Search Results (1,762)

Immune checkpoint inhibitors and antibody–drug conjugates have rapidly expanded treatment options for gynecologic malignancies, although the magnitude of benefit varies substantially across tumor types and biomarker-defined populations. This narrative review summarizes the biologic rationale, predictive biomarkers, pivotal clinical trials, regulatory approvals, guideline-supported strategies, and emerging directions for immune checkpoint blockade and antibody–drug conjugates in endometrial, cervical, and ovarian cancers. In endometrial cancer, molecular classification and mismatch repair status have transformed treatment selection, with PD-1 or PD-L1 blockade now integrated into first-line chemoimmunotherapy and recurrent disease management. HER2-directed and TROP-2-directed antibody–drug conjugates are also emerging as biomarker-directed strategies. In cervical cancer, human papillomavirus-driven tumor biology, PD-L1 expression, and tissue factor expression support the use of checkpoint inhibitors, antibody–drug conjugates, and therapeutic vaccine approaches across locally advanced and recurrent or metastatic settings. In ovarian cancer, single-agent checkpoint blockade has shown limited activity in unselected populations, but recent advances include biomarker-selected chemoimmunotherapy in platinum-resistant disease and clinically meaningful activity of folate receptor alpha-directed and HER2-directed antibody–drug conjugates. Across gynecologic cancers, key challenges include refining predictive biomarkers, optimizing sequencing after prior immunotherapy exposure, managing overlapping toxicities, and designing trials that enrich for biologically responsive subgroups. Future progress will depend on integrating molecular classification, immune contexture, ADC target expression, and patient-specific clinical factors into treatment selection. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. Full article

Background: Cervical cancer remains one of the leading causes of cancer-related morbidity among women worldwide. The Papanicolaou (Pap) smear is widely used for early detection; however, its manual interpretation is time-consuming, requires substantial expertise, and is often affected by inter-observer variability, particularly in cases with dense and overlapping cells. Methods: This study developed an optimized deep learning framework for cervical cell instance segmentation, specifically targeting the separation of overlapping cells in Pap smear images. The proposed framework was based on Mask R-CNN with a ResNet-50 backbone and Feature Pyramid Network. A public development dataset of 460 cervical smear images was used for model development and internal evaluation, while an independent 210-image dataset collected from King Abdullah University Hospital was reserved as an external held-out clinical assessment set. To improve small-cell detection and mask refinement, the Region Proposal Network was adapted using biologically informed anchor scales (16, 32, 64, 128, 256), followed by soft calibration-based post-processing. Results: The proposed framework achieved an AP50 of 89.90% and a Mask IoU of 90.44%. Small-cell performance, measured using APs under the COCO small-object convention, reached 22.80%, while APm and APl reached 68.45% and 81.42%, respectively. Clinical cell-count evaluation on the independent KAUH held-out set was performed using the mean count of five physicians as the reference standard and achieved an overall clinical detection accuracy of 93.00%. Conclusions: The optimized Mask R-CNN framework improved the detection and separation of overlapping cervical cells in Pap smear images and may serve as a supportive tool for cytopathology workflows. The results suggest that biologically informed anchor optimization and soft calibration can improve cell-level instance segmentation, particularly for small and overlapping cells. Further validation on larger multi-center datasets remains necessary before routine clinical deployment. Full article

Background/Objectives: Thymidylate synthase (TYMS) represents an important therapeutic target. Methods: In this study, TYMS expression was analyzed by immunohistochemistry on a tissue microarray containing 17,371 samples from 136 different tumor types. Results: TYMS staining was seen in 42.9% of 15,361 analyzable tumors, with weak staining in 35.4%, moderate in 5.7%, and strong in 1.8%. TYMS occurred in at least one case of 127 categories, of which 71 showed TYMS staining in at least 50% of cases, and 56 included at least one case with strong positivity. TYMS positivity occurred most commonly in lymphomas (81.3–96.5%), sarcomas and sarcomatoid carcinomas (33.3–100%), malignant melanoma (70.5–90.7%), cervical adenocarcinoma (78.3%), and squamous cell carcinomas of various sites (57.1–77.9%). High TYMS expression was linked to advanced pT (p = 0.0097), high grade (p < 0.0001), ER negativity (p < 0.0001), and PR negativity (p = 0.0002) in invasive breast cancer of no special type; high grade (p < 0.0050), high UICC stage (p = 0.0060), and nodal metastasis (p = 0.0120) in clear cell renal cell carcinoma (RCC); high grade (p < 0.05) and nodal metastasis (p = 0.0045) in papillary RCC; high Gleason grade (p < 0.0001) and advanced pT stage (p = 0.0149) in prostatic adenocarcinoma; high pT (p < 0.0001), nodal metastasis (p = 0.005), lymphatic (p = 0.0064) and venous invasion (p = 0.0005), left side location (p < 0.0001), and microsatellite instability (p < 0.0001) in colorectal adenocarcinoma; and high grade (p < 0.0001) in squamous cell carcinomas of different sites. Conclusions: TYMS is often overexpressed across different cancer entities and shows associations with several adverse histopathological parameters commonly used to describe tumor phenotypes. Full article

