Search Results (720)

Objective: Ovarian, fallopian tube, and primary peritoneal cancers remain among the deadliest gynecological malignancies, largely because most cases are diagnosed at an advanced stage and no effective screening strategy is currently available. Increasing evidence suggests that many high-grade serous ovarian carcinomas originate from the fallopian tube. We aimed to explore the diagnostic performance of ex vivo fallopian tube cytology and the CytoSaLPs score for detecting tubal and adnexal malignancies in women undergoing salpingectomy or salpingo-oophorectomy. Methods: We conducted a prospective single-center observational study including 304 women undergoing salpingectomy or salpingo-oophorectomy for benign, premalignant or malignant gynecological indications between 2020 and 2023. Ex vivo cytological brushing of the distal fallopian tube was performed before fixation, followed by histopathological examination using the SEE-FIM protocol where appropriate. The primary analysis was performed at the specimen level. Of 544 paired specimens initially available for cytology–histology correlation, 53 non-diagnostic cytological specimens were excluded from the primary diagnostic performance analysis, leaving 491 evaluable paired specimens. Fallopian tube cytological findings were compared with histopathology as the reference standard. The discriminatory ability of the CytoSaLPs score was explored using receiver operating characteristic analysis. Results: Fallopian tube cytology demonstrated high sensitivity for histologically confirmed tubal malignancy, although specificity was moderate. Based on the primary specimen-level analysis, sensitivity was 94.4% and specificity was 71.0%. When fallopian tube cytology was compared with ovarian histology, sensitivity was 72.9% and specificity was 72.4%. For the adnexa considered as a single anatomical entity, sensitivity was 76.5% and specificity was 70.7%. The CytoSaLPs score showed good discriminatory ability for fallopian tube malignancy (AUC 0.8534), moderate discrimination for ovarian malignancy (AUC 0.6790), and fair discrimination for adnexal malignancy (AUC 0.730). The optimal score thresholds were derived from the same dataset and should therefore be considered provisional. Three serous tubal intraepithelial carcinoma lesions were identified histologically; two showed cytological abnormalities and elevated CytoSaLPs scores, whereas one specimen was non-diagnostic. Conclusions: This exploratory proof-of-concept study suggests that ex vivo fallopian tube and the CytoSaLPs score may provide a structured approach for detecting cytological abnormalities associated with tubal and adnexal malignancy. However, the findings were obtained in a tertiary gynecologic oncology population under ex vivo conditions, non-diagnostic specimens occurred in approximately 10% of samples, and the scoring system was developed and evaluated within the same cohort. Independent external validation and evaluation using clinically applicable in vivo sampling methods are required before any clinical implementation can be considered. Full article

Background/Objectives: HER2-directed antibody–drug conjugates have expanded the clinical relevance of low-level HER2 expression. However, the prevalence and clinical significance of HER2-ultralow expression in gynecologic malignancies remain insufficiently defined. This study characterized the full spectrum of HER2 expression in endometrial carcinoma (EC) and high-grade serous ovarian carcinoma (HGSOC), including matched metastatic lesions. Methods: HER2 expression was assessed by immunohistochemistry in tissue microarrays from 117 EC and 52 HGSOC patients. Available matched metastatic lesions were analyzed in 23 EC and 18 HGSOC cases. HER2 expression was categorized as zero, ultralow, 1+, 2+, or 3+. Associations with clinicopathological parameters and progression-free survival were evaluated. Results: HER2-ultralow expression was common in primary tumors, occurring in 49/117 EC cases (41.9%) and 11/52 HGSOC cases (21.2%), whereas HER2 3+ expression was rare (EC: 2/117, 1.7%; HGSOC: 1/52, 1.9%). HER2 expression in primary tumors was associated with progression-free survival in both entities, with HER2-zero tumors showing the longest estimated progression-free survival. HER2 score discordance between matched primary tumors and metastases occurred in 16/23 EC cases (69.6%) and 8/18 HGSOC cases (44.4%). Conclusions: HER2-ultralow expression represents a frequent and previously underrecognized category in EC and HGSOC. While its prognostic impact remains limited, the high prevalence of HER2-ultralow tumors suggests potential relevance for future HER2-targeted therapeutic strategies. Prospective studies are needed to determine whether this subgroup may benefit from a HER2-targeted therapy. Full article

Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are surrogate markers of the systemic immune-inflammatory response proposed as perioperative prognostic biomarkers in epithelial ovarian cancer (EOC), yet their performance across subgroups remains unexamined. In 373 EOC patients undergoing primary cytoreductive surgery, postoperative day-1 changes (ΔSII, ΔNLR, ΔPLR) were compared for overall survival (OS) and progression-free survival (PFS) across 10 subgroups, and a Clinical-Inflammatory Risk Score (CIRS) combining inflammation with stage and residual disease was developed. Individual markers showed modest discrimination (area under the curve [AUC] 0.579–0.615); the marker with the highest AUC varied by context, with ΔPLR ranking first most often, notably in non-serous tumors, though none was statistically superior. Seeking a molecular counterpart, two public transcriptomic cohorts were re-analyzed: VWF was consistently higher in clear cell than serous carcinoma, whereas IL6–STAT3-related differences were cohort-dependent. The CIRS achieved AUCs of 0.752 (OS) and 0.764 (PFS), a six-fold mortality gradient (7.2% vs. 44.4%), and remained independently associated with OS and PFS (hazard ratio 2.55 and 2.24 per standard deviation), though discrimination was not significantly better than stage and residual disease alone. These biomarkers show subgroup-dependent prognostic value, and the CIRS provides an exploratory risk-stratification framework warranting prospective validation. Full article

Objectives: Deubiquitinating enzymes have been increasingly implicated in tumor progression and metastasis. Ubiquitin-specific protease 17 (USP17) and translationally controlled tumor protein 1 (TPT1) are associated with cell proliferation, migration, and cancer progression; however, their differential expression in matched primary and metastatic tissues of high-grade serous ovarian carcinoma (HGSC) has not been well defined. This study aimed to compare USP17 and TPT1 expression between matched primary and metastatic HGSC tissues and to explore their association with metastatic disease. Methods: This retrospective study included 33 patients diagnosed with HGSC. Immunohistochemical analysis of USP17 and TPT1 expression was performed using tissue microarrays (TMA) constructed from matched primary ovarian tumor tissues and corresponding metastatic tissues. USP17 expression was evaluated using a semi-quantitative composite immunohistochemical scoring system, while TPT1 expression was assessed using a semi-quantitative immunoreactivity index. Paired statistical analyses were applied to compare expression patterns between primary and metastatic tissues. Results: Primary and metastatic USP17 expression levels showed a positive correlation (Spearman’s rho = 0.349, p = 0.047) whereas paired comparison showed no significant difference between the two sites (p = 0.438). In contrast, TPT1 expression showed no statistically significant correlation (Spearman’s rho = 0.285, p = 0.107) or paired comparison showed no difference (p = 0.107) between matched primary and metastatic tissues. USP17 and TPT1 expression levels were significantly positively correlated in both primary (Spearman’s rho = 0.406, p = 0.019) and matched metastatic tissues (Spearman’s rho = 0.351, p = 0.045). Neither USP17 nor TPT1 expression showed a significant association with International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node involvement, or receipt of neoadjuvant chemotherapy (NACT). Conclusions: These findings indicate a positive correlation between USP17 expression in paired primary and metastatic HGSC tissues without significant changes in overall expression levels, though causality cannot be inferred. Conversely, TPT1 expression showed no significant correlation or site-specific variation between matched tumor tissues. Further prospective and functional studies are required to validate these findings and clarify their biological significance. Full article

