen-rich clear cell pattern was made. Identifying these rare entities is important along with assessing hormone status for avoiding overtreatment and undertreatment and applying appropriate targeted therapies.

Significance and Possible Biological Mechanism for CLDN8 Downregulation in Kidney Renal Clear Cell Carcinoma Tissues.

Background: The clinical role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined. Methods: High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8. In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8. A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8. Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC. Results: A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM, ACO2, NDUFS1, PDHB, SDHD, SUCLA2, SUCLG1, and SUCLG2. Conclusions: CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction.

Status and development of research on clear cell carcinoma of the ovary-a visualization-based bibliometric analysis.

Background: Clear cell carcinoma of the ovary (CCCO) is a relatively rare type of epithelial ovarian cancer (EOC) that has unique biological characteristics and clinical features. Researchers have paid less attention to this disease than to other types of EOCs. However, in recent years, research in this area has still progressed. In this paper, a bibliometric analysis is used to integrate and analyse the literature in the field of CCCO in the past 20 years to determine research development, better understand the current status of research, and provide a reference for future study directions in this field. Methods: With CCCO as the research subject, relevant publications indexed in the Web of Science (WOS) core dataset from September 2003 to September 2023 were retrieved. After screening the publications, we used EXCEL, VOSviewer, CiteSpace, Charticulator, Gephi, OriginPro and other tools to perform in-depth analyses of and to visualize the data. Results: Through a comprehensive analysis of the literature in this field, we found that research on CCCO experienced a relatively rapid increase in 2006 and is now in a period of relatively high fluctuation. The quality of the literature in this field is generally high. In this field, countries in East Asia and North America play core roles, with Japan accounting for the most studies. A stable research group has been formed in this field, and extensive collaboration has occurred among the various research groups. In the past 20 years, basic research and clinical research in the field of CCCO have developed together, and a healthy development model in which basic and clinical research promote each other has formed. Research in this field has been continuously developed from a preliminary understanding of clinical features to in-depth explorations of the pathogenesis and the continuous optimization of treatment methods. The key molecular events in the pathogenesis and development of this disease and the application of novel antitumour drugs for this disease are the current research focuses and the future development direction in this field. Conclusions: Research on CCCO has progressed significantly in the past 20 years, but there are still many important issues regarding its pathogenesis and treatment that need to be addressed, and therefore, more research in this area should be conducted in the future. The study of key molecular events and the use of novel antitumour drugs are future development directions in this field.

Systematic analysis of the expression profiles and prognostic significance of the MED gene family in renal clear cell carcinoma.

The mediator complex (MED) family is a contributing factor in the regulation of transcription and proliferation of cells, and is closely associated with the development of various types of cancer. However, the significance of the expression levels and prognostic value of MED genes in kidney renal clear cell carcinoma (KIRC) have rarely been reported. The present study analyzed the expression and prognostic potential of MED genes in KIRC. The Search Tool for the Retrieval of Interacting Genes/Proteins was used to construct the protein-protein interaction network (PPI), the Assistant for Clinical Bioinformatics database was used to perform correlation analysis, GEPIA 2 was utilized to draw the Kaplan-Meier plot and analyze prognostic significance and the Tumor Immune Estimation Resource was used to assess the association of MED genes with the infiltration of immune cells in patients with KIRC. A total of 30 MED genes were identified, and among these genes, 11 were selected for the creation of a prognostic gene signature based on the results of a LASSO Cox regression analysis. Furthermore, according to univariate and multivariate analyses, MED7, MED16, MED21, MED25 and MED29 may be valuable independent predictive biomarkers for the prognosis of individuals with KIRC. Furthermore, there were significant differences in the expression levels of MED7, MED21 and MED25 in KIRC among different tumor grades. Additionally, patients with KIRC with high transcription levels of MED7, MED21 and MED29 had considerably longer overall survival times. The expression levels of MED genes were also linked to the infiltration of several immune cells. Overall, MED genes may have potential significance in predicting the prognosis of patients with KIRC.

A novel cancer-associated fibroblast signature for kidney renal clear cell carcinoma via integrated analysis of single-cell and bulk RNA-sequencing.

Cancer-associated fibroblasts (CAFs), integral components of the tumor microenvironment, play a pivotal role in tumor proliferation, metastasis, and clinical outcomes. However, its specific roles in Kidney Renal Clear Cell Carcinoma (KIRC) remain poorly understood. Employing the established Seurat single-cell analysis pipeline, we identified 21 CAFs marker genes. Subsequently, a prognostic signature consisting of 6 CAFs marker genes (RGS5, PGF, TPM2, GJA4, SEPT4, and PLXDC1) was developed in a cohort through univariate and LASSO Cox regression analyses. The model's efficacy was then validated in an external cohort, with a remarkable predictive performance in 1-, 3-, and 5-year. Patients in the high-risk group exhibited significantly inferior survival outcomes (p < 0.001), and the risk score was an independent prognostic factor (p < 0.05). Distinct differences in immune cell profiles and drug susceptibility were observed between the two risk groups. In KIRC, the PGF-VEGFR1 signaling pathway displayed a notable increase. PGF expression was significantly elevated in tumor tissues, as demonstrated by quantitative real-time polymerase chain reaction. In vitro, transwell assays and CCK8 revealed that recombinant-PGF could enhance the capability of cell proliferation, migration, and invasion in 769P and 786-O cells. This study firstly developed a novel predictive model based on 6 CAFs genes for KIRC. Additionally, PGF may present a potential therapeutic target to enhance KIRC treatment.

