Search Results (1,722)

Background/Objectives: Surgery is the standard treatment for early-stage endometrial cancer (EC); however, some patients are medically inoperable due to comorbidities or morbid obesity. Definitive image-guided brachytherapy (BT) with or without external beam radiotherapy (EBRT) is a curative alternative, although comparative data with surgery remains limited. This study compared cancer-specific survival (CSS) at 2 and 5 years in high-risk surgical patients with early-stage EC (FIGO 2009 I–II), treated with definitive radiotherapy or surgery. Secondary endpoints included overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), and toxicity. Methods: Retrospective comparative study including 72 patients treated between 2011 and 2023: 36 medically inoperable treated with BT +/- EBRT and 36 matched undergoing surgery. Survival outcomes were estimated using Kaplan–Meier methods and compared using log-rank tests. Results: Median age was 74 years and mean BMI was 38.1 kg/m²; 75% were morbidly obese, with endometrioid carcinoma being the predominant histology (88.9%). Five-year CSS was 97.2% in the radiotherapy group versus 91.7% in the surgery group (p = 0.39). Five-year RFS was identical in both groups (86.1%), with recurrence rates of 13.9%. Five-year OS was lower in the radiotherapy group (66.7% vs. 77.8%; p = 0.3), without statistical significance. Grade ≥3 radiotherapy-related toxicity occurred in 19.4%, whereas severe surgical complications occurred in 8.3%. Conclusions: Definitive BT ± EBRT is an effective and well-tolerated curative option for medically inoperable early-stage EC, with survival and recurrence outcomes comparable to surgery, supporting its role as a valid therapeutic alternative in high-risk surgical patients. Full article

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status. Full article

Background and Clinical Significance: Advanced-stage and recurrent metastatic endometrial cancer (EC) is a complex and challenging disease with a poor prognosis. Immunotherapy is a promising treatment for advanced and recurrent mismatch repair deficiency (MMRd) EC. Case Presentation: A 57-year-old female patient with stage 2 dedifferentiated EC with MMRd (immunohistochemistry revealed PMS2 loss) and stage 1 renal clear cell carcinoma received neoadjuvant chemotherapy, underwent radical hysterectomy, received adjuvant chemotherapy and radiotherapy, and underwent partial nephrectomy. Disease progression with recurrent metastases to the third rib and T12 + L1 vertebrae was observed by positron emission tomography–computed tomography (PET-CT) in April 2024. She also had concurrent papillary thyroid carcinoma. Genetic testing confirmed sensitivity to dostarlimab-gxly and pembrolizumab, leading to the initiation of pembrolizumab (200 mg Q3W) and lenvatinib (20 mg QD) in June 2024 after spine surgery. Treatment-related skin toxicities prompted a dose reduction to pembrolizumab 100 mg and lenvatinib 10 mg, but persistent discomfort led to lenvatinib discontinuation in December 2024, with symptom improvement. PET-CT in October 2024 revealed significant improvement in metastatic disease, with probable residual malignancy in the left third rib and posterior pleura, whereas recent follow-up PET-CTs in April and November 2025 showed significantly decreased ¹⁸F-fluorodeoxyglucose avidity in the spine and ribs compared with prior studies. She was admitted for her 30th Keytruda cycle in February 2026, with stable vital signs, normal tumor markers, and no post-infusion adverse reactions. Conclusions: We present a 57-year-old female patient initially diagnosed with FIGO Stage 2 EC, who subsequently developed distant metastases and was restaged as FIGO Stage 4B recurrent disease. The management of this patient illustrates the multimodal treatment approach and the critical role of molecular subtyping in guiding immunotherapeutic strategies for recurrent advanced EC. Full article