Background/Objectives: High-grade serous carcinoma (HGSC) represents the most frequent subtype of epithelial ovarian cancer (OC) and is associated with malignant ascitic fluid (MAF), which fosters a pro-inflammatory microenvironment that supports tumor progression. Given its rich cellular and soluble content, MAF offers a valuable window into tumor–host interactions and disease dynamics. This study examines the immune landscape of MAF samples from 22 newly diagnosed treatment-naïve HGSC patients. Methods: Immune cell phenotypes and cytokine profiles were analyzed via flow cytometry. Patients were stratified according to time to death or recurrence (TDR), using a six-month interval from diagnosis to either documented recurrence or disease-specific death as the cutoff: TDR < 6 months defined as the worse prognosis group, whereas TDR ≥ 6 months defined the better prognosis group. The expression of immune checkpoint molecules on T cells and the effects of PD-1 blockade with Pembrolizumab were also assessed. Results: Patients with worst prognosis exhibited a marked pro-inflammatory cytokine milieu, with elevated levels of TNFα, IL-1β, IL-23, and IFNγ. Concurrently, their CD4⁺ and CD8⁺ T cells displayed evidence of a functional exhaustion-associated phenotype, marked by heightened expression of the inhibitory receptors TIM-3, PD-1, and LAG-3. Notably, treatment with Pembrolizumab (a PD-1 checkpoint inhibitor) significantly enhance T cell effector function. Conclusions: These results underscore a potential immunotherapeutic approach in anti-tumor immunity among selected HGSC patients, presenting a compelling direction for advancing OC treatment. Full article

Background: Neoadjuvant chemotherapy followed by interval debulking surgery is an established treatment strategy for selected patients with advanced epithelial ovarian cancer. However, simple postoperative prognostic tools integrating pre-treatment disease extent and post-treatment pathological stage remain limited. The neoadjuvant rectal (NAR) score was originally developed as a composite stage-migration endpoint in rectal cancer and has subsequently been explored in other solid tumors. We evaluated the feasibility and prognostic value of an ovarian NAR-like score (oNAR) in patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking surgery. Methods: This single-center retrospective cohort included patients with advanced ovarian cancer treated with platinum-taxane-based neoadjuvant chemotherapy followed by interval debulking surgery. The oNAR score was calculated using clinical T category before neoadjuvant chemotherapy and pathological T and N categories after interval surgery: oNAR = [5 × ypN − 3 × (cT − ypT) + 12]²/9.61. The primary analysis evaluated oNAR as a continuous score. Low, intermediate, and high oNAR categories based on the original rectal NAR thresholds were used only for exploratory visualization. The primary endpoint was progression-free survival (PFS). Cox regression, Kaplan–Meier analysis, log-rank testing, Harrell concordance index, and exploratory ROC analysis were used. Results: Among 74 reviewed records, 73 patients had sufficient cT, ypT, and ypN data for oNAR calculation and were included in the primary analysis. Thirty-one PFS events and 10 deaths occurred. The median oNAR was 14.98 (IQR, 14.98–30.07). As a continuous variable, higher oNAR was associated with shorter PFS (HR per 1-point increase, 1.036; 95% CI, 1.010–1.061; p = 0.0055), corresponding to an HR of 1.42 per 10-point increase. The Harrell C-index for PFS was 0.669. In a parsimonious comparison, oNAR showed higher discrimination than ypN alone and discrimination comparable to a combined ypT/ypN model. PFS differed significantly across low-, intermediate-, and high-oNAR groups (log-rank p = 0.0053). Median PFS was not reached in the low-oNAR group, compared with 13.47 months in the intermediate group and 12.09 months in the high group. The association persisted in sensitivity analyses restricted to patients with complete/optimal cytoreduction, maximal cytoreduction, and high-grade serous histology. Conclusions: The oNAR score was feasible to calculate using routinely available clinical and pathological staging variables and was significantly associated with PFS after neoadjuvant chemotherapy and interval debulking surgery. These findings support oNAR as a feasible stage-migration-based prognostic summary that may help capture post-NACT pathological T/N information and warrants external validation in larger ovarian cancer cohorts. Full article

