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Human papilloma virus (HPV) testing is the preferred primary screening method for cervical cancer, and HPV self-sampling has the potential to improve screening uptake. We compared the test performance and agreement of self- and clinician-sampling HPV in women living with HIV (WLWH) and HIV-negative women in Gauteng and Western Cape Province, South Africa. Cervical cancer screening was performed in previously unscreened women using cytology, self- and clinician-collected HPV (Hybrid Capture 2 assay). Screen-positive participants underwent colposcopy and biopsy, and a random sample of negative screens had punch biopsy regardless of colposcopy findings. Performances of screening tests were evaluated against histology results adjusted for verification bias. The kappa statistic for HPV concordance between self- and clinician-collected HPV was also calculated. Included for analysis were 903 women with a mean age of 41.5 years, of which 43.3% were WLWH. In WLWH/HIV-negative women, the sensitivity of self-sampling HPV was 74.7%/67.4% and of clinician-sampling HPV was 77.1%/59.2% to detect cervical intraepithelial neoplasia (CIN) grade3+, whereas the specificity for clinician-sampling HPV was 75.0%/86.8% compared with 70.3%/79.8% for self-sampling HPV to detect CIN2+. In both HIV groups, Cohen's kappa agreement between the two sampling methods was good (0.63 and 0.62, respectively). Self-collected HPV sampling is an acceptable and viable option for primary cervical cancer screening in all women given the superior sensitivity to cytology. The statistically significant difference in HPV test performance among HIV-negative women according to sampling method confirms the benefit of a further triage test when self-sampling is used for HPV-base cervical screening, especially in HIV-negative women.

Triage of human papillomavirus (HPV)-positive women with atypical squamous cells of undetermined significance (ASC-US) remains a longstanding clinical challenge in cervical cancer screening, as conventional strategies often lead to excessive colposcopy referrals. We conducted a diagnostic cohort study of 195 HPV-positive women who underwent ASC-US cytology. Multigene DNA methylation analysis was performed on residual cervical exfoliated cells, using histology from colposcopy-directed biopsy and/or endocervical sampling as the reference standard to minimise colposcopy referrals. Our results showed that methylation levels of PAX1, EPB41L3, and FAM19A4 increased progressively from ≤ CIN1 to CIN2, CIN3, and cervical cancer, with significant decreases in ΔCt values from ≤ CIN1 to CIN3 for all three genes ( p < 0.05). For detection of CIN2+, the assay achieved a sensitivity of 85.19%, specificity of 96.43%, positive predictive value (PPV) of 79.31%, negative predictive value (NPV) of 97.59%, and an area under the receiver operating characteristic curve (AUC) of 0.91, thereby avoiding colposcopy referrals in 96.43% (162/168). For CIN3+, the assay demonstrated sensitivity, specificity, PPV, NPV, and AUC values of 94.44%, 93.22%, 58.62%, 99.4%, and 0.94, respectively. Stratified analyses showed high and comparable sensitivity (81.82% vs. 87.50%), specificity (96.92% vs. 96.12%), and AUC (0.89 vs. 0.92) in women with HPV16/18 compared with those with non-16/18 high-risk HPV. Optimal diagnostic accuracy was observed in women aged ≥30 years, with sensitivities ranging from 85.70% to 100%, specificities from 94.44% to 100%, and AUC values ranging from 0.93 to 0.97. In contrast, the performance was suboptimal in women aged <30 years (sensitivity, 33.33%; AUC, 0.64). The host multigene DNA methylation assay demonstrates high specificity and good sensitivity for triaging HPV-positive ASC-US women, with the potential to reduce colposcopy referrals while maintaining robust detection of high-grade lesions, particularly in those aged ≥30 years. In cervical cancer screening, management of human papillomavirus-positive individuals with atypical squamous cells of undetermined significance presents a clinical challenge, as the routine approach of direct referral for colposcopy often results in many patients undergoing unnecessary invasive procedures. In this study, we applied a combined multigene DNA methylation assay in this population, using histology as the gold standard. The results demonstrated that the assay accurately stratifies high- and low-risk groups, enables more than 96% of low-risk individuals to avoid colposcopy, and shows optimal performance in women aged ≥30 years. Overall, this assay is an effective tool for achieving precise triage, as it not only optimises cervical cancer screening pathways but also substantially reduces medical burden and psychological anxiety.

Management of gynecologic brachytherapy (BT) procedural pain or discomfort varies across institutions. We sought to determine the prevalence of post-BT post-traumatic stress disorder (PTSD) symptoms among locally advanced cervical cancer (LACC) patients and assess differences based on type of analgesia. We queried an IRB-approved institutional database for women at one high-volume academic medical center who received high-dose-rate (HDR)-BT for LACC between January 1, 2015 and September 30, 2021. Enrolled patients completed two validated questionnaires by phone: (1) Impact of Event Scale-Revised (IES-R), and (2) European Organization for Research and Treatment of Cancer Quality of Life Group Core Questionnaire-Cervical Cancer Module (EORTC QLQ-CX24). Optional open commentary was offered. Of 56 eligible patients, 21 patients aged 30-69 years were enrolled; 17 were treated for intact LACC and 4 were treated postoperatively. FIGO stage ranged from 1B1-IVA. Five Black/African American, 6 Hispanic, 2 Asian, 14 unknown race, and 9 unknown ethnicity patients were included. Mean time since treatment was 3.27 years (1.5-6 years). The mean IES-R score was 16.62 (0-73). Three women scored >32, indicating probable PTSD symptoms. Three scored between 24 and 32, suggesting partial PTSD symptoms. Six scored <24, equating to a partial to full PTSD symptom rate of 28.6% (95% CI: 11.3%, 52.2%). Small sample size precluded analyses of associations between AS technique and PTSD symptoms. Partial to full PTSD symptoms were present in 28.6% of women treated with HDR-BT for LACC in a population largely receiving BT without sedation. Further prospective study into associations between HDR-BT AS practices and PTSD symptoms is warranted.

