Search Results (449)

Background/Objectives: Ovarian epithelial cancers (EOCs) comprise heterogeneous subtypes with distinct clinical outcomes, making accurate histological subtyping essential for prognosis and treatment planning. Although deep learning using digitized hematoxylin and eosin (H&E) whole-slide images (WSIs) is now widely used, its application to ovarian cancer diagnosis remains limited. Methods: In this multicenter study, we analyzed 319 H&E-stained slides from 152 patients with surgically resected EOC. An attention-based multiple instance learning (MIL) framework built on a pathology-specific foundation model (UNI) was used. WSIs were divided into 512 × 512-pixel patches at 40× magnification, and slide-level classification were generated through attention-based aggregation of patch-level feature, followed by patient-level prediction. External validation was performed specifically on the high-grade serous carcinoma (HGSC) cases from The Cancer Genome Atlas (TCGA) dataset. Results: The model achieved strong performance, with slide-level and patient-level accuracies of 0.918 and 0.900, respectively, on the test set. In five-fold cross-validation, the mean slide-level AUC was 0.990 (95% CI: 0.983–0.997), and the patient-level AUC was 0.993 (95% CI: 0.989–0.996), indicating consistent results. External validation on TCGA HGSC cases showed robust generalizability, with slide-level and patient-level accuracies of 0.794 and 0.898. F1-scores ranged from 0.832 to 1.000 at the slide-level and from 0.831 to 0.966 at the patient-level, with particularly strong performance for HGSC and clear-cell carcinoma. Conclusions: These findings demonstrate the feasibility of deep learning-based models for histological subtyping of EOC using H&E-stained WSIs. This approach may help pathologists achieve more accurate and consistent histological diagnoses of EOC. Full article

Ovarian cancer remains the most lethal gynecologic malignancy, with the majority of patients presenting at advanced stages and exhibiting poor long-term survival. High-grade serous carcinoma (HGSC), the predominant subtype, likely originates from fallopian tube epithelial cells (FTECs), whose biology is strongly influenced by hormonal signaling. Progesterone receptor (PR) expression, particularly of the PR-B isoform, is associated with improved prognosis in HGSC; however, the isoform-specific molecular mechanisms in precancerous FTECs remain unclear. This study investigated the distinct biological and transcriptomic effects of PR-A and PR-B in p53- and Rb-defective FE25 FTEC-derived cells. Stable overexpression of PR-A suppressed cell proliferation, enhanced apoptosis, and induced robust senescence, whereas PR-B promoted proliferation and activated JNK/c-Jun signaling. Upon progesterone (P4) treatment, both isoforms mediated cell-cycle arrest and apoptosis, with PR-A exhibiting stronger Sub-G1 induction. PR-A and PR-B differentially regulated cell-cycle inhibitors, senescence markers, and downstream pathways, including the PI3K–Akt and MAPK pathways, while RNA sequencing analyses revealed broader P4-induced transcriptomic changes in PR-B than in PR-A, involving immune, angiogenic, and proliferative programs. Collectively, these findings demonstrate that PR-A and PR-B exert distinct yet complementary regulatory roles in FTEC biology and progesterone responsiveness. The observed PR isoform-dependent effects in FE25 cells should be interpreted as context-specific mechanistic insights rather than direct predictors of clinical prognosis or treatment response. Full article

Background/Objectives: High-grade serous ovarian carcinoma (HGSOC) is associated with high relapse rates despite aggressive multimodal treatment. BRCA mutations, present in a substantial subset of patients, confer homologous recombination deficiency and increased sensitivity to platinum-based chemotherapy. This study evaluated the association between BRCA mutation status and clinical outcomes, focusing on dissemination patterns, treatment allocation, perioperative parameters, and progression-free survival (PFS). Methods: This prospective single-center cohort included 133 consecutive patients with newly diagnosed HGSOC treated between January 2020 and December 2025. Primary treatment strategy (primary debulking surgery [PDS] or neoadjuvant chemotherapy [NACT]) was determined by multidisciplinary assessment. BRCA testing was performed using tumor tissue or germline analysis. Patients were followed for 24 months. PFS was analyzed using Kaplan–Meier estimates and Cox regression models. Results: Pathogenic BRCA mutations were identified in 39.1% of patients. BRCA-mutated tumors demonstrated significantly lower rates of peritoneal carcinomatosis (50% vs. 77.77%, p = 0.001) and were more frequently managed with PDS (59.6% vs. 41.8%, p = 0.048). Perioperative outcomes were comparable between groups. Disease progression occurred less frequently in BRCA-mutated patients (32.69% vs. 51.85%, p = 0.017). In univariate analysis, BRCA mutation was associated with a 48% reduction in progression risk (HR 0.52, 95% CI 0.27–0.99, p = 0.048). After adjustment for age, FIGO stage, and residual disease, BRCA mutation was not independently associated with progression (HR 0.57, p = 0.124), although a protective trend was observed, while residual disease remained a significant predictor. Conclusions: In this prospective cohort, BRCA mutation status was associated with distinct dissemination patterns and a significant reduction in progression risk in HGSOC. Although residual disease remained the strongest independent prognostic factor after multivariable adjustment, a trend toward improved PFS observed among BRCA-mutated patients supports the role of homologous recombination deficiency as a meaningful modifier of disease trajectory. These findings reinforce the clinical relevance of molecular stratification in the contemporary management of HGSOC. Full article