Background: Serous ovarian cancer (SOC) is the most aggressive subtype of epithelial ovarian cancer, frequently diagnosed at advanced stages with poor prognosis and chemotherapy resistance. Checkpoint kinase 1 (CHEK1), a key regulator of the DNA damage response, is overexpressed in ovarian cancer, making it a promising therapeutic target. No study has systematically evaluated natural compounds as CHEK1 inhibitors in SOC through an integrative transcriptomic and computational framework. Methods: A meta-analysis of three GEO datasets (GSE27651, GSE36668, GSE54388; n = 83) was performed using ImaGEO. DEGs were identified at |log₂FC| ≥ 2 and FDR < 0.05. Pathway enrichment, PPI network analysis, virtual screening of 40 phytochemicals against CHEK1 (PDB: 9CE4), 100 ns MD simulations, and ADMET profiling were conducted using established bioinformatics and computational tools. Results: A total of 511 DEGs were identified, with significant dysregulation of apoptosis, DNA repair, and cell cycle pathways. CHEK1 emerged as the central hub gene. Baicalein exhibited the highest binding affinity (−9.334 kcal/mol), surpassing Prexasertib (−7.2 kcal/mol). MD simulations confirmed complex stability, and ADMET profiling demonstrated favorable drug-likeness with zero Lipinski violations. Conclusions: CHEK1 is established as a validated therapeutic target in SOC, and Baicalein is identified as a computationally superior natural lead compound, warranting experimental validation in ovarian cancer models. Full article

Background/Objectives: High-grade serous ovarian cancer (HGSOC) shows variable response to platinum-based neoadjuvant chemotherapy (NACT), with outcomes strongly linked to upfront treatment sensitivity. We evaluated whether oxidative DNA damage in pathologic samples is associated with improved clinical outcomes and reflects tumor–immune interactions. Methods: We analyzed matched pre- and post-NACT tumors from patients with stage III–IV HGSOC using Repair Assisted Damage Detection (RADD) to quantify total and oxidative DNA lesions (oxRADD). Gene expression profiling was performed on a subset of tumors using the NanoString PanCancer I/O 360. Associations with homologous recombination status, platinum sensitivity, recurrence, and survival were assessed. Results: Higher pre-NACT oxidative DNA damage was observed in tumors from patients who later recurred. Among recurrent tumors, elevated oxidative lesions were associated with improved overall survival (61.8 vs. 35.0 months; HR = 0.42, p = 0.037). Oxidative damage predicted recurrence (AUC = 0.71), supporting its utility in risk stratification. Tumors with serious oxidative damage showed reduced IDO1 and TGFβ signaling signatures, along with decreased B cell- and T cell-associated TIGIT signatures after NACT. Conclusions: These findings identify oxidative DNA damage as a potential pretreatment biomarker associated with recurrence, survival, and tumor–immune state, supporting its potential to impact therapeutic decision-making in HGSOC. Full article