Polycystic ovary syndrome has been renamed polyendocrine metabolic ovarian syndrome following a multistep international consensus process endorsed by 56 professional and patient organizations. The new name corrects a longstanding misnomer. The characteristic ovarian morphology reflects numerous arrested antral follicles, not pathologic cysts, and the legacy term has reinforced an overly ovarian and fertility-centered view of a lifelong endocrine-metabolic condition. For obstetrician-gynecologists, this reframing has immediate clinical relevance. Polyendocrine metabolic ovarian syndrome affects approximately 10% to 13% of reproductive-age women, yet it remains underdiagnosed and inconsistently documented in routine care. It is associated with insulin resistance, hyperandrogenism, ovulatory dysfunction, psychological morbidity, and cardiometabolic risk across the life course. During pregnancy, polyendocrine metabolic ovarian syndrome is linked to higher risks of miscarriage, gestational diabetes, hypertensive disorders of pregnancy, cesarean delivery, preterm birth, fetal growth restriction, low birthweight, and small-for-gestational-age infants, with many associations persisting after adjustment for age and body mass index. Despite this evidence, polyendocrine metabolic ovarian syndrome is not routinely captured as an obstetric risk modifier at the first obstetric visit, nor is it consistently embedded in antenatal decision-support pathways. Patients also remain inconsistently screened and counseled for psychological, metabolic, and long-term cardiometabolic risks. This Special Report discusses the rationale for the polycystic ovary syndrome-to-polyendocrine metabolic ovarian syndrome rename, reviews evidence linking polyendocrine metabolic ovarian syndrome with adverse pregnancy and offspring outcomes and outlines practical implications for obstetric and gynecologic care. Diagnostic criteria remain unchanged; namely, 2 of the following 3: irregular menstrual cycles and ovulatory dysfunction, clinical or biochemical hyperandrogenism, and elevated anti-Müllerian hormone levels or multiple follicles on ovarian ultrasound in adults. What changes is the clinical frame. Obstetrician-gynecologists are uniquely positioned to improve earlier diagnosis, risk recognition, counseling, and coordinated care from adolescence through menopause and beyond.

Cervical cancer remains a major global health burden, particularly in low- and middle-income countries. In Kazakhstan, cervical cancer incidence is rising, despite an established cytology-based screening program. Self-sampling for human papillomavirus (HPV) genotyping is suggested as a promising strategy to improve screening participation, yet it has not been evaluated in Kazakhstan. Thus, this study aims to perform a preliminary assessment of self-sampling approach acceptance among Kazakhstani women. A cross-sectional study was conducted among women attending outpatient clinics in large cities in Kazakhstan between August 2024 and June 2025. Participants used both the Evalyn Brush and BGI Sentis self-sampling kits and completed structured questionnaires assessing knowledge, perceptions, ease of use, discomfort, confidence and willingness to recommend. Descriptive and bivariate statistics were performed to evaluate associations with acceptance and usability. A total of 124 women were included in this pilot study, with a median age of 34.5 years (IQR: 27.5-44.0). Only 28.2% of respondents preferred self-sampling for their next screening, whereas 62.1% preferred gynaecologist-collected samples. The Evalyn Brush demonstrated higher ease of use (93.5%) compared to the BGI kit (45.2%). Confidence in correct self-collection was also higher for the Evalyn Brush (85.4% vs. 67.7%). Women who believed that home-based self-sampling is easier than Pap-smear were significantly more likely to prefer self-sampling for future screening ( p < 0.001). Education level was associated with HPV knowledge but not with acceptance. Self-sampling is acceptable for a proportion of Kazakhstani women, with the Evalyn Brush showing greater comfort, ease and confidence, indicating that device selection is critical for successful implementation. The findings support further large-scale evaluation that will guide improvements to Kazakhstan's cervical cancer screening programme. A nationwide study is required for a more precise assessment of the self-sampling approach acceptance and the strategy's feasibility. HPV self-sampling had low acceptance among Kazakhstani women (28.2%), with preference strongly driven by the perceived convenience, ease of use, comfort and confidence of using the device correctly.The Evalyn Brush had better acceptability than the BGI Sentis, with significantly better ease of use, perceived convenience compared with the Pap smear, confidence in using the device and willingness to recommend the device compared with the other device.Low acceptance of the self-sampling approach, despite positive experiences with ease of use, emphasizes the need to address concerns about the reliability of self-samples and the user’s confidence with devices before national roll-out.

This study aims to uncover the role and mechanism of transforming growth factor α (TGFA) on the malignant progression of cervical cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to examine the expression levels of TGFA in cancer cells and tissues. Changes in cell viability, apoptosis, and malignant metastatic ability of cancer cells were detected using methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, and Transwell method respectively. Autophagy was evaluated via microtubule-associated proteins light chain 3 (LC3) and sequestosome 1 (p62) expression. A nude mouse xenograft model was used for in vivo validation. RNA pull-down assay was performed to explore the interaction between TGFA and desmoglein 2 (DSG2). These results indicated that TGFA expression was elevated in both cervical cancer tissues and cells. TGFA overexpression promoted cell proliferation, metastasis, and autophagy, whereas TGFA knockdown exerted the opposite effects and inhibited tumor growth. Mechanistically, TGFA bound to DSG2 and affected the downstream MYC oncogene (c-MYC)/ADAM metallopeptidase domain 17 (ADAM17) pathway. In conclusion, TGFA serves as an upstream regulator of the DSG2/c-MYC/ADAM17 axis, which is correlated with autophagy and malignant progression of cervical cancer.