Landscape analysis of alternative splicing in kidney renal clear cell carcinoma and their clinical significance.

A growing number of studies reveal that alternative splicing (AS) is associated with tumorigenesis, progression, and metastasis. Systematic analysis of alternative splicing signatures in renal cancer is lacking. In our study, we investigated the AS landscape of kidney renal clear cell carcinoma (KIRC) and identified AS predictive model to improve the prognostic prediction of KIRC. We obtained clinical data and gene expression profiles of KIRC patients from the TCGA database to evaluate AS events. The calculation results for seven types of AS events indicated that 46276 AS events from 10577 genes were identified. Next, we applied Cox regression analysis to identify 5864 prognostic-associated AS events. We used the Metascape database to verify the potential pathways of prognostic-associated AS. Moreover, we constructed KIRC prediction systems with prognostic-associated AS events by the LASSO Cox regression model. AUCs demonstrated that these prediction systems had excellent prognostic accuracy simultaneously. We identified 34 prognostic associated splicing factors (SFs) and constructed homologous regulatory networks. Furthermore, in vitro experiments were performed to validate the favorable effect of SFs FMR1 in KIRC. In conclusion, we overviewed AS events in KIRC and identified AS-based prognostic models to assist the survival prediction of KIRC patients. Our study may provide a novel predictive signature to improve the prognostic prediction of KIRC, which might facilitate KIRC patient counseling and individualized management.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay.

BACKGROUND: Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. METHODS AND RESULTS: The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion. CONCLUSIONS: In conclusion, anti-PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

A Rare Case of Extra-renal Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the predominant solid lesion found in the kidney. Extra-renal RCC is a rare entity. We present the case of a 75-year-old male with an incidentally discovered mass in the right iliac fossa. The patient underwent active surveillance because a percutaneous biopsy revealed a mesenchymal neoplastic lesion of benign biological behavior. As the mass had high growth rates, a decision for open surgical exploration and excision was made. The pathology results indicated clear cell renal carcinoma, and negative results on 18F-FDG whole-body positron emission tomography-computed tomography (PET/CT) established the diagnosis of extra-renal clear cell RCC. Similar types of neoplasms are extremely rare and are estimated to have developed primarily in mesodermal embryonic remnants. Clinicians should be aware of this rare entity as its diagnosis is challenging and is based on pathology.

ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.

Ultrasound contrast-enhanced radiomics model for preoperative prediction of the tumor grade of clear cell renal cell carcinoma: an exploratory study.

BACKGROUND: This study aims to explore machine learning(ML) methods for non-invasive assessment of WHO/ISUP nuclear grading in clear cell renal cell carcinoma(ccRCC) using contrast-enhanced ultrasound(CEUS) radiomics. METHODS: This retrospective study included 122 patients diagnosed as ccRCC after surgical resection. They were divided into a training set (n = 86) and a testing set(n = 36). CEUS radiographic features were extracted from CEUS images, and XGBoost ML models (US, CP, and MP model) with independent features at different phases were established. Multivariate regression analysis was performed on the characteristics of different radiomics phases to determine the indicators used for developing the prediction model of the combined CEUS model and establishing the XGBoost model. The training set was used to train the above four kinds of radiomics models, which were then tested in the testing set. Radiologists evaluated tumor characteristics, established a CEUS reading model, and compared the diagnostic efficacy of CEUS reading model with independent characteristics and combined CEUS model prediction models. RESULTS: The combined CEUS radiomics model demonstrated the best performance in the training set, with an area under the curve (AUC) of 0.84, accuracy of 0.779, sensitivity of 0.717, specificity of 0.879, positive predictive value (PPV) of 0.905, and negative predictive value (NPV) of0.659. In the testing set, the AUC was 0.811, with an accuracy of 0.784, sensitivity of 0.783, specificity of 0.786, PPV of 0.857, and NPV of 0.688. CONCLUSIONS: The radiomics model based on CEUS exhibits high accuracy in non-invasive prediction of ccRCC. This model can be utilized for non-invasive detection of WHO/ISUP nuclear grading of ccRCC and can serve as an effective tool to assist clinical decision-making processes.

The "Road" to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review.