Background: p53 immunohistochemistry is widely used as a surrogate marker for molecular classification in endometrial cancer and is generally associated with aggressive tumor behavior. However, its independent prognostic value in real-world clinical settings remains uncertain. Methods: This retrospective cohort study included patients with histologically confirmed endometrial cancer treated at a tertiary center between 2015 and 2023. Patients with available p53 immunohistochemical results were classified as p53 wild-type or p53-abnormal status. Clinicopathologic characteristics were compared between groups. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazards models were used to identify independent prognostic factors. Sensitivity analyses were performed to assess the impact of treatment-related variables. Results: A total of 132 patients were included. p53-abnormal tumors were associated with older age, high-grade non-endometrioid histology, and more frequent use of adjuvant therapy. In Kaplan–Meier analysis, p53-abnormal status was associated with poorer OS (5-year OS: 54.8% vs. 77.1%, p = 0.029), with a similar trend observed for PFS. However, in multivariable analysis, p53 status was not independently associated with survival. Instead, advanced stage and residual disease remained significant prognostic factors. Sensitivity analyses incorporating treatment-related variables yielded consistent results, confirming the lack of independent prognostic impact of p53. Conclusions: Although p53-abnormal status was associated with adverse clinicopathologic features and worse unadjusted survival, it was not an independent prognostic factor after adjustment. These findings suggest that the prognostic impact of p53 is context-dependent and largely mediated by established clinical factors, particularly tumor burden. Integrated clinicopathologic and molecular assessment remains essential for accurate risk stratification in endometrial cancer. Full article

Background: Endometrial cancer is a common gynecological malignancy, and elucidating its molecular basis may provide new clues for targeted intervention. This study investigated the role of ERBB3 in endometrial cancer cells and explored whether Ras-ERK/MAPK signaling is involved in ERBB3-mediated regulation. Methods: Bioinformatic screening was performed using public databases to identify candidate genes associated with endometrial cancer. ERBB3 was selected for further analysis. ERBB3 expression was evaluated in public datasets and examined in endometrial cancer cells. Loss-of-function experiments, rescue assays, Western blotting, and co-immunoprecipitation were used to assess the biological function and potential mechanism of ERBB3. Results: ERBB3 knockdown significantly inhibited proliferation, migration, and invasion, and promoted apoptosis in Ishikawa and RL95-2 cells. These changes were accompanied by decreased Ras-ERK/MAPK signaling. Moreover, Ras overexpression partially reversed the effects induced by ERBB3 knockdown. Co-immunoprecipitation suggested a molecular association between ERBB3 and Ras within a protein complex, but did not demonstrate direct physical binding. Conclusions: ERBB3 appears to promote malignant behaviors in endometrial cancer cells, and the Ras-ERK/MAPK pathway may be one of the downstream mechanisms involved. Further validation in additional experimental models and clinical samples is needed. Full article

Background: Minimally invasive surgery is widely used in endometrial cancer management, but recurrence remains a concern. Methods: A retrospective review of 1201 patients treated from 2012 to 2019 with robotic laparoscopy was conducted. Recurrence-free survival and hazard ratios were calculated using multivariate Cox models. Results: Of 1278 patients, 155 cases of recurrent disease were identified. Age (HR 1.01, p = 0.045), LVSI (HR 3.54, p < 0.001), stage and high-grade histology (HR 3.39, p < 0.001) were associated with increased risk of recurrence. Hazard ratios for stages IB, II and III/IV were 1.92 (p = 0.007), 2.67 (p = 0.001), and 3.23 (p < 0.001) respectively. The use of a uterine manipulator was an independent risk factor on multivariate analysis (HR 2.12, p < 0.001). Adjuvant chemotherapy (HR 0.67, p = 0.239) and radiotherapy (HR 0.64, p = 0.056) trends favored reduced risk but were not significant. Chemoradiotherapy was found to have a reduction in recurrence with a HR 0.44 (p = 0.002). Conclusions: Traditional prognostic factors remain important for patients with endometrial cancer having undergone robotic laparoscopic hysterectomy. Uterine manipulator use should be carefully reconsidered in endometrial cancer surgery. Full article

Quercetin is a naturally occurring flavonoid found in fruits, vegetables, and teas that is widely available as a dietary supplement. Numerous studies have investigated quercetin’s therapeutic potential across a broad range of diseases and conditions. Collectively, these studies reveal its anti-inflammatory, antioxidant, anti-proliferative, anti-cancer, anti-fibrotic, antibacterial, endocrine-modulating, and senolytic properties, establishing quercetin as a polypharmacologic agent with diverse biological activities. This review describes quercetin’s biochemical properties, bioavailability, and proposed mechanisms of action. It highlights the unique characteristics of the human uterus vs. other species and evaluates published evidence from pre-clinical and clinical studies supporting quercetin’s pleiotropic effects and potential therapeutic benefits for six uterine-related conditions: endometrial cancer, endometriosis, adenomyosis, uterine infections, uterine fibroids, and polycystic ovary syndrome (PCOS). The findings support that quercetin targets multiple endometrial and other uterine cell types and may attenuate key pathological processes relevant to uterine disease. However, robust human clinical evidence supporting quercetin’s efficacy is generally lacking. Critical knowledge gaps and translational barriers to advancing quercetin from a ‘promising preclinical candidate’ into an ‘evidence-based therapeutic’ for improving uterine health are discussed. Full article