Cervical cancer elimination is a global public health goal, with vaccination against Human Papillomavirus (HPV) and HPV screening being two major prevention pillars. This review focuses on how vaccinations can be used in order to reach the timepoint of cervical cancer elimination faster. The concepts in previously published reviews on 'faster cervical cancer elimination' are summarised and explained. Major concepts explained are: HPV vaccines prevent not only cancer precursors, but also the HPV infection itself resulting in public health gains that exceed the individual direct vaccine protection because of herd immunity. The effective population coverages of vaccine-induced immunity required to reach the critical extinction level for infection elimination are moderate, in particular when gender-neutral vaccination is used. Major suggested enabling strategies include catch-up vaccinations of adolescents, one-dose HPV vaccination and use of HPV prevalences to monitor and optimise HPV vaccination programs. Finally, cervical screening with HPV testing is predicted to be easier if there are no new HPV infections. The major challenge for faster cervical cancer elimination is to design HPV vaccination strategies that achieve an effective population immunity against the HPV infection as fast as possible.

Major gynecological malignancy like cervical cancer faces global challenges in conventional treatments, leading researchers to explore newer anticancer therapeutics with reduced toxicity and off-target effects. Traditional ethnomedicinal plants with source of novel adjuvant chemotherapeutics are attracting considerable interest. β-catenin pathway dysregulation is cardinal in cancer propagation, with well-noted regulation in migration/EMT-potential and cancer cell stemness. Present study focuses towards identifying molecular mechanisms of anti-migratory efficacy of Croton caudatus leaf-extract and its bioflavonoid Kaempferol against metastatic cervical cancer cells. C. caudatus leaf-extract exhibited most cytotoxicity towards cervical cancer HeLa and SiHa cells. Leaf-extract and Kaempferol significantly reduced cervical cancer cellular migration via downregulating EMT markers (N-cadherin, Vimentin, Twist, Zeb2, Snail, Slug) and upregulating epithelial marker E-cadherin (p < 0.0001). In silico investigation depicted β-catenin's importance in cervical cancer patient-cohorts and its correlation with major EMT markers. C. caudatus leaf-extract and Kaempferol altered EMT by inhibiting β-catenin's nuclear translocation in vitro via upregulating 14-3-3 and downregulating Importin β-1 (p < 0.0001). Also they had upregulated upstream GSK3β and Phospho-β-catenin expression, demonstrating their anti-migratory potential, most of which are imparted by extract's Kaempferol, at low IC 50 dose. Both leaf-extract and Kaempferol significantly reduced expression of downstream c-MYC, Cyclin D1, MMP-7, and MMP-9 by reducing β-catenin's nuclear translocation (p < 0.0001). Moreover, Kaempferol reduced expression of major stemness factors OCT4 and SOX2 in cervical cancer cells and decreased their physical association with β-catenin. Thus, current study uncovers unknown pharmacological roles of C. caudatus leaf-extract and Kaempferol in modulating β-catenin's subcellular localization,altering EMT, thereby reducing cancer migration and stemness, encouraging their future use as alternative anti-cancer therapeutics.

Human papillomavirus (HPV) can cause a variety of epithelial lesions, including the malignant proliferation of host cells and even cervical cancer. HPV E2 can play an important role in regulating viral gene expression, viral replication and transcription, and also can participate in the isolation of viral genome during cell division. HPV16 E2 protein is highly expressed in low-differentiated cervical lesion cells, but decreased or disappeared with the increase of cervical lesion grade. As both the initiation protein for DNA replication and the major transcriptional regulator for HPV16 gene expression, E2 protein may play a key role in the viral life cycle. HPV16 E2 protein as a sequence specific DNA binding protein, can bind with the specific DNA recognition sequence on the promoters of E6 and E7 oncogenes, and then inhibit the transcription and expression of E6 and E7 oncogenes, thus inducing cell apoptosis and suppressing tumor formation. Therefore, therapeutic strategies aimed at restoring or enhancing HPV16 E2 function may hold promise for the prevention and treatment of HPV-related cancers, including (i) gene-therapy-mediated E2 restoration; (ii) direct delivery of E2 protein; (iii) E2 stabilization through modulation of interacting pathways (e.g., TopBP1, Brd4); and (iv) E2-based therapeutic vaccines. These approaches may exert antitumor effects by repressing E6/E7 oncogenes, regulating the cell cycle, inhibiting cell proliferation, and inducing apoptosis.