Cervical cancer is the fourth most frequent malignancy in women globally. Pap smear screening is important for early cancer detection, but manual smear analysis is time-consuming, labor-intensive and error-prone for diagnosis. Such issues in resource-limited areas have led to the introduction of deep learning (DL) methods for automated cervical cancer diagnosis. But the majority of current methodologies depend on models pretrained on natural image datasets like ImageNet, which may inadequately represent domain-specific pathological characteristics. To mitigate this constraint, this research employs a domain-specific transfer learning algorithm approach using the PathMNIST histopathological dataset to enhance cervical cell classification. An accuracy score of 96.77% is achieved for the proposed YOLO* model, using the SIPAKMED dataset. To the best of available knowledge, no previous study has reported the use of PathMNIST as a pretraining source for cytology image classification. As domain-specific medical pretraining is becoming more popular, our study shows the importance of cross-domain generalization. Full article

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic strategy for cervical cancer. However, the mitochondrial factors governing ferroptosis sensitivity in this malignancy remain incompletely understood. PET117, a conserved mitochondrial protein, has been implicated in mitochondrial homeostasis, yet its role in ferroptosis regulation and cervical cancer pathophysiology is unknown. Here, we report a novel role of PET117 in regulating ferroptosis. PET117 expression was significantly elevated in cervical cancer tissues and loss of PET117 in HeLa cells markedly suppressed erastin- and RSL3-induced ferroptosis. Mechanistically, PET117 deficiency attenuated intracellular reactive oxygen species (ROS) accumulation, lipid peroxidation, and iron overload. Mitochondrial proteomics and RNA-seq revealed extensive remodeling of the mitochondrial proteome and ferroptosis-related transcriptional networks upon PET117 depletion. Notably, integrative analysis of mitochondrial and nascent proteomes identified acyl-CoA synthetase family member 2 (ACSF2) as a downstream target of PET117. These findings establish PET117 as a novel regulator of ferroptosis in cervical cancer, thereby linking mitochondrial function to ferroptosis regulation. Full article

Antiproliferative activity of pyrrolo[3,4-d]isoxazolines and pyrrolo[2,1-a]isoquinolines derived from them was studied against human erythroleukemia (K562), cervical carcinoma (HeLa), and melanoma (Sk-mel-2) cell lines in vitro by MTS assays followed by study of their effect on actin cytoskeleton and cell motility by confocal microscopy, and apoptotic activity by flow cytometry. Most effective among the screened compounds were bicyclic hydroxylactams 6–9 with a pyrrolo[3,4-d]isoxazoline structure; they showed IC₅₀ values ranging from 12 to 36 μg/mL for all tested cancer cell lines with selectivity indexes up to 12 (as compared to the embryonic kidney HEK293T cell line). Loss of stress fibers with diffuse redistribution of granular actin throughout the cytoplasm in up to 25% of treated cells and a decrease in filopodia-like protrusions up to 69% were observed by confocal microscopy during an actin cytoskeleton study. Such cytoskeletal changes and the proposed altered cell motility were confirmed by scratch-test (revealed a three-fold decrease in cell motility). Full article

Cancer therapy remains limited by drug resistance and poor selectivity, while inflammation-driven tumor progression further complicates treatment outcomes. Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives due to their multifunctional properties. In this study, we investigated the anticancer and immunomodulatory activities of KI17, a rationally designed peptide derived from GL18, a peptide fragment identified from the talisin protein of Talisia esculenta. KI17 exhibited dose-dependent antiproliferative effects against murine and human melanoma (B16F10-Nex2, SK-MEL-2, A375) and cervical cancer (HeLa) cell lines, while displaying reduced cytotoxicity toward non-tumoral BV-2 microglial cells, resulting in a favorable selectivity index. Mechanistic analyses revealed that KI17 induces morphological alterations, mitochondrial dysfunction, caspase activation, and late-stage apoptosis, together with G0/G1 cell cycle arrest accompanied by accumulation of the Sub-G0 population, indicating coordinated regulation of cell death and cell cycle progression. KI17 effectively suppressed lipopolysaccharide (LPS)-induced microglial activation, markedly reducing pro-inflammatory cytokine and nitric oxide production without compromising cell viability. These biological activities are consistent with the peptide’s optimized physicochemical features, including increased cationicity, amphipathicity, and α-helical folding. Overall, our findings demonstrate that KI17 combines selective anticancer activity with potent immunomodulatory effects, highlighting its potential as a bioinspired peptide for further preclinical development in cancer therapy. Full article