Aim: The purpose of this study was to investigate the safety, efficacy, and clinical outcomes of the vaginal natural orifice transluminal endoscopic surgery (vNOTES) technique in patients suffering from gynecological cancer. Methods: A systematic review of the literature was conducted from inception to October 2025 following the PRISMA guidelines. PubMed, Google Scholar, and the Cochrane Library were searched for studies investigating vNOTES in gynecological malignancies. Study quality was evaluated using the Newcastle–Ottawa Scale, the National Institute of Health and the Joanna Briggs Institute critical appraisal tools. Results: The search identified 11 observational cohort studies, 28 case series, and 22 case reports. A total of 926 patients with suspected or confirmed gynecologic malignancies underwent surgery via vNOTES approach. The combination of hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node biopsy represented the most commonly performed surgical procedure. Endometrial cancer was the most frequent oncological indication. The included studies evaluated the perioperative outcomes, including operative time, estimated blood loss, lymph node assessment, conversion rates and complications. Conclusions: The vNOTES approach appeared to be feasible and at least non-inferior to standard surgical treatments for patients with early-stage gynecologic malignancies. However, the small sample sizes and heterogeneity among studies limit the strength of the evidence and preclude definitive conclusions. Full article

In recent years, liquid biopsy has emerged as a promising non-invasive strategy for the identification of tumor-derived biomarkers. Among circulating analytes, cell-free DNA (cfDNA), including both nuclear and mitochondrial fractions, has been extensively investigated in a variety of biological fluids for its potential applications in cancer diagnosis, disease monitoring, and prognostic stratification. Owing to its higher copy number per cell compared with nuclear DNA, mitochondrial DNA (mtDNA) is typically present at higher concentrations in body fluids and is therefore potentially detectable. Circulating cell-free mitochondrial DNA (cfmtDNA) is closely associated with pro-inflammatory signaling pathways and cellular damage responses, including apoptosis, necrosis, and neutrophil extracellular trap formation (NETosis). This review provides a comprehensive overview of the reported alterations of cfmtDNA in the most prevalent gynecological malignancies, namely ovarian and endometrial cancers, which are characterized by a chronic inflammatory microenvironment. We further critically assess the current evidence supporting cfmtDNA as a potential non-invasive biomarker in these malignancies, highlighting current limitations and future research directions. Full article

Background/Objectives: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence and limited options in advanced disease. Molecular classification has redefined risk stratification and therapeutic decision-making, particularly with the incorporation of immunotherapy. This review provides a clinically oriented overview of immunotherapy in EC across molecular subgroups and treatment settings. Methods: A narrative review was conducted using PubMed/MEDLINE, Embase, and Web of Science, focusing on clinical trials and studies with direct clinical relevance. Results: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated significant benefit in EC, particularly in mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) tumors, where durable responses are observed. In contrast, mismatch repair-proficient (pMMR) tumors show limited sensitivity to monotherapy and require combination approaches. Recent phase III trials have established chemoimmunotherapy as a first-line standard, with greater benefit in dMMR tumors and clinically meaningful improvements in pMMR disease. In the second-line setting, PD-1 inhibitor monotherapy is standard for dMMR tumors, while lenvatinib plus pembrolizumab is a key option for pMMR disease. However, responses remain heterogeneous and are not fully explained by MMR status alone. Conclusions: Immunotherapy is a cornerstone in advanced EC management, guided by molecular classification. Key challenges include limited efficacy in pMMR tumors, lack of robust predictive biomarkers, and uncertainty in treatment sequencing. Future strategies should focus on biomarker-driven approaches and rational combinations. Full article