Background/Objectives: High-grade serous ovarian carcinoma (HGSC) is the most aggressive subtype of epithelial ovarian cancer and is characterized by marked heterogeneity of the tumor immune microenvironment. SET morphology has been associated with homologous recombination deficiency and BRCA1/2 mutations; however, its relationship with the immune microenvironment and progression-free survival (PFS) remains insufficiently understood. This study investigated the association between SET morphology, immune microenvironment characteristics, and PFS in patients with advanced-stage HGSC. Methods: A retrospective cohort of 305 patients with FIGO stage III–IV HGSC treated with primary surgery between 1996 and 2021 was analyzed. Histopathological assessment included evaluation of SET morphology, stromal and intraepithelial tumor-infiltrating lymphocytes (sTILs and itTILs), tumor immune phenotype, and lymphoid aggregates. Immunohistochemical analyses included CD8 and PD-L1 expression. Associations between SET morphology and immune parameters were evaluated using χ² and logistic regression analyses. PFS was assessed using Kaplan–Meier analysis, log-rank testing, and Cox proportional hazards regression. Results: SET morphology was significantly associated with higher sTIL and itTIL levels, increased stromal and intraepithelial CD8⁺ T-cell infiltration, higher PD-L1 TPS and CPS, more frequent primary and secondary lymphoid aggregates, and a predominance of the inflamed immune phenotype (all p < 0.05). Despite these features of an immune-active tumor microenvironment, SET morphology, CD8⁺ T-cell density, PD-L1 expression, lymphoid aggregates, and immune phenotype were not independently associated with prolonged PFS. In contrast, age remained an independent prognostic factor, with patients older than 55 years having a 50% higher risk of disease progression than younger patients (HR = 1.5, 95% CI: 1.1–2.1; p = 0.012). Higher intraepithelial TIL levels (>10%) were independently associated with improved PFS (HR = 2.1, 95% CI: 1.0–4.4; p = 0.045). Conclusions: SET morphology identifies an immune-active subtype of HGSC characterized by increased immune infiltration and PD-L1 expression but does not independently predict prolonged PFS. The dissociation between immune cell abundance and clinical outcome suggests that immune cell functionality, rather than immune infiltration alone, may determine prognosis. Routine histopathological assessment of SET morphology may facilitate biological characterization of HGSC and provide a practical surrogate marker for future biomarker-driven studies evaluating immunotherapy and targeted treatment strategies. Full article

Background/Objectives: Cytological analysis of pleural and peritoneal effusions is minimally invasive but may show limited sensitivity for malignancy detection because tumor cells can be scarce or morphologically difficult to identify. Proteomics-based mass spectrometry imaging (MSI) enables direct molecular profiling of cytological specimens and may improve the distinction between malignant and benign samples. This study investigated whether MALDI-based MSI profiling of formalin-fixed paraffin-embedded (FFPE) cytology cell blocks could discriminate high-grade serous ovarian carcinoma (HGSOC) from benign effusions and identify discriminatory peptide signatures. Methods: Forty-one FFPE cytological specimens derived from pleural and peritoneal effusions were analyzed, including 18 malignant samples and 23 benign control specimens with reactive or inflammatory cytological backgrounds. MALDI-MSI analyses were performed using proteomic profiling. In a preliminary comparative experiment, two section thicknesses (3 µm and 5 µm) were evaluated to optimize ion peak intensity yield. Classification analyses using linear discriminant analysis (LDA) and support vector machine (SVM) models were performed to identify discriminatory peptide signatures. Results: Comparative analysis of average mass spectra identified multiple differentially expressed ions with significant discriminatory performance (AUROC ≥ 0.7 or ≤0.3; Wilcoxon/Kruskal–Wallis, p < 0.001). Classification analyses achieved accuracy ranged from 91% to 94% for the discrimination of malignant and benign samples. Differential proteomic profiling identified Complement C3, Perilipin-3, arachidonate 5-lipoxygenase, Leukotriene A-4 hydrolase, fibrinogen beta and gamma chains, and serotransferrin as discriminatory proteins associated with immune modulation, lipid metabolism, cytoskeletal and extracellular matrix organization, and metabolic regulation. Notably, Complement C3 was found to be overexpressed in malignant tumor cells, supporting its potential role as a marker of tumor presence and progression. Conclusions: Proteomics-based mass spectrometry imaging enabled reliable discrimination of HGSOC from benign cytological specimens and revealed cancer-associated proteins linked to relevant biological processes. These findings support MALDI-MSI as a complementary molecular approach for the classification of challenging cytological specimens in routine diagnostic pathology. Full article