Polyendocrine metabolic ovarian syndrome (PMOS), previously known as polycystic ovary syndrome, affects 10%-13% of women of reproductive age and remains underdiagnosed despite its substantial health burden. The introduction of the new PMOS nomenclature in 2026 reflects a fundamental shift in understanding the condition as a lifelong endocrine and metabolic disorder with prominent reproductive, psychological, dermatological, and cardiometabolic consequences. Once considered primarily a reproductive disorder, PMOS is now recognized as a multisystem condition. Insulin resistance and compensatory hyperinsulinemia are central pathophysiological mechanisms linking endocrine and metabolic features to reproductive dysfunction. In PMOS, insulin resistance affects 75% of lean and 95% of overweight women. Here we focus on the metabolic features. Recent advances in epidemiology include the first systematic review and meta-analysis examining regional variations in PMOS prevalence. In parallel, contemporary population-based studies of unselected women have confirmed that increased risks of metabolic complications observed in selected clinical cohorts also apply at the population level and have demonstrated increased risk of major adverse cardiovascular events (MACE). These studies report an almost 3-fold increased risk of Type 2 diabetes (OR 2.9) and MACE (HR 1.2-2.5), with cardiovascular risk diverging from approximately 35 years of age. In this review, we summarize recent advances in epidemiology, pathophysiology, metabolic dysfunction, and cardiovascular risk of PMOS, together with their implications for diagnosis and clinical management. Recognizing PMOS as an early-life marker of cardiometabolic disease highlights opportunities for earlier diagnosis, prevention, and individualized risk stratification, supporting integrated, patient-centered care across the life course.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system, and its frequent recurrence and treatment resistance are major obstacles to improving patient outcomes. Studies indicate that the progression and treatment resistance of OC are driven by substantial metabolic and mitochondrial reprogramming. As key byproducts and signaling molecules of mitochondrial metabolism, reactive oxygen species (ROS) have emerged as a central regulatory node in both OC progression and treatment response. While tumor cells enhance their redox-buffering capacity to maintain survival, a trait that exhibits high heterogeneity across histologic subtypes, ROS ultimately exert a biphasic effect determined by dose, spatiotemporal dynamics, and cellular state. On the one hand, a chronic low-to-moderate oxidative burden sustains redox-sensitive prosurvival signaling and drives tumor proliferation, angiogenesis, and invasion. This is primarily achieved by activating antioxidant pathways, such as the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which mediates resistance to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. On the other hand, an acute surge in oxidative stress that breaches the cellular antioxidant-buffering threshold triggers regulated cell death, primarily through the intrinsic mitochondrial apoptotic pathway and iron-dependent lipid peroxidation (ferroptosis). Crucially, ROS-induced ferroptosis and metabolic shifts do not occur in isolation; they actively participate in extensive crosstalk with the tumor immune microenvironment (TIME). Given this complex biology, targeting redox balance represents a highly promising therapeutic strategy. Interventions include scavenging ROS to block prosurvival signaling, or employing specific drugs and nanodelivery systems to amplify oxidative stress to lethal levels. When rationally combined with immunotherapies, these ROS-modulating strategies can effectively reverse tumor resistance by remodeling the TIME. This review systematically summarizes the biological properties of ROS, the mechanisms of metabolic and mitochondrial reprogramming across OC histologic subtypes, and the dual protumor and antitumor roles of ROS, with particular emphasis on the interplay between ferroptosis and immune regulation. Furthermore, we highlight emerging pro-oxidant therapies, ferroptosis inducers, nanodelivery systems, and immune-based combinatorial strategies. Ultimately, we propose a dynamic ROS modulation framework that advocates for precise, personalized pro-oxidant or antioxidant interventions based on each patient's tumor subtype, real-time redox state, and TIME characteristics, offering a robust translational path for next-generation precision oncology in OC.

The homologous recombination repair (HRR) RAD51 recombinase is essential for ensuring accurate DNA repair, and its expression levels are inversely correlated with Poly (ADP-ribose) Polymerase inhibitor (PARPi) sensitivity. Artesunate (ART), a semisynthetic water-soluble sesquiterpene lactone derived from artemisinin, a natural product of Artemisia annua, was previously identified from an HRR reporting system as a potential HRR modulator, suggesting its utility as a PARPi sensitizer. The clinical relevance of RAD51 was assessed using the TCGA database. In vitro studies employed A2780 and SKOV3 ovarian cancer cell lines, utilizing RAD51 siRNA, the inhibitor IBR2, and ART alone or in combination with Olaparib (Ola). Used cell counting kit-8, colony formation, and EdU assays to evaluate cell proliferation.; apoptosis by flow cytometry; and DNA damage by γ-H2AX immunofluorescence and comet assays. Protein levels were analyzed by Western blotting (p-ATM, γ-H2AX, RAD51). The ART-RAD51 interaction was validated via cellular thermal shift assay, drug affinity responsive target stability, and molecular docking. In vivo efficacy and safety were evaluated in a nude mouse xenograft model. RAD51 expression was correlated with ovarian cancer progression, and PARPi treatment itself promoted RAD51 expression. siRNA and inhibitior of RAD51 sensitized ovarian cells to Ola. We identified ART as a direct inhibitor of RAD51, which binds to RAD51 and promotes its protein degradation, thereby inhibiting HRR. The combination of ART and Ola significantly increased DNA damage, inhibited proliferation, and induced apoptosis in vitro. This combination also potently suppressed tumor growth in vivo without observable significant toxicity. Our findings establish RAD51 as a key target for addressing PARPi-resistant in ovarian cancer. We demonstrate that ART counteracts this resistance through directly binding to and degrading RAD51, thereby inhibiting HRR. The ART-Ola combination presents a novel, synergistic, and well-tolerated strategy in preclinical models, providing a strong mechanistic rationale for future clinical translation.