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are still lacking. This study aimed to identify genomic alterations associated with platinum sensitivity, resistance, or refractoriness, and to assess their prognostic relevance. Methods: Tumor DNA from 24 HG-SOC patients with optimal cytoreductive resection, classified as platinum-sensitive (n = 9), platinum-resistant (n = 8), or platinum-refractory (n = 7) underwent targeted next-generation sequencing of 409 cancer-associated genes. Somatic variants were filtered and classified for oncogenicity using established criteria incorporating predicted functional impact, REVEL scores, and population allele frequencies. Associations between mutational profiles, platinum response, and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Key findings were validated in the TCGA ovarian serous carcinoma (TCGA-OV) dataset using survival analyses. Results: A total of 1367 protein-altering somatic variants across 301 genes were identified. While TP53 mutations were ubiquitous, platinum-resistant and platinum-refractory tumors showed enrichment of pathogenic alterations affecting DNA repair, transcriptional regulation, epigenetic modification, and oncogenic signaling, including FANCA, ATF1, MAF, NCOA2, PIK3CA, and TET1. Mutations in these genes were associated with reduced overall survival in exploratory analyses (median 2.5–9 months vs. 27.5–45 months). Multivariate analysis identified FANCA and ATF1 as potential independent predictors in exploratory modeling. In the TCGA-OV cohort, patients harboring pathogenic variants in a multi-gene panel derived from this study (excluding BRCA1/2) exhibited significantly worse survival compared with both BRCA1/2-mutated cases and the overall cohort. Conclusions: This exploratory study identifies a set of genomic alterations converging on transcriptional and epigenetic regulation, DNA repair, and oncogenic signaling that are associated with platinum resistance and adverse prognosis in HG-SOC. Independent validation in TCGA supports the potential clinical relevance of this mutational signature. These findings warrant further validation in larger prospective cohorts and functional studies to clarify their role as biomarkers of aggressive disease and therapeutic vulnerability. Full article

Background: High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer and is frequently diagnosed at advanced stages. Because currently available blood-based biomarkers have limited performance in early-stage disease, there is a need to identify circulating biomarker candidates associated with early-stage HGSOC. In this retrospective multi-institutional case–control study, we evaluated whether serum extracellular vesicle (EV)-associated protein signatures distinguish early-stage HGSOC from healthy controls. Methods: Serum samples (n = 252) were obtained retrospectively from multiple institutions and included healthy controls and patients with early- and advanced-stage HGSOC. EV-associated proteins were profiled using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and proximity extension assay (PEA) to identify candidate proteins enriched in early-stage HGSOC. Selected candidates were evaluated by enzyme-linked immunosorbent assay (ELISA), and tissue-level expression was examined in early-stage HGSOC specimens. A multimarker combination model was generated using a smoothed empirical estimate of hyper-volume under the manifold (SHUM) approach and internally assessed by leave-one-out cross-validation. Results: Ten EV-associated serum proteins were prioritized on the basis of differential expression and fold change and were confirmed to be expressed in early-stage HGSOC tissues. In ELISA-based analyses, the combined 10-protein EV panel distinguished early-stage HGSOC from healthy controls with an area under the curve (AUC) of 0.99 in the study dataset, whereas MUC16 (CA-125) showed substantially lower performance in this comparison. The SHUM-based model yielded a true-positive rate of 0.971, a false-positive rate of 0.057, and a Matthews correlation coefficient of 0.915 in the analyzed cohort. Several candidate proteins were differentially enriched in EV fractions but not in matched whole serum. Conclusions: Serum EV-associated proteins are altered in early-stage HGSOC and define a multi-protein signature associated with this disease state in a retrospective case–control setting. These findings support further evaluation of EV-based biomarker candidates in clinically representative and prospectively collected cohorts that include benign gynecologic conditions, symptomatic patients, and pre-diagnostic samples. Full article