Reliable biomarkers for high-grade serous carcinoma (HGSC) with prognostic and microenvironmental relevance remain limited. Here, we developed a machine learning–guided cross-cohort transcriptomic framework to identify stable biomarkers in HGSC. Three GEO cohorts comprising 68 samples (34 HGSC and 34 normal) and 21,355 genes were integrated, and five classifiers were benchmarked under strict Leave-One-Dataset-Out (LODO) validation. Differential expression and random-effects meta-analysis were used to support cross-cohort feature prioritization, and external validation was performed in TCGA-OV tumors (n = 427) versus GTEx normal ovaries (n = 88). This framework identified a robust 22-gene consensus panel with strong cross-cohort discrimination between HGSC and normal tissue. Among these, ALDH1A2 and SPON1 emerged as the only two genes consistently prioritized by all five models. Prognostic analysis showed opposite clinical associations, with higher ALDH1A2 linked to poorer progression-free and overall survival and higher SPON1 linked to better outcomes. Immune-module analysis further demonstrated that predicted HGSC probability was positively associated with T cell, cytotoxic/NK, Treg, checkpoint, and inflammatory programs, indicating an immune-active yet immunoregulatory microenvironment. Together, these findings define a reproducible 22-gene HGSC signature and highlight ALDH1A2 and SPON1 as robust diagnostic and prognostic biomarkers. Full article

Background/Objectives: Borderline ovarian tumor (BOT) is an ovarian neoplasm of low malignant potential that lacks stromal invasion. The aim of this study was to compare intraoperative frozen section analysis (IFSA) findings with final pathology results in patients diagnosed with BOT on frozen sections and to identify risk factors associated with cancer. Methods: This study included data from patients who underwent surgery for an ovarian mass between 2020 and 2024 and were diagnosed with BOT on IFSA. Demographic, obstetric, and clinical characteristics, as well as frozen section and final pathology findings, were recorded. The CAR, NLR, and PNI scores were calculated. Patients were grouped as premenopausal or postmenopausal and compared. Based on the final pathology report, patients were also classified as having BOT or cancer and compared. Results: A total of 92 patients were included in the study, and 53 (57.6%) were postmenopausal. The prevalence of cancer was significantly higher in the postmenopausal group (p = 0.022). Final pathology revealed cancer in 11 patients (11.9%). Age group > 45 years (OR = 12.50) and serous subtype on IFSA (OR = 10.77) were significant risk factors for cancer detection. Cutoff values for distinguishing carcinoma from BOT were identified for CAR (≥1.75), NLR (≥2.64), and PNI (≤48.64). Conclusions: In this study, the rate of invasive carcinoma on final pathology among patients diagnosed with BOT on IFSA was 11.9%. Age group > 45 years and serous subtype on IFSA were independent risk factors. The cutoff values for CAR, NLR, and PNI may support risk stratification for carcinoma. Full article

High-grade serous ovarian carcinoma (HGSOC) shows limited benefit from immune checkpoint blockade, partly because stromal barriers impair antitumor immunity. We developed a cancer-associated fibroblast (CAF)-associated mitochondrial metabolic and matrix-remodeling signature, termed CMMS, to characterize this immune-suppressive stromal state. CMMS integrated contractile/myCAF, extracellular matrix (ECM), and mitochondrial metabolic genes. Its clinical, metabolic, and immune relevance was evaluated in TCGA-HGSOC, independent GEO cohorts, single-cell RNA-seq datasets, and an anti-PD-L1-treated cohort, followed by cell–cell communication and experimental validation. LASSO-weighted CMMS stratified overall survival, with high CMMS indicating poorer prognosis. CMMS-high tumors exhibited ECM/TGFβ activation; associations with COL1A1, POSTN, and LOX; and a hypoxia-dominant metabolic phenotype. Mediation analysis suggested that hypoxia largely linked CMMS to glycolytic remodeling. Immune profiling revealed stromal-rich immune exclusion, checkpoint activation, and exhaustion-prone T-cell dysfunction. Single-cell analysis localized CMMS mainly to myCAF-like ECM-remodeling CAFs. In validation datasets, CMMS-high CAFs were associated with reduced CD8 abundance, increased CD8 exhaustion, and stronger matrix- and chemokine-related communication with T cells. Experiments further supported a link between TGFβ-related fibroblast activation, ECM-remodeling features, and impaired CD8⁺ T-cell effector function. Overall, CMMS defines a CAF-enriched fibrotic–hypoxic stromal program associated with immune exclusion-related features, exhaustion-prone T-cell dysfunction, and poor outcome in HGSOC. Full article