Objective: Squamous cell carcinoma antigen (SCC-A) is a widely used biomarker for squamous cell cervical carcinoma and pretreatment elevation is associated with poor prognosis. Normalization during chemoradiation correlates with PET-CT response and survival. This study assessed the prognostic value of SCC-A normalization for biopsy-proven pathological response and survival outcomes. Materials and Methods: This retrospective single-center cohort study included patients with locally advanced or node-positive squamous cell cervical cancer treated with definitive chemoradiation at the Medical University Innsbruck between 2008 and 2023. Eligible patients had baseline SCC-A ≥ 2 ng/mL and at least two additional measurements within 42 days of treatment. SCC-A normalization was evaluated at predefined weekly time points. Associations with biopsy-assessed residual disease, PFS, and OS were assessed. Results: Of 186 screened patients, 83 met the inclusion criteria. Within 42 days, 70% achieved SCC-A normalization, with a median time of 21 days (IQR 19–32). Among predefined time points, normalization by day 28 was associated with reduced odds of residual disease (OR 0.14; 95% CI 0.04–0.44) and improved PFS (HR 0.28; 95% CI 0.12–0.63) and OS (HR 0.37; 95% CI 0.14–0.96), remaining independently significant after multivariate adjustments. Conclusions: SCC-A normalization during chemoradiation is a non-invasive independent biomarker of treatment response. Normalization within 28 days identifies patients at low risk of residual disease, progression, and death, supporting its use for early risk stratification and response monitoring for potential treatment adaptations. Full article

At present, cervical cancer is the fourth most common cancer among women worldwide. Current treatments for cervical cancer, most notably chemotherapy, can induce various adverse side effects, such as nausea, vomiting, hair loss, and fatigue, among others. Therefore, alternative therapies are being developed. Intravaginal drug delivery systems based on biopolymers are the subject of extensive research for the treatment of this condition. Some of the most sought-after qualities in these systems are mucoadhesiveness, biocompatibility, and biodegradability, while ensuring controlled and prolonged drug release. Taking these aspects into consideration, this study develops hydrogel ovules composed of O-carboxymethyl chitosan (OCMC) and gelatin, crosslinked with genipin, containing retinyl palmitate at various concentrations, as well as curcumin. The characterization of functional groups and potential interactions between the polymeric matrix and the drugs was carried out by Fourier Transform Infrared (FTIR) spectroscopy. Physicochemical tests, including swelling, contact angle, and in vitro degradation assays, were also performed to determine the system’s hydrophilicity and its potential duration of use. In vitro release assays for both curcumin and retinyl palmitate were conducted to investigate the release kinetics of these two substances. To assess the mucoadhesiveness of the ovules, a sliding analysis was conducted using porcine uterine tissue. Finally, cell viability studies were performed using mouse fibroblasts and HeLa cells to evaluate the system’s specificity. The results of this study demonstrate that the system, composed of gelatin, OCMC, retinyl palmitate, and curcumin, is mucoadhesive, hydrophilic, and exhibits controlled swelling behavior. In vitro assays demonstrated that the system maintains control of both degradation and drug release for up to 72 h; moreover, it proved non-toxic to healthy cells, with the incorporation of curcumin shown to enhance the selective cytotoxicity against HeLa cells. Based on the foregoing, this drug delivery system containing retinyl palmitate represents a promising potential intravaginal treatment for cervical cancer. Full article