Cancer-related cognitive impairment (CRCI) is a common, persistent complication of cancer and its treatment, yet its etiology in ovarian cancer remains poorly understood. Preclinical rat models integrating tumor burden and cognitive outcomes in ovarian cancer remain limited, and the contribution of tumor-associated processes has been insufficiently characterized. We developed an SKOV3.ip1 human ovarian cancer xenograft model of CRCI in female RNU rats, combined with a clinically relevant cisplatin regimen (4 cycles, 5 mg/kg, i.p.). Animals were randomly assigned to non-tumor (NT) or ovarian tumor-bearing (OvT) groups and to receive cisplatin (CDDP) or vehicle (VEH), resulting in four groups: NT + VEH, NT + CDDP, OvT + VEH, and OvT + CDDP. Anxiety-like behavior was assessed using the open field test, and cognitive function was evaluated using context object discrimination and novel object recognition tasks. Serum cytokine levels were measured in relation to behavioral outcomes. CDDP significantly impaired novel object recognition in non-tumor-bearing animals, but not in tumor-bearing animals which were impaired in object recognition regardless of treatment. NT + CDDP, OvT + VEH, and OvT + CDDP animals were significantly impaired relative to NT + VEH. Tumor implantation and cisplatin exposure were associated with alterations in systemic cytokine levels. Exploratory analyses identified IL-10 and C-reactive protein as candidate markers of reduced cognitive performance, although overall discriminative performance was modest. These findings demonstrate that the cognitive effects of chemotherapy depend on tumor status and underscore the importance of incorporating tumor-bearing conditions into preclinical CRCI models. Our model provides a translational platform to investigate tumor-treatment interactions and explore candidate inflammatory markers associated with cognitive outcomes in ovarian cancer.

Patient-derived organoids (PDOs) have emerged as promising preclinical models for functional drug testing in ovarian cancer, with potential to support personalized treatment selection. However, their predictive value for clinical treatment response remains unclear. This systematic review evaluated the predictive accuracy of ovarian cancer PDOs for treatment efficacy. A systematic search of was conducted from inception to January 29, 2026. Eligible studies included patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer from whom PDOs were generated for in vitro drug testing and directly correlated with clinical outcomes. The primary outcome was predictive accuracy, defined as concordance/ correlation between in vitro PDO drug response and in vivo patient outcomes. Because of substantial heterogeneity, a narrative synthesis was performed. Twelve studies published between 2019 and 2026 were included. Cohort sizes ranged from 6 to 61 patients and comprised two prospective validation studies and ten retrospective translational or feasibility studies. Clinical endpoints were heterogeneous and included radiologic, biochemical and histopathologic response, progression-free survival, and descriptive clinical course. Four studies reported statistically significant associations between PDO drug response and clinical outcome, six reported concordant findings without formal statistical testing, two showed limited or mixed concordance, and one relied on descriptive comparison only. The strongest evidence came from two prospective studies, which reported accuracies of 89% and 91.7%. Ovarian cancer PDOs show promise as functional predictors of treatment response, but current evidence is limited by small cohorts, methodological heterogeneity, and scarce prospective validation. Standardized prospective studies are needed to define their clinical applicability.

The high value of surgery aimed at macroscopic complete resection is undisputed. The TRUST trial (Trial of Radical Upfront Surgical Therapy) aimed to determine the ideal timing of surgery (primary vs. interval debulking). While a significant progression-free survival benefit for primary surgery was demonstrated, the overall survival benefit was only numerical and not statistically significant. Based on the TRUST trial, primary surgery should still be recommended if macroscopic complete resection can be achieved with acceptable morbidity. Careful patient selection at specialized centers is crucial. A milestone in the systemic treatment of advanced ovarian cancer is the option of maintenance therapy with bevacizumab, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, or the combination of olaparib plus bevacizumab. Biomarker testing, specifically BRCA and homologous recombination deficiency (HRD) testing, is essential for treatment selection. In case of recurrence, where platinum-based chemotherapy is an option, platinum-containing combination chemotherapy should be administered, and the use of maintenance therapy should be considered. If platinum is not an option, three phase III trials have fortunately now demonstrated a significant overall survival benefit with the antibody-drug conjugate (ADC) mirvetuximab soravtansine (MIRV) in patients with high α‑folate receptor expression (MIRASOL trial), or with pembrolizumab plus paclitaxel ± bevacizumab in patients with CPS ≥ 1 (KEYNOTE-B96 trial), as well as with relacorilant plus nab-paclitaxel (ROSELLA trial), each compared to standard chemotherapy. MIRV and Pembrolizumab are already approved. The increasingly complex treatment of ovarian cancer should therefore be carried out in specialized German Cancer Society (DKG)-certified gynecological cancer centers as an effective tool for quality improvement. Der hohe Stellenwert der Operation mit dem Ziel der makroskopischen Komplettresektion ist unstrittig. In der TRUST (Trial of Radical Upfront Surgical Therapy)-Studie sollte der ideale Operationszeitpunkt (Primär- vs. Intervall-Debulking) geklärt werden. Es zeigte sich hier ein signifikanter Benefit für das progressionsfreie Überleben bei Primäroperation, aber nur ein numerischer, nicht signifikanter Gesamtüberlebensvorteil. Auf Grundlage der TRUST-Studie sollte weiterhin eine Primäroperation empfohlen werden, wenn bei vertretbarer Morbidität eine Primäroperation mit makroskopischer Komplettresektion ermöglicht werden kann. Eine gute Selektionierung der Patientinnen an ausgewiesenen Zentren ist entscheidend. Meilenstein in der Systemtherapie des fortgeschrittenen Ovarialkarzinoms ist die Option der Erhaltungstherapie mit Bevacizumab, PARP („poly adenosine diphosphate-ribose polymerase“)-Inhibitoren oder der Kombination von Olaparib plus Bevacizumab. Biomarkertestungen im Sinne von BRCA- und HRD („homologous recombination deficiency“)-Testung sind für die Auswahl entscheidend. Im Falle eines Rezidivs, bei dem Platin eine Option darstellt, sollten platinhaltige Kombinationschemotherapien appliziert und der Einsatz einer Erhaltungstherapie geprüft werden. Wenn Platin keine Option ist, zeigten nun erfreulicherweise drei Phase-III-Studien einen signifikanten Gesamtüberlebensvorteil mit dem ADC (Antikörper-Wirkstoff-Konjugat) Mirvetuximab Soravtansin (MIRV) bei Folatrezeptor α high (Mirasol-Studie) oder mit Pembrolizumab plus Paclitaxel ± Bevacizumab bei CPS ≥ 1 (KEYNOTE-B96-Studie), aber auch für Relacorilant plus nab-Paclitaxel (ROSELLA-Studie) jeweils im Vergleich zu Standardchemotherapien. MIRV und Pembrolizumab sind bereits zugelassen. Die immer komplexer werdende Therapie des Ovarialkarzinoms sollte daher in spezialisierten DKG (Deutsche Krebsgesellschaft)-zertifizierten Gynäkologischen Krebszentren als ein wirksames Instrument zur Qualitätsverbesserung erfolgen.