Background/Objectives: Claudin-6 (CLDN6) is an oncofetal tight junction protein that has recently emerged as a promising therapeutic target in various solid tumors. Despite this potential, the clinical significance of CLDN6 expression in advanced-stage high-grade serous ovarian carcinoma (HGSC)—specifically its role in platinum resistance—remains poorly understood. Methods: This retrospective study analyzed 119 patients with newly diagnosed FIGO stage III–IV HGSC who received platinum-based chemotherapy at a single tertiary center between 2015 and 2025. CLDN6 expression was evaluated via immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tumor samples. High CLDN6 expression was defined as moderate-to-strong membranous staining in ≥50% of tumor cells. Clinicopathologic associations were assessed using chi-square tests, while logistic regression analysis identified predictors of platinum resistance. Finally, overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier methods and Cox proportional hazards models. Results: High CLDN6 expression was observed in 31 patients (26%). CLDN6 expression was not significantly associated with age, CA-125 level, lymph node metastasis, distant metastasis, surgical approach, or residual disease status. However, high CLDN6 expression was significantly associated with platinum resistance (61.3% vs. 28.4%, p = 0.001). In multivariable logistic regression analysis, residual disease (OR = 10.12, p > 0.001), high CLDN6 expression (OR = 4.52, p = 0.008), and elevated CA-125 levels (OR = 0.64, p = 0.041) were independently associated with platinum resistance. Median OS for the entire cohort was 43.8 months. High CLDN6 expression was associated with shorter OS (38.0 vs. 45.7 months, p = 0.042) and remained an independent predictor of mortality in multivariable Cox analysis (HR = 1.90, p = 0.026). CLDN6 expression showed a trend toward shorter PFS but did not reach statistical significance (p = 0.096). Conclusions: High CLDN6 expression is associated with platinum resistance and inferior overall survival in patients with advanced-stage HGSC. These findings suggest that CLDN6 may serve as a clinically relevant biomarker for chemoresistance and tumor aggressiveness. In the context of emerging CLDN6-targeted therapies, routine assessment of CLDN6 expression may facilitate the development of biomarker-driven therapeutic strategies for advanced ovarian cancer. Full article

Endometriosis is a chronic estrogen-dependent disorder affecting approximately 10% of women of reproductive age. Increasing epidemiological and molecular evidence indicates that it may represent a precursor condition for a subset of ovarian malignancies collectively defined as endometriosis-associated ovarian cancer (EAOC), predominantly endometrioid and clear cell carcinomas. Malignant transformation is driven by the interplay between chronic inflammation, oxidative stress, and local hyperestrogenism within the endometriotic microenvironment. Recurrent hemorrhage and persistent immune activation further promote genomic instability and clonal expansion. Shared somatic mutations have been identified in both atypical endometriosis and adjacent carcinomas, supporting a model of stepwise tumorigenesis. Dysregulation of signaling pathways and epigenetic mechanisms, including microRNA alterations, further contribute to tumor development. Although the absolute risk of malignant transformation remains low, women with ovarian endometriosis and deep infiltrating disease show an increased risk of ovarian cancer. EAOC is frequently diagnosed at earlier stages and generally demonstrates a more favorable prognosis than high-grade serous carcinoma, although clear cell histotypes may exhibit chemoresistance and distinct molecular vulnerabilities. This review summarizes current evidence on the pathogenesis, molecular mechanisms, and clinical implications of EAOC, highlighting future strategies for risk stratification and personalized surveillance. Full article