Mesothelin (MSLN) is a cell surface glycoprotein with limited expression in normal tissues but frequent overexpression in solid tumors, including gynecological malignancies. This review summarizes the state of the art on the biological role, diagnostic value, prognostic significance, and therapeutic potential of MSLN in ovarian, endometrial, and cervical cancers. Evidence from clinical and experimental studies indicates that MSLN contributes to tumor progression through interactions with CA125, promotion of cell adhesion and peritoneal metastasis, activation of oncogenic signaling pathways, modulation of immune responses, and development of chemoresistance. Elevated MSLN expression has been associated with advanced clinical stage of the disease, platinum resistance, and poorer survival outcomes, particularly in ovarian cancer patients, although prognostic findings remain inconsistent. Circulating soluble MSLN may serve as a minimally invasive biomarker and may improve diagnostic accuracy when combined with established markers. Therapeutic MSLN strategies—antibody-drug conjugates, CAR-T and NK cell therapies, monoclonal antibodies, immunotoxins, vaccines, and checkpoint blockade—provide promising pre-clinical and early clinical results, particularly in resistant or recurrent forms of the disease. Overall, MSLN constitutes a promising target for precision oncology in gynecological cancers, although further clinical studies are required to validate its diagnostic utility and optimize targeted therapeutic approaches. Full article

Background: Endometrial carcinoma (EC) is now classified primarily by molecular subtype—POLE-ultramutated, mismatch repair–deficient (dMMR), TP53-mutant/copy-number-high (CNH), and “no specific molecular profile” (NSMP)—a framework that has reshaped prognostic counseling and adjuvant therapy decisions. Yet several practically important questions remain insufficiently addressed in real-world cohorts: whether all four mismatch repair genes confer an equivalent favorable prognosis, whether all POLE alterations carry the same survival benefit or only specific pathogenic variants, and whether molecular subtypes retain prognostic value after adjustment for histology and tumor burden. Methods: We addressed these questions in 2901 patients pooled from the MSK-IMPACT 50K Clinical Sequencing Cohort (n = 2372; discovery) and the TCGA UCEC PanCancer Atlas (n = 529; validation)—the largest dual-cohort genomic analysis of EC reported to date. We performed individual MMR gene and combined dMMR survival stratification, multivariable Cox regression adjusted for age, histology, and sample type, and a pathogenicity-aware sensitivity analysis for POLE variants, with tumor mutational burden (TMB) compared across subgroups. Results: Across both cohorts, all four MMR gene–mutant subgroups (MLH1, MSH2, MSH6, PMS2) conferred equivalently favorable overall survival (OS) (six-group log-rank p = 7.66 × 10⁻¹² in discovery; p = 6.78 × 10⁻³ in validation), confirming dMMR as a class-level prognostic designation independent of which MMR gene is altered. Multivariable Cox regression demonstrated that POLE-ultramutated status retained an independent favorable effect (HR = 0.62, p = 0.038 in MSK; HR = 0.35, p = 0.028 in TCGA) after adjustment for age, histology, and sample type, while the favorable dMMR effect was largely accounted for by histologic context. Critically, a pathogenicity-aware sensitivity analysis revealed that the exceptional survival of the POLE subgroup is confined to canonical exonuclease-domain hotspot mutations (event rate 0.9% in MSK), whereas POLE variants of uncertain significance behave indistinguishably from NSMP-like tumors. Consistent with this finding, TMB was markedly elevated in canonical pathogenic POLE cases (median 138.7 mut/Mb in MSK; 247.4 in TCGA) but not in POLE-VUS-only cases (median 29.0 and 15.0, respectively; p < 0.001 between groups in both cohorts), confirming that the ultramutator phenotype is confined to canonical pathogenic POLE variants. We additionally characterize Uterine Clear Cell Carcinoma as a distinct histologic entity (n = 73; 3.0%) and report the POLE + TP53 co-mutant group (n = 90; 3.8%). Conclusions: These findings refine the molecular classification of EC in clinically meaningful ways: they support class-level immunotherapy eligibility based on dMMR status regardless of the specific MMR gene altered, demonstrate that POLE-ultramutated classification requires variant-level pathogenicity assessment, and identify TP53-mutant/CNH patients as the population with the most urgent unmet therapeutic need. Full article