Neoadjuvant chemotherapy followed by interval debulking surgery is standard treatment for advanced ovarian cancer that is unlikely to achieve optimal cytoreduction. We aimed to evaluate a chemotherapy-free regimen of neoadjuvant niraparib monotherapy in homologous recombination deficiency (HRD)-positive disease initially unsuitable for primary debulking surgery. This single-arm, phase 2 trial was conducted at six tertiary hospitals in China. Eligible patients were aged 18-75 years, had treatment-naïve, FIGO stage III-IV HRD-positive high-grade serous or endometrioid ovarian cancer, an ECOG performance status of 0-2, with a low likelihood of complete primary debulking surgery based on prespecified criteria. Patients received oral niraparib monotherapy for two 28-day cycles with an individualised starting dose of 200 mg or 300 mg. Protocol-permitted supportive care was provided as clinically indicated. Co-primary endpoints were investigator-assessed objective response rate in the response-evaluable population and R0 resection rate after interval debulking surgery in the operated population. Safety was assessed in all patients who received at least one dose of niraparib. The trial was registered with ClinicalTrials.gov (NCT04507841), is closed to enrolment, and this report presents the primary analysis. Between Jan 8, 2021, and Jul 18, 2023, 127 patients were screened, and 67 were enrolled into the study. All enrolled patients were female and self-identified as Han Chinese (median age 55 years [IQR 50-62]). At the data cutoff (Dec 29, 2025), median follow-up was 37·7 months (IQR 31·8-48·5). Among 48 response-evaluable patients, 30 achieved an objective response, with an objective response rate of 63% (95% CI 47-76). Among 40 operated patients, 32 achieved R0 resection, with an R0 resection rate of 80% (95% CI 64-91). The most common grade 3-4 treatment-related adverse events were thrombocytopenia in 32 (48%) of 67 patients, leukopenia in 13 (19%) patients, anaemia in 12 (18%) patients, and neutropenia in nine (13%) patients. Serious adverse events occurred in 19 (28%) patients. No treatment-related deaths occurred. Neoadjuvant niraparib showed anti-tumour activity and enabled R0 resection in selected patients with HRD-positive advanced ovarian cancer who were initially unsuitable for primary debulking surgery. This strategy remains investigational and requires randomised validation against standard platinum-taxane neoadjuvant chemotherapy. National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Natural Science Foundation of Hubei Province, Innovative Drug Research and Development National Science and Technology Major Project, and Zai Lab (Shanghai). For the Chinese translation of the abstract see Supplementary Materials section.

Ovarian cancer (OC) is the second lethal gynecological malignancy, with chemoresistance being a major therapeutic challenge. Interestingly, although malignant ascites is generally associated with poor prognosis, tumor-suppressing factors have been identified in ascitic fluid. This study aims to identify chemotherapy-sensitizing peptides in OC ascites and elucidate its underlying mechanisms. Mass spectrometry was exployed to identify differentially enriched peptides. The feasibility of therapeutic administration was evaluated by an in vivo toxicity assay. The mechanism of peptide was identified through peptide pull-down combined with mass spectrometry, western blots, immunofluorescence, RNA-sequencing, as well as in vitro and in vivo functional analysis. Peptidome analysis identified 10 upregulated and 8 downregulated peptides in chemoresistant versus chemosensitive OC ascites. Among these, CPAP1 demonstrated platinum-sentitizing effects. Its membrane-penetrating modified version, TAT-CPAP1, showed enhanced stability, improved anti-proliferation effects and improved platinum sensitivity in both TP53 wild-type A2780 and its chemoresistant counterpart cells. Administration of TAT-CPAP1 showed no apparent liver and kidney damage. Mechanistically, TAT-CPAP1 directly binds and colocalizes with NOLC1 in the nucelus, and alters the expression of genes within the DNA damage response pathway. Both TAT-CPAP1 treatment or NOLC1 knockdown improved the platinum sensitivity, increased MDM4/MDM2 ratio and promoted cytoplasmic MDM4 localization. The TAT-modified, ascites-derived peptide CPAP1 enhances platinum sensitivity in TP53 wild-type OC cells by targeting NOLC1 and modulating MDM2 and MDM4 expression, while exhibiting no detectable hepatotoxicity or nephrotoxicity.

Germline pathogenic or likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 are major determinants of hereditary breast and ovarian cancer susceptibility. Although clinical management has traditionally relied on the presence of a BRCA1/BRCA2 alteration regardless of its specific characteristics, growing evidence suggests that not all BRCA P/LPVs are biologically and clinically equivalent. Variant location within BRCA1 and BRCA2 influences the relative distribution of breast and ovarian cancer risk. Breast cancer cluster regions (BCCRs) are associated with a higher relative risk of breast versus ovarian cancer, whereas ovarian cancer cluster regions (OCCRs), largely encompassing exon 11, are associated with a relative shift toward ovarian cancer risk. Variant type may also be clinically relevant. Protein-truncating P/LPVs have been associated with higher cancer risks than selected missense variants with residual protein function and lower penetrance. Some studies have also reported poorer outcomes for carriers of protein-truncating P/LPVs and more favorable outcomes for those with missense variants. In this narrative review, we summarize current evidence on the clinical implications of BRCA1/BRCA2 P/LPV type and genomic location. While associations between variant location and breast or ovarian cancer risk are supported by large international consortia, prognostic and predictive associations remain largely exploratory. A better understanding of variant-specific genotype-phenotype correlations may ultimately refine risk prediction, preventive strategies, and treatment selection in hereditary breast and ovarian cancer.