Background/Objectives: Since non-invasive implants and invasive implants (metastases) are a key point of differentiation between serous borderline tumors (SBTs) and low-grade serous carcinoma (LGSC), the correct diagnosis of these two types of extraovarian lesions is crucial for patient treatment and prognosis. However, accurate diagnosis can be challenging even for experienced pathologists. The aim of this study was to evaluate interobserver agreement in the classification of these extraovarian lesions. Methods: Twenty-four cases of ovarian SBT and LGSC with 33 samples of non-invasive implants of SBT and metastasis of LGSC were independently reviewed by three gynecologic pathologists and three general pathologists. Diagnostic criteria included destructive invasion, micropapillary architecture, and retraction clefts. To measure interobserver agreement, Fleiss’ kappa and Cohen’s kappa were calculated, with consensus diagnoses determined by the majority of gynecologic pathologists. Results: According to the consensus, diagnosis 42.4% biopsies were classified as metastases of LGSC and 57.6% as non-invasive implants of SBT. Overall reproducibility was substantial (κ = 0.61). The agreement among gynecologic pathologists, as well as between gynecologic pathologists and the consensus (using leave-one-out reference), was substantial to near-perfect (κ = 0.745–0.821). General pathologists’ agreement with the consensus was moderate (κ = 0.467–0.698). Agreement between general pathologists was also moderate, with κ values ranging from 0.413 to 0.518. The difference in pairwise agreement between the two groups was statistically significant, confirming that gynecologic pathologists outperformed general pathologists in classifying extraovarian lesions. Conclusions: The results showed that current diagnostic reproducibility remains suboptimal, particularly among general pathologists, underscoring the need for improved training and standardized criteria. Ultimately, a multidisciplinary approach combining morphological expertise, immunohistochemical validation and molecular stratification will be essential for optimizing diagnosis and treatment. Full article

Background/Objectives: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer characterized by high recurrence rates and poor response to conventional therapies, resulting in unfavorable clinical outcomes. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, has demonstrated anti-cancer activity in multiple malignancies. Methods: This study used two USC cell lines, ARK1 and SPEC2, to evaluate the effects of EPA on cell proliferation, invasion, cell cycle profile, stress response, and apoptosis. The potential synergistic effects of EPA combined with carboplatin were also examined. Western blotting was used to examine EPA’s effects on downstream pathways related to cellular stress, inflammation, and epithelial–mesenchymal transition (EMT). Results: EPA treatment markedly reduced cell proliferation and colony formation, with IC₅₀ values of 28.96 µM for ARK-1 cells and 14.96 µM for SPEC-2 cells compared with control groups. It also induced G1 phase cell cycle arrest, increased cellular stress, triggered caspase-dependent apoptotic cell death, and suppressed invasive capacity. Moreover, EPA effectively counteracted TNF-α-stimulated upregulation of COX-2 and phosphorylated NF-κB. The combined treatment with EPA and carboplatin resulted in synergistic inhibition of cell viability and migration. Western blotting analysis showed that EPA attenuates the NF-κB and AKT/mTOR signaling pathways, promotes the expression of cellular stress-related proteins, and inhibits the expression of EMT-related proteins in both cell lines. Conclusions: EPA exhibits potent anti-tumor activity against USC cells and enhances the efficacy of carboplatin. These data indicate that EPA has potential as a low-toxicity, multi-target adjuvant treatment for USC, necessitating additional pre-clinical and clinical investigation. Full article

Background and Objectives: High-grade serous ovarian carcinoma (HGSOC) remains the most lethal gynecologic malignancy, with outcomes heavily dependent on early diagnosis and timely multimodal treatment. The COVID-19 pandemic profoundly disrupted oncologic care, leading to diagnostic delays, modified treatment algorithms, and deferred surgeries. This study aimed to assess how these disruptions influenced disease presentation, surgical complexity, and postoperative outcomes during the pandemic and post-pandemic periods in a Romanian tertiary oncology center. Materials and Methods: A retrospective, single-center cohort analysis was conducted on 112 patients with histologically confirmed HGSOC who underwent surgical treatment between 26 February 2020 and 25 February 2024. The cohort was divided into two equal groups: a pandemic cohort (2020–2022) and a post-pandemic cohort (2022–2024). Clinical, pathological, and therapeutic parameters were compared, including FIGO and T staging, surgical duration, ICU admissions, and treatment intervals. Results: The post-pandemic period was marked by a significant rise in advanced-stage presentations (FIGO IV: 17.8% vs. 33.9%, p = 0.003), peritoneal carcinomatosis (58.9% vs. 82.1%, p = 0.004), and multiorgan invasion (7.1% vs. 16.0%, p = 0.039). Mean operative time increased significantly post-pandemic (94.0 ± 36.3 vs. 123.5 ± 52.5 min, p = 0.003), as did ICU admissions (35.7% vs. 60.7%, p = 0.002). While the number of neoadjuvant and adjuvant chemotherapy cycles remained consistent between cohorts, a greater surgical complexity and longer postoperative recovery characterized the post-pandemic cases, suggesting cumulative disease progression and increased treatment demands. Conclusions: The findings indicate an association between the post-pandemic period and more advanced disease profiles at presentation, as well as increased surgical complexity, highlighting potential long-term effects of healthcare disruption. These results highlight the necessity for resilient cancer care systems emphasizing early detection, multidisciplinary coordination, and adaptive treatment models to mitigate future systemic disruptions and preserve survival outcomes in women with HGSOC. Full article