This study investigates the combined effects of cisplatin (CDDP) and ε-viniferin (ε-VNF), a natural stilbenoid, on oxidative stress and apoptosis in HeLa cells. Cytotoxicity was assessed using the MTT assay, and IC₅₀ values were determined as 28 µM for CDDP and 21 µM for ε-VNF. Synergistic and antagonistic combination ratios of these doses were tested. Oxidative stress was evaluated via Total Oxidant Status (TOS), Total Antioxidant Status (TAS), Oxidative Stress Index (OSI), Superoxide Dismutase (SOD), Reduced Glutathione (GSH), and Malondialdehyde (MDA). Apoptosis was measured using Annexin V-FITC/PI staining and caspase-9 activation assays. TAS levels significantly increased in all combination groups compared to the control (control: 266.7 ± 0.1 µmol/L; 20% combo: 2466.7 ± 1.0 µmol/L). OSI values decreased accordingly (control: 22.5 ± 7.1; 10% combo: 1.6 ± 0.5). GSH levels decreased in the combination groups (e.g., 20%: 0.8 ± 0.2 µM vs. control: 1.4 ± 0.1 µM), while MDA levels increased (20%: 3.8 ± 0.5 µM vs. control: 0.5 ± 0.1 µM). Caspase-9 positive cells increased markedly (20%: 55.0% vs. control: 13.2%), supporting activation of the mitochondrial apoptotic pathway. Annexin V analysis revealed increased late apoptosis (20%: 76.1%) and early apoptosis (20%: 17.0%). Full article

Background/Objectives: Manual Pap smear analysis for cervical cancer screening is limited by inter-observer variability, time constraints, and restricted expert availability. Although convolutional neural networks (CNNs) have automated cervical cell classification, they remain limited in modeling long-range spatial dependencies and often lack clinical interpretability. Methods: In this study, Vision Transformer (ViT) architectures were systematically optimized to enhance automated cervical cancer screening and improve interpretability. The Herlev dataset (917 images: 242 normal, 675 abnormal) was utilized to optimize ViT-Tiny, a lightweight ViT architecture designed for reduced computational complexity, through a comprehensive evaluation of augmentation strategies, class weighting, and hyperparameters. Results: The optimal configuration achieved a cross-validation accuracy of approximately 95% (94.89% for the best replicated configuration), in which random horizontal flipping and class weighting (0.7 × 1.3) were identified as most effective. Gradient-weighted Class Activation Mapping (Grad-CAM) analysis confirmed that model attention corresponded to clinically relevant morphological features, including nuclei regions, cell boundaries, and chromatin texture, which align with cytopathological criteria. Conclusions: These findings indicate that Vision Transformers can deliver accurate and interpretable decision support for cervical cancer screening by combining competitive classification performance with attention-based transparency relevant to medical AI. Further validation on larger, multi-center datasets remains necessary before clinical deployment. Full article

Background/Objectives: Endocrine-disrupting chemicals (EDCs) interfere with hormonal homeostasis and have been implicated in gynecological malignancy pathogenesis. This narrative review synthesizes current evidence regarding EDC exposure and breast, endometrial, ovarian, and cervical cancers, examining molecular mechanisms, epidemiology, and diagnostic and clinical implications. Methods: We conducted a literature review using PubMed/MEDLINE, Embase, Scopus, and Cochrane databases through April 2026, including systematic reviews, meta-analyses, prospective cohorts, case-control studies, and mechanistic investigations examining EDC-cancer associations. Methodological quality was appraised using the Newcastle-Ottawa Scale and AMSTAR-2, with overall certainty of evidence rated using the GRADE framework. Results: Major EDC classes—bisphenol compounds, phthalates, polychlorinated biphenyls, organochlorine pesticides, and per- and polyfluoroalkyl substances—demonstrate carcinogenic potential through estrogen receptor modulation, epigenetic alterations, oxidative stress, and oncogenic signaling disruption. Breast cancer shows the strongest evidence, with prenatal and early-life DDT/DDE exposure associated with up to a 3.7-fold increased risk. Endometrial cancer demonstrates associations with xenoestrogen mixtures exhibiting non-monotonic dose-responses, whereas ovarian and cervical cancers show emerging but limited associations. Common mechanisms include receptor crosstalk, epigenetic dysregulation with transgenerational effects, oxidative genomic instability, metabolic reprogramming, and cancer stem cell enrichment. Conclusions: Evidence supports EDC contributions to gynecological malignancy through convergent pathways, though causal inference remains constrained by observational epidemiology, long latency periods, and challenges in characterizing real-world mixture exposures. Diagnostic and prevention strategies should integrate EDC exposure into risk-prediction models, leverage multi-omics biomarkers for early detection, and emphasize exposure reduction during critical developmental windows alongside regulatory reform. Full article