Accurate interpretation of BRCA1 and BRCA2 variants is essential for meaningful genotype-phenotype correlations and informed clinical decision-making. However, general frameworks such as the ACMG 2015 criteria frequently result in high rates of variants of uncertain significance (VUS), which may generate misleading clinicopathological associations and complicate genetic counseling. We conducted a retrospective analysis of 3,706 individuals tested for BRCA1/2 variants due to BRCA-related malignancies in a large Turkish cohort. Variants were initially classified according to ACMG 2015 criteria and subsequently re-evaluated using ENIGMA consensus recommendations. Clinicopathological data were compared between variant categories before and after reclassification. Pathogenic or likely pathogenic variants were detected in 6.7% of patients, while 3.8% were initially classified as VUS. Following ENIGMA-guided reclassification, a substantial proportion of VUS, particularly missense variants lacking functional impact, were reclassified as benign or likely benign. Clinicopathological differences observed between ACMG-defined pathogenic and VUS groups-including age at onset, tumor distribution, receptor status, and progression-free survival-were eliminated after ENIGMA-based reassessment, revealing biological heterogeneity within the VUS category. Post-reclassification analyses allowed more precise distinction of benign variant profiles, refining genotype-phenotype interpretations. ENIGMA-guided variant interpretation enhances analytical precision, reduces false-positive associations, and improves clinical utility in hereditary breast and ovarian cancer genetics, offering a more reliable framework for genetic counseling and risk assessment in populations with diverse variant spectra.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy where matrix proteins enhance ascites-associated recurrent tumor growth. Elevated focal adhesion kinase (FAK/PTK2) and collagen protein expression support tumor survival, chemoresistance, and immune evasion. However, the sources and regulation of collagen production within HGSOC tumorspheres is unclear. Using CRISPR-mediated FAK knockout and FAK re-expression in two syngeneic HGSOC models (MOVCAR and KMF), FAK loss impaired tumorsphere growth in vitro and in vivo while reducing collagen expression, as determined by RNA sequencing, quantitative RT-PCR, and protein mass spectrometry. FAK re-expression promoted spontaneous metastatic ovarian tumor dissemination. Integrated bioinformatic analyses of MOVCAR, KMF, and HGSOC patient datasets identified 56 common mRNAs co-elevated with PTK2, including COL3A1 and COL5A2. Single-cell RNA sequencing of murine KMF ascites revealed a subset of tumor cells expressing Col3a1 and Col5a2 that exhibited epithelial-to-mesenchymal pathway enrichment that was diminished by genetic or pharmacologic FAK inhibition. In primary HGSOC ascites samples, FAK inhibitor (IN10018 or VS-4718) or FAK protein degrader (PROTAC) treatment selectively reduced COL1A1, COL3A1, and COL5A2 mRNA levels in tumor cells. Further, human OVCAR8 spheroid COL1A1, COL3A1, and COL5A2 mRNA and spheroid structure were significantly impacted by FAK inhibition and blocking anti-α1 or anti-β1 integrin antibodies. As elevated PTK2 and COL3A1 expression correlate with poor ovarian cancer patient survival, and FAK, α1, and β1 integrin inhibition reduced spheroid COL3A1 protein levels, our findings support a feed-forward linkage whereby FAK regulates fibrillar collagen acting in part via collagen binding integrins supporting HGSOC tumorsphere survival and metastatic spread.

Serous ovarian cancer (SOC), a prevalent histological subtype of ovarian cancer, poses a notable global threat to women's health. Ferroptosis has emerged as a pivotal focus in cancer research, presenting a promising novel therapeutic target. The present study aimed to identify key ferroptosis-related genes in SOC and evaluate their clinical implications. Gene expression profiles for SOC were obtained from the Gene Expression Omnibus database. Differential expression analysis and weighted gene co-expression network analysis, in conjunction with ferroptosis-related datasets, identified 22 differentially expressed genes associated with both SOC and ferroptosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated their involvement in critical biological processes and pathways. Protein-protein interaction (PPI) network analysis identified four central hub genes: Kruppel-like factor 2 (KLF2), fatty acid binding protein 4 (FABP4), caveolin 1 (CAV1) and α-synuclein (SNCA). Validation using The Cancer Genome Atlas (TCGA) database confirmed significant downregulation of these genes in SOC (P<0.05), with an assessment of their potential diagnostic value. Peripheral blood samples were collected from 20 patients with SOC (experimental group) and 20 healthy volunteers (control group). Reverse transcription-quantitative PCR demonstrated that KLF2 was significantly downregulated in patients with SOC (P<0.05), while FABP4, CAV1 and SNCA did not show significant differences. Consequently, subsequent experiments concentrated on KLF2. The downregulation of KLF2 was further validated using the Human Protein Atlas database. Kaplan-Meier survival analysis revealed that low KLF2 expression was associated with a poor prognosis in patients with SOC. A nomogram suggested that KLF2 could serve as a prognostic biomarker for SOC. Immune infiltration analysis was performed based on TCGA data. Finally, interaction networks for microRNA-KLF2, transcription factor-KLF2 and chemical-KLF2 were constructed to predict potential molecular mechanisms and therapeutic drugs targeting KLF2 in SOC. These findings indicate that KLF2 may serve as a prognostic and potential therapeutic target related to ferroptosis in serous ovarian cancer, warranting further investigation.