Ovarian cancer is an umbrella term covering a number of distinct subtypes. Endometrioid and clear-cell ovarian carcinoma are endometriosis-associated ovarian cancers (EAOCs) frequently arising from ectopic endometrium in the ovary. The mechanistic target of rapamycin (mTOR) is a crucial regulator of cellular homeostasis and is dysregulated in both endometriosis and endometriosis-associated ovarian cancer, potentially favouring carcinogenesis across a spectrum from benign disease with cancer-like characteristics, through an atypical phase, to frank malignancy. In this review, we focus on mTOR dysregulation in endometriosis and EAOCs, investigating cancer driver gene mutations and their potential interaction with the mTOR pathway. Additionally, we explore the complex pathogenesis of transformation, considering environmental, hormonal, and epigenetic factors. We then discuss postmenopausal endometriosis pathogenesis and propensity for malignant transformation. Finally, we summarize the current advancements in mTOR-targeted therapeutics for endometriosis and EAOCs.

Genome-wide DNA methylation in relation to ARID1A deficiency in ovarian clear cell carcinoma.

BACKGROUND: The poor chemo-response and high DNA methylation of ovarian clear cell carcinoma (OCCC) have attracted extensive attentions. Recently, we revealed the mutational landscape of the human kinome and additional cancer-related genes and found deleterious mutations in ARID1A, a component of the SWI/SNF chromatin-remodeling complex, in 46% of OCCC patients. The present study aims to comprehensively investigate whether ARID1A loss and genome-wide DNA methylation are co-regulated in OCCC and identify putative therapeutic targets epigenetically regulated by ARID1A. METHODS: DNA methylation of ARID1Amt/ko and ARID1Awt OCCC tumors and cell lines were analyzed by Infinium MethylationEPIC BeadChip. The clustering of OCCC tumors in relation to clinical and mutational status of tumors were analyzed by hierarchical clustering analysis of genome-wide methylation. GEO expression profiles were used to identify differentially methylated (DM) genes and their expression level in ARID1Amt/ko vs ARID1Awt OCCCs. Combining three pre-ranked GSEAs, pathways and leading-edge genes epigenetically regulated by ARID1A were revealed. The leading-edge genes that passed the in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines were regarded as candidate genes and finally verified by bisulfite sequencing and RT-qPCR. RESULTS: Hierarchical clustering analysis of genome-wide methylation showed two clusters of OCCC tumors. Tumor stage, ARID1A/PIK3CA mutations and TP53 mutations were significantly different between the two clusters. ARID1A mutations in OCCC did not cause global DNA methylation changes but were related to DM promoter or gene-body CpG islands of 2004 genes. Three pre-ranked GSEAs collectively revealed the significant enrichment of EZH2- and H3K27me3-related gene-sets by the ARID1A-related DM genes. 13 Leading-edge DM genes extracted from the enriched gene-sets passed the expression-based in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines. Bisulfite sequencing and RT-qPCR analysis showed promoter hypermethylation and lower expression of IRX1, TMEM101 and TRIP6 in ARID1Amt compared to ARID1Awt OCCC cells, which was reversed by 5-aza-2'-deoxycytidine treatment. CONCLUSIONS: Our study shows that ARID1A loss is related to the differential methylation of a number of genes in OCCC. ARID1A-dependent DM genes have been identified as key genes of many cancer-related pathways that may provide new candidates for OCCC targeted treatment.

An analysis of AURKB's prognostic and immunological roles across various cancers.

Aurora kinase B (AURKB), an essential regulator in the process of mitosis, has been revealed through various studies to have a significant role in cancer development and progression. However, the specific mechanisms remain poorly understood. This study, therefore, seeks to elucidate the multifaceted role of AURKB in diverse cancer types. This study utilized bioinformatics techniques to examine the transcript, protein, promoter methylation and mutation levels of AURKB. The study further analysed associations between AURKB and factors such as prognosis, pathological stage, biological function, immune infiltration, tumour mutational burden (TMB) and microsatellite instability (MSI). In addition, immunohistochemical staining data of 50 cases of renal clear cell carcinoma and its adjacent normal tissues were collected to verify the difference in protein expression of AURKB in the two tissues. The results show that AURKB is highly expressed in most cancers, and the protein level of AURKB and the methylation level of its promoter vary among cancer types. Survival analysis showed that AURKB was associated with overall survival in 12 cancer types and progression-free survival in 11 cancer types. Elevated levels of AURKB were detected in the advanced stages of 10 different cancers. AURKB has a potential impact on cancer progression through its effects on cell cycle regulation as well as inflammatory and immune-related pathways. We observed a strong association between AURKB and immune cell infiltration, immunomodulatory factors, TMB and MSI. Importantly, we confirmed that the AURKB protein is highly expressed in kidney renal clear cell carcinoma (KIRC). Our study reveals that AURKB may be a potential biomarker for pan-cancer and KIRC.

Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes.

BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.