Background: Vulvar cancer is a rare gynecologic malignancy comprising 1–3% of all cases. No established standard exists for advanced disease, and treatment is often extrapolated from cervical cancer. Although HER2 overexpression is well defined in breast cancer and recognized across multiple solid tumors, its prevalence and significance in vulvar cancer remain unclear. Recent activity of HER2-directed antibody–drug conjugate Trastuzumab deruxtecan in solid tumors with an objective response rate (ORR) of around 37% highlights the need to better characterize HER2 expression in vulvar cancer. Methods: We performed a systematic search of Medline, Embase, and the Cochrane Library up to May 2025. Eligible studies included ≥10 vulvar cancer cases, predominantly vulvar squamous cell carcinoma (VSCC), excluding vulvar Paget’s disease, with available HER2 assessment by immunohistochemistry and/or in situ hybridization. Two reviewers independently screened the studies. A random-effects model was used to estimate pooled HER2 positivity. Heterogeneity was assessed using Cochrane’s Q and Higgins’s I². Results: Of 506 records, nine retrospective studies including 769 patients with predominantly squamous cell carcinoma histology (98%, n = 752) met inclusion criteria. A total of 50 HER2-positive cases were observed. Median age at diagnosis of vulvar cancer was between 55 and 78, reported in three studies. Molecular profiling was limited. Among three studies with known TP53 status (n = 206), 59% of the tumors expressed TP53 (n = 122), and among two studies with known human papilloma virus (HPV) status (n = 128), 21% (n = 27) were HPV-positive. Six studies used American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines in breast cancer. Pooled HER2-positive expression across ASCO/CAP-based studies was 2% (95% CI: 1%, 3%) and for non-ASCO/CAP-based studies was 21% (95% CI: 2%, 52%). Exploratory pooled estimated proportion of HER2-positive expression was 5% (95% CI: 0.4%, 14%). There was substantial heterogeneity across studies, I² value of 91.1% [95% CI: 85.4%; 94.6%], and no significant publication bias was observed (Egger’s test p = 0.364). This study could not assess prognostic value of HER2 overexpression in VSCC. Conclusions: HER2 positivity in VSCC appears uncommon but it remains to be fully explored. Standardized assessment using contemporary ASCO/CAP breast, endometrial-specific and/or gastric criteria are needed to clarify the prevalence of HER2-positive versus HER2-low/ultralow disease to inform potential use of HER2-targeted therapy. Full article

Background/Objectives: Drug repurposing has emerged as a promising strategy for identifying novel anticancer agents among clinically established drugs. Fexofenadine, a second-generation H1 antihistamine, has been proposed as a candidate for repurposing in oncology; however, the molecular mechanisms underlying its biological activity remain insufficiently characterized. This study investigated the effects of fexofenadine on oxidative stress, mitochondrial function, apoptosis, and pro-survival signaling pathways in cervical and lung cancer cells. Methods: HeLa and A549 cancer cells, as well as non-tumorigenic Beas-2B epithelial cells, were exposed to fexofenadine under in vitro conditions. Cell viability, apoptosis, reactive oxygen species generation, mitochondrial membrane potential, DNA damage, autophagy-associated responses, and PI3K/AKT and MAPK/ERK pathway activation were assessed using flow cytometry, fluorescence microscopy, electron microscopy, and biochemical assays. Three-dimensional spheroid cultures and N-acetyl-L-cysteine rescue experiments were additionally employed to evaluate biological relevance and the contribution of oxidative stress. Results: Fexofenadine induced concentration-dependent accumulation of reactive oxygen species, mitochondrial membrane depolarization, Bcl-2 inactivation, caspase-3/7 activation, DNA damage, and apoptotic cell death in HeLa and A549 cells. Antioxidant pretreatment with N-acetyl-L-cysteine significantly reduced oxidative stress, attenuated mitochondrial dysfunction, and partially suppressed apoptosis. Fexofenadine was associated with reduced PI3K/AKT and MAPK/ERK pathway activation and promoted autophagy-associated responses. In three-dimensional spheroid cultures, treatment disrupted spheroid integrity and increased apoptotic cell death. Non-tumorigenic Beas-2B cells exhibited lower sensitivity to treatment than malignant cells. Conclusions: Fexofenadine disrupts redox homeostasis and is associated with reduced activation of pro-survival signaling pathways, resulting in oxidative stress-associated mitochondrial dysfunction and apoptosis in cancer cells. These findings provide mechanistic support for further evaluation of fexofenadine as a candidate for anticancer drug repurposing, while additional pharmacokinetic and in vivo studies are required to determine its translational relevance. Full article