Background: Primary peritoneal carcinoma (PPC) is an uncommon malignancy typically diagnosed in postmenopausal women, accounting for less than 1% of all gynecologic cancers. Its occurrence in adolescents is extremely rare. We present a case of a 16-year-old female with low-grade serous carcinoma (LGSC) arising from the anterior rectal peritoneum, highlighting diagnostic challenges and therapeutic considerations. Case Presentation: A 16-year-old girl presented with a 7-day history of lower abdominal pain. Ultrasound revealed an 8 cm mixed cystic–solid pelvic mass anterior to the rectum. Laboratory tests showed elevated CA-125 (106 U/mL). Exploratory laparotomy demonstrated an 8 cm solid mass attached to the anterior rectal wall, extending into the right mesorectum with peritoneal nodules at the bladder reflection. The uterus and adnexa appeared grossly normal. Frozen section analysis revealed adenocarcinoma with psammoma body formation. Histopathology and immunohistochemistry confirmed low-grade serous carcinoma: PAX8(+), WT1(+), CK7(+), ER(60%), PR(40%), CK20(–), and P53 wild-type. Peritoneal washings contained rare malignant cells. Postoperatively, the patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Final pathology confirmed low-grade serous carcinoma involving the anterior rectal wall, bilateral adnexal surfaces, and peritoneum. She completed six cycles of adjuvant chemotherapy (paclitaxel + carboplatin, TC regimen). No recurrence was observed during follow-up. Conclusions: This case underscores the importance of considering PPC in the differential diagnosis of pelvic masses in young females, even when the ovaries appear normal. Full article

Introduction and Background: High-grade serous ovarian carcinoma (HGSOC) is notorious for its poor prognosis owing to its inherent biological aggressiveness and development of chemoresistance. The mechanistic target of rapamycin (mTOR) pathway is dysregulated in 55% of epithelial ovarian cancers, representing an appealing therapeutic target. To date, the clinical trials of mTOR inhibitors have shown modest response. In this study, we investigated the mTOR pathway in a clinical cohort of primary, chemo-naive, high-grade ovarian cancer samples, along with its regulatory post-transcriptional miRNA regulation. Methodology: We performed differential gene expression analysis on 100 HGSOC patients from TCGA and 80 healthy controls (i.e., normal ovarian tissue) from GTEx. The differentially expressed genes (DEGs) were overlaid onto the KEGG mTOR signalling pathway, followed by functional enrichment analysis. Next, we conducted differential miRNA expression analysis on the same cohort and identified regulatory miRNA–mTOR gene pairs involved in cancer pathogenesis. Finally, we constructed an interaction network and identified key hub genes and miRNAs with potential prognostic significance. Results: We identified 95 mTOR pathway genes that were significantly differentially expressed, involving upstream regulators, core components, and downstream effectors. Functional pathway analysis revealed a prominent shift toward mTORC1 activation, accompanied by paradoxical activation of autophagy. The let-7 miRNA family was identified as a key regulator of the mTOR pathway, potentially facilitating disease progression. RICTOR downregulation, a key component of the mTORC2 complex, appears to play a critical role in this histotype. In addition, FNIP1, a tumour suppressor gene implicated in mTOR dysregulation, was found to correlate with survival outcomes. Conclusions: We propose a model of dual activation of mTORC1 and autophagy in HGSOC as the metabolic rewiring enabling cancer progression under nutrient and cellular stress. Full article