Background/Objectives: We evaluated perioperative morbidity, recurrence patterns and survival outcomes following pelvic exenteration (PE) at a tertiary referral centre. Methods: A retrospective observational study was conducted in women undergoing PE from 2004 to 2024. We collected demographics, performance status (PS), comorbidities, body mass index (BMI), tumour histology, intraoperative details, postoperative morbidity (Clavien–Dindo classification), mortality, length of stay (LOS), recurrence patterns and cancer-related death. Descriptive statistics were performed alongside Kaplan–Meier survival analysis. Results: Forty-seven patients underwent PE; median PS was 0 [interquartile range (IQR) 0–0]. Median ages at diagnosis and surgery were 55 (IQR 49–66) and 60 (IQR 50–68) years, respectively, with a median follow-up of 26 months (IQR 12–64). Thirty-two procedures (68%) were performed for recurrent and N = 15 (32%) for primary disease. Histology included N = 17 endometrial (36%), N = 10 vulval (23%), ovarian (15%), N = 5 cervical (11%) and N = 7 vaginal (15%) cases. Eighteen patients (38%) underwent total PE, N = 15 (32%) anterior PE and N = 14 (30%) posterior PE. Median blood loss was 1.5 L (IQR 0.85–2.0) and median operative time was 391 mis (IQR 313–482). Median HDU stay was 4 days (IQR 2–5) and LOS was 17 days (IQR 13–31). One postoperative death occurred. Major complications (Clavien–Dindo ≥3) occurred in 15 patients (32%). Late complications occurred in n = 17 (36.2%) women. Nineteen patients (41%) remained recurrence-free; N = 4 (9%) developed local and N = 24 (51%) distant recurrence. Mean overall survival time post-surgery for curative intent PE (N = 46) was 94 months (95%CI = 57–131 months); for primary tumours this was 51.6 (95%CI = 31–72) vs. 99 (56.01–142) for recurrent disease (p > 0.05). Conclusions: Pelvic exenteration is associated with acceptable morbidity and mortality in carefully selected patients, offering excellent locoregional disease control. Full article

Background/Objectives: The triglyceride–glucose (TyG) index, a reliable marker for insulin resistance, is strongly associated with T2DM, hypertension, and cardiovascular disease. Less well known is its relationship with cancer risk. The aim of this study was to quantify the association between the TyG index and risk of different types of cancer. Methods: Publications were searched in the PubMed, Web of Science, and Scopus databases using appropriate keywords. The PICOS framework was used to select the studies, and their quality was evaluated according to the “Newcastle–Ottawa Scale” (NOS). Meta-analysis was performed through a random-effects model using cancer risk parameters (RR: relative risk, OR: odds ratio and HR: hazard ratio) extracted from 26 selected studies associated with TyG index values. The weighted mean difference (WMD) was used to compare the mean of the TyG index in cancer patients to that of the control group. Heterogeneity was assessed by Cochran’s Q and I² statistics, while publication bias was evidenced using the Egger test and the Begg test, and funnel plot asymmetry. Results: A higher TyG index value was observed in cancer subjects (9483) compared to healthy controls (978,675) (WMD: 0.23, 95% CI: 0.16–0.31, p < 0.0001, n = 15). A statistically significant increase in cancer risk was associated with the TyG index level, expressed as both a categorical (OR 1.33, 95% CI 1.22–1.45, p < 0.0001, n = 29) and continuous (OR 1.14, 95% CI 1.10–1.19, p < 0.0001, n = 27) variable. The effect was more evident in case–control/cross-sectional studies compared to cohort studies (OR 1.78, 95% CI 1.51–2.09 vs. OR 1.19, 95% CI 1.10–1.29 TyG categorical; OR 1.46, 95% CI 1.21–1.76 vs. OR 1.09, 95% CI 1.05–1.12 TyG continuous). Stratified analysis showed an increased risk of cancer occurrence for gastrointestinal, gynecological, colorectal, breast, and gastric sites, while no association was observed for endometrial, ovarian, prostate, lung or esophageal cancers. Conclusions: Our results evidence an increase in cancer risk associated with higher TyG index values. However, due to the low number of studies, the effect on specific tumor sites was not statistically significant. Additional epidemiological studies with a cohort design are necessary to confirm these associations. Full article