The role of secondary cytoreductive surgery (SCS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in platinum-sensitive recurrent ovarian cancer remains challenging. While chemotherapy (CHT) remains the standard approach, interest has grown in SCS, either with or without HIPEC. Despite promising results, the comparative effectiveness of SCS, SCS + HIPEC, and chemotherapy alone remains controversial, with no trials directly comparing SCS + HIPEC with CHT alone. This systematic review and network meta-analysis included five randomized controlled trials (GOG-0213, DESKTOP III, SOC-1, CHIPOR, and HORSE) identified through PubMed, Embase, Scopus, and Cochrane. The analysis encompassed 1831 patients. A frequentist random-effects network meta-analysis was performed, with CHT as the reference. Heterogeneity was quantified using I 2 . Neither SCS (HR 0.97, 95% CI 0.80-1.19) nor SCS + HIPEC (HR 0.76, 95% CI 0.54-1.08) significantly improved 5-year OS compared to CHT alone (I 2 = 68.4%). Both interventions significantly prolonged 5-year PFS (SCS HR 0.75, 95% CI 0.63-0.88; SCS + HIPEC HR 0.71, 95% CI 0.53-0.94, I 2 = 13.8%). When excluding GOG-0213, SCS + HIPEC significantly improved OS (HR 0.65, 95% CI 0.44-0.94, p = 0.023, I 2 = 0%). For CC-0 patients, SCS + HIPEC and SCS improved both OS and PFS compared to CHT. For CC-1 patients, SCS + HIPEC may be associated with improved OS and PFS, whereas SCS alone may be associated with worse OS. SCS with or without HIPEC is associated with increased PFS and may also increase OS in certain scenarios. The comparison of SCS + HIPEC versus CHT rests on indirect evidence and possible bias given that CHIPOR trial used neoadjuvant chemotherapy. The apparent benefit of SCS + HIPEC in CC-1 patients remain exploratory.

We evaluated the clinical significance of systematic lymph node dissection (SyLND) during interval debulking surgery (IDS) in patients with stage III ovarian cancer, focusing on subgroups that might benefit from SyLND. The multicenter retrospective study included patients with FIGO stage III ovarian, fallopian tube, and primary peritoneal cancers, who underwent IDS following neoadjuvant chemotherapy (NACT), at Gynecologic Cancer Study Group of the Japan Clinical Oncology Group (JCOG-GCSG) institutions between 2017 and 2021. Patients were classified into SyLND and no/selective lymph node dissection (NoLND/SeLND) groups. Progression-free survival (PFS) was the primary outcome, and overall survival (OS) and postoperative complications were secondary outcomes. Inverse probability of treatment weighting was applied. Among 696 eligible patients, SyLND was associated with better PFS (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.55-0.97) and OS (HR 0.66, 95% CI 0.48-0.92) than NoLND/SeLND. In subgroup analyses of patients achieving complete resection, SyLND yielded no survival advantage in those with clinical-negative nodes (cN0). Conversely, among patients with clinical-positive nodes (cN1) before NACT, PFS and OS favored SyLND, although differences were not statistically significant. Similar trends were observed in cN1 patients whose lymph nodes decreased to <10 mm before IDS. SyLND was associated with higher complication rates. SyLND was associated with better PFS and OS in patients with stage III ovarian cancer undergoing IDS. Exploratory subgroup analyses suggested only a favorable but statistically inconclusive trend in patients with cN1. Pre-NACT nodal assessment may help determine the indications for SyLND during IDS.

Most patients with epithelial ovarian cancer (EOC) treated with cisplatin (cDDP) ultimately develop resistance. Owing to its anti-tumor effects and low toxicity, ginsenoside Rg2 (G-Rg2) is regarded as a potential active compound for the chemotherapy of EOC. By leveraging expression profiles of cDDP-sensitive and -resistant EOC patients from GEO datasets, we employed weighted gene co-expression network analysis (WGCNA) to screen for candidate differentially expressed genes relevant to the treatment of cDDP-resistant EOC. Based on this analysis, we identified the key target of G-Rg2 for addressing cDDP resistance in EOC through network pharmacology, clinical data analysis, and molecular docking techniques. Following screening, CACNA1G was selected as the potential target of G-Rg2 for treating cDDP-resistant EOC. Subsequently, G-Rg2 was extracted from American ginseng berry using a chromatographic separation and purification method involving a saturated n-butanol layer. Experimental validation was performed via RNA sequencing, immunostaining, western blot, and flow cytometry in cDDP-resistant EOC cells to ascertain the alterations induced by G-Rg2 treatment. The stereoisomers of G-Rg2 [20(S)-G-Rg2 and 20(R)-G-Rg2] were utilized to treat cDDP-resistant EOC cells, demonstrating that G-Rg2 inhibits CACNA1G-mediated calcium signaling and downstream ERK phosphorylation, processes associated with cell proliferation. Compared to 20(S)-G-Rg2, 20(R)-G-Rg2 exhibited a more significant inhibitory effect on the CACNA1G-mediated calcium influx and downstream signaling, avoiding activation of anti-apoptotic pathways. Collectively, this study elucidates that G-Rg2 inhibits the cell viability of cDDP-resistant EOC by suppressing CACNA1G-mediated calcium signaling pathway, suggesting its potential application as an adjuvant chemotherapy agent for cDDP-resistant EOC.