Background and Objectives: High-grade serous ovarian carcinoma (HGSC) is characterized by aggressive tumor behavior, frequent recurrence, and limited long-term survival. Despite the established clinicopathological prognostic factors, significant heterogeneity in clinical outcomes persists, highlighting the need for biologically relevant molecular biomarkers. HER3 and folate receptor alpha (FOLR1) have promising prognostic biomarkers in ovarian cancer; however, the combined biological and prognostic impact of these two molecules has not yet been clearly demonstrated. Materials and Methods: This retrospective observational study included 66 patients with histopathologically confirmed HGSC. The immunohistochemical expression of HER3 and FOLR1 was evaluated using a standardized immunoreactivity scoring system. Associations with clinicopathological features were analyzed, and survival outcomes were analyzed using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: High HER3 expression was significantly associated with distant metastasis and was identified as an independent adverse prognostic factor for both overall survival (OS) and progression-free survival (PFS). FOLR1 expression was associated with OS in univariate analysis, but did not retain independent prognostic significance in multivariate models. A moderate yet statistically significant positive correlation between HER3 and FOLR1 expression was observed, suggesting a potential association between proliferative signaling and metabolic pathways that may warrant further mechanistic investigation. Conclusions: Our findings demonstrate that HER3 is a robust prognostic biomarker in HGSC and support a biologically relevant HER3–FOLR1 interaction contributing to tumor aggressiveness. These results provide a translational rationale for combined biomarker assessment and for the development of HER3- and FOLR1-targeted therapeutic strategies, particularly antibody–drug conjugates, for HGSC. Full article

Ferroptosis is an iron-dependent programmed cell death (PCD) implicated in cancer therapy response, yet its transcriptional control remains unevenly characterized and often centered on a limited subset of transcription factors (TFs) rather than systematically addressing TF families. The Activating enhancer-binding Protein-2 (AP-2) family of TFs is a plausible but understudied regulatory node linking oncogenic programs to ferroptosis, with prior research limited to AP-2α and AP-2γ, suggesting anti-ferroptotic and pro-tumorigenic roles. Thus, the present study aimed to provide a family-wide analysis of the relationships between AP-2 and ferroptosis across tumors in which this PCD type is considered biologically and clinically relevant. The research integrates ferroptosis gene modules with AP-2 targetomes, tumor–normal expression comparisons, survival stratification, ferroptosis scoring, cross-cohort functional analyses, and signaling pathway projection extending canonical ferroptosis circuits with AP-2–associated non-canonical elements. Consistent associations between AP-2 expression, prognosis, and ferroptosis score were observed in five tumor cohorts: cervical squamous cell carcinoma, glioblastoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, and thyroid carcinoma. In addition, cross-cohort clustering highlighted genes enriched in redox- and lipid-metabolism programs linked to apoptosis and autophagy-dependent death. Among the candidates emerging from these analyses, ferroptotic markers (LOX, PTGS2, and NQO1) and AP-2–linked nodes such as CD36, DUOX1, EPHA2, MUC1, PTPRC, SNAI2, and TP63 warrant targeted functional and binding validation to infer whether these associations reflect direct AP-2 regulatory mechanisms. Most importantly, AP-2–centered research appears to be a valuable area for guiding studies of tumor-specific ferroptosis vulnerability or resistance. Full article

Background: Uterine serous carcinoma (USC) represents a rare but aggressive subtype of endometrial cancer, accounting for a disproportionate number of disease-related deaths. Although molecular classification has improved risk stratification, prognostic heterogeneity highlights the need for new prognostic markers. Methods: We retrospectively analyzed 83 patients with USC treated at our institution between 1 January 2015 and 31 December 2023. Clinicopathological characteristics, treatment strategies, molecular biomarkers accessed by immunohistology (TP53, ER, PR, HER2, and MMR status), and survival outcomes were collected. Patients were first staged by FIGO 2009 and retrospectively reclassified by FIGO 2023. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan–Meier and Cox regression analyses. Results: The majority of patients were presented with advanced disease (FIGO stage IIIC-IV). TP53 mutations were found in 88% of cases, HER2 amplification in 18%, and ER expression in 57.8%. ER-positive patients showed significantly improved DFS in the adjuvant setting compared with ER-negative patients, whereas no significant associations were observed for first-line PFS or OS in multivariable analyses. HER2 amplification was not associated with inferior survival in our cohort. The advanced stage remained an independent predictor of worse OS. Conclusions: USC is a biologically heterogeneous disease, and its treatment should be guided by its molecular profile. ER expression identifies a subset of patients with improved DFS, suggesting potential prognostic relevance in this high-risk histology. Full article