Cancer Medicine

Retracted: Long non‐coding RNA ARAP1‐AS1 promotes tumorigenesis and metastasis through facilitating proto‐oncogene c‐Myc translation via dissociating PSF/PTB dimer in cervical cancer

AbstractLong non‐coding RNA (lncRNA) is emerging as a pivotal regulator in tumorigenesis and aggressive progression. Here, we focused on an oncogenic lncRNA, ARAP1 antisense RNA 1 (ARAP1‐AS1), which was notably upregulated in cervical cancer (CC) tissues, cell lines and serum. High ARAP1‐AS1 expression was closely associated with larger tumor size, advanced FIGO stage as well as lymph node metastasis. Importantly, it was identified as an effective diagnostic and prognostic biomarker for CC. In vitro and in vivo assays showed that knockdown of ARAP1‐AS1 inhibited, while overexpression of ARAP1‐AS1 promoted CC cell growth and dissemination. Stepwise mechanistic dissection unveiled that ARAP1‐AS1 could directly interact with PSF to release PTB, resulting in accelerating the internal ribosome entry site (IRES)‐driven translation of proto‐oncogene c‐Myc, thereby facilitating CC development and progression. Moreover, c‐Myc was able to transcriptionally activate ARAP1‐AS1 by directly binding to the E‐box motif located on ARAP1‐AS1 promoter. Taken together, our findings clearly reveal the crucial role of ARAP1‐AS1 in CC tumorigenesis and metastasis via regulation of c‐Myc translation, targeting ARAP1‐AS1 and its related regulatory loop implicates the therapeutic possibility for CC patients.

Internal validation of Automated Visual Evaluation (AVE) on smartphone images for cervical cancer screening in a prospective study in Zambia

Abstract Objectives Visual inspection with acetic acid (VIA) is a low‐cost approach for cervical cancer screening used in most low‐ and middle‐income countries (LMICs) but, similar to other visual tests, is subjective and requires sustained training and quality assurance. We developed, trained, and validated an artificial‐intelligence‐based “Automated Visual Evaluation” (AVE) tool that can be adapted to run on smartphones to assess smartphone‐captured images of the cervix and identify precancerous lesions, helping augment VIA performance. Design Prospective study. Setting Eight public health facilities in Zambia. Participants A total of 8204 women aged 25–55. Interventions Cervical images captured on commonly used low‐cost smartphone models were matched with key clinical information including human immunodeficiency virus (HIV) and human papillomavirus (HPV) status, plus histopathology analysis (where applicable), to develop and train an AVE algorithm and evaluate its performance for use as a primary screen and triage test for women who are HPV positive. Main Outcome Measures Area under the receiver operating curve (AUC); sensitivity; specificity. Results As a general population screening tool for cervical precancerous lesions, AVE identified cases of cervical precancerous and cancerous (CIN2+) lesions with high performance (AUC = 0.91, 95% confidence interval [CI] = 0.89–0.93), which translates to a sensitivity of 85% (95% CI = 81%–90%) and specificity of 86% (95% CI = 84%–88%) based on maximizing the Youden's index. This represents a considerable improvement over naked eye VIA, which as per a meta‐analysis by the World Health Organization (WHO) has a sensitivity of 66% and specificity of 87%. For women living with HIV, the AUC of AVE was 0.91 (95% CI = 0.88–0.93), and among those testing positive for high‐risk HPV types, the AUC was 0.87 (95% CI = 0.83–0.91). Conclusions These results demonstrate the feasibility of utilizing AVE on images captured using a commonly available smartphone by nurses in a screening program, and support our ongoing efforts for moving to more broadly evaluate AVE for its clinical sensitivity, specificity, feasibility, and acceptability across a wider range of settings. Limitations of this study include potential inflation of performance estimates due to verification bias (as biopsies were only obtained from participants with visible aceto‐white cervical lesions) and due to this being an internal validation (the test data, while independent from that used to develop the algorithm was drawn from the same study).

HPV16 E6 promoting cervical cancer progression through down‐regulation of miR‐320a to increase TOP2A expression

AbstractBackgroundCervical cancer (CC) has become the fourth most common cancer worldwide and it is mainly caused by the infection of human papillomavirus (HPV), especially high‐risk HPV16. Aberrant miRNA expression in CC is closely related to HPV16 infection, and the regulation of HPV16 E6 expression can affect a variety of miRNA expression. This study aims to exploring the miRNAs involved in E6 regulation in CC.MethodsOur study screened differentially expressed miRNAs in cervical cells of HPV16 infected and uninfected cervical cancer patients by analyzing the GSE81137 dataset of the gene expression omnibus database (GEO), and identified miR‐320a that plays an anti‐tumor role and is associated with good prognosis of cervical cancer. Explore the effect of HPV16 E6 on the expression of miR‐320a in cervical cancer, and verify whether HPV16 E6 regulates the downstream target gene TOP2A expression through miR‐320a, thereby affecting cervical cancer cell proliferation, apoptosis, migration, invasion, and EMT in vitro and in vivo.ResultsThe bioinformatic methods selected the miR‐320a, which was differentially expressed in cervical cells from HPV16‐infected patients compared to uninfected patients. We further demonstrated that miR‐320a level was regulated by HPV16 E6, which promoted the CC cell proliferation, migration, invasion, and inhibited apoptosis. In addition, we predicted the downstream target genes of miR‐320a and confirmed that TOP2A was one of its targeting proteins. Moreover, HPV16 E6 promoted the TOP2A expression in CC cells through down‐regulating miR‐320a, leading to promoting CC development.ConclusionsWe confirmed that HPV16 E6 promoted the TOP2A expression through down‐regulation of miR‐320a, thus promoting CC development, and the HPV16 E6/miR‐320a/TOP2A axis may perform as a potential target for CC treatment.

LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy

ABSTRACT Background Cervical cancer remains a significant health burden for women worldwide, with persistent high‐risk HPV infection being a major etiological factor. Despite treatment advances, prognosis for recurrent or metastatic disease remains poor. Pyroptosis, a form of programmed cell death, plays a dual role in tumor immunity, but its implications in cervical cancer are not fully elucidated. This study aims to systematically characterize pyroptosis‐related genes (PRGs) in cervical cancer and explore their prognostic and therapeutic relevance. Methods Multi‐omics data from TCGA and GEO databases were integrated to analyze genetic variations, expression patterns, and prognostic significance of 52 PRGs in cervical cancer. Consensus clustering was used to identify PRG subtypes. A prognostic risk score model was constructed using LASSO‐Cox regression based on differentially expressed genes (DEGs). Functional validation was performed via in vitro and in vivo experiments, including Western blot, CCK‐8, colony formation, transwell assays, and a subcutaneous tumor model. Single‐cell RNA sequencing data (GSE171894, GSE168652) were analyzed to explore LAG3 expression in the tumor immune microenvironment. Results Two distinct PRG subtypes were identified, with subtype A showing immune activation features. A five‐gene prognostic signature (GNAZ, LAG3, IL‐1β, CA2, SPRR3) effectively stratified patients into high‐ and low‐risk groups. Low LAG3 expression was associated with poor prognosis. Functional experiments demonstrated that LAG3 overexpression suppressed cervical cancer cell proliferation, migration, and tumor growth, while its knockdown promoted malignant phenotypes. Single‐cell analysis revealed high LAG3 expression in Treg and CD8⁺ T cells, suggesting its role in immune regulation. Conclusion This study establishes a novel PRG‐based prognostic model and highlights LAG3 as a key tumor suppressor and immune regulator in cervical cancer. These findings provide insights into the interplay between pyroptosis and antitumor immunity, supporting LAG3 as a potential therapeutic target for cervical cancer immunotherapy.

Weekly Image Guidance in Patients With Cervical Cancer Treated With Intensity‐Modulated Radiation Therapy: Results of a Large Cohort Study

ABSTRACTBackgroundImage guidance is recommended for patients undergoing intensity‐modulated radiation therapy (IMRT) for cervical cancer. In this study, we evaluated the feasibility of a weekly image guidance pattern and analyzed the long‐term outcomes in a large cohort of patients.MethodsThe study enrolled patients with Stage IB‐IVA cervical cancer who received definitive radiotherapy or concurrent chemoradiotherapy. IMRT was delivered at a dose of 50.4 Gy in 28 fractions, with weekly cone‐beam computed tomography (CBCT). Physicians advised patients on rectum and bladder preparation to help them prepare on nonimaging guidance days. When significant tumor regression was observed, a second computed tomography simulation and replanning were performed.ResultsThe median follow‐up periods were 63.4 months. The incidence rates of loco‐regional and distant failure were 9.9% and 13.6%. The 5‐year overall survival (OS), disease‐free survival (DFS), loco‐regional relapse‐free survival (LRFS), and distant metastasis‐free survival (DMFS) rates were 80.1%, 72.9%, 78.3%, and 74.8%, respectively. For patients with different stages, the 5‐year OS, DFS, LRFS, and DMFS rates were statistically significant. For patients with and without positive regional lymph nodes, the 5‐year OS, DFS, LRFS, and DMFS rates were 64.5% and 86.0%, 56.8% and 78.8%, 62.7% and 84.3%, and 58.8% and 81.0%, respectively. Multivariate analysis showed that age, histology, tumor size, cancer stage, pretreatment squamous cell carcinoma antigen level, and para‐aortic metastatic lymph nodes were independent prognostic factors of OS. Fifty‐six (4.0%) patients experienced late Grade 3/4 chronic toxicities.ConclusionsIMRT with weekly CBCT is an acceptable image guidance strategy in countries with limited medical resources.

Prediction value with a novel and accurate tissue‐based human papillomavirus detection method in low‐grade squamous intraepithelial lesions

AbstractBackgroundThe progression rate from CIN1 to CIN3 is 9.0% and that for invasive cancer is 1.0%. The large majority of CIN1 lesions regress spontaneously, and the treatment of CIN1 is still controversial.AimsThe aim of this study is to investigate the responsible HPV genotype in the low‐grade SILs, then to predict the presence of high‐grade SILs, and determine whether further treatment is needed.MethodsWe use the methods of manual microdissection with FFPE tissue specimens and the E6/E7 uniplex polymerase chain reaction (PCR) to detect HPV in the lesions.ResultsThe HPV test was performed on 72 biopsy tissue specimens, and 55 (76.4%, 55/72) of them were HPV positive. Nine (16.4%, 9/55) of them escalated to CIN2 after LEEP or cervical conization, and 46 (83.6%, 46/55) were still CIN1. There were 17 (23.6%, 17/72) cases with HPV‐negative results in cervical biopsy tissues.HPV test of cervical biopsy diagnosed with CIN1 has a positive predictive value of 16.4% in the presence of CIN2 or higher lesions, a negative predictive value of 94.1%, a specificity of 25.8%, and a sensitivity of 90.0%. HPV test of cervical biopsy tissues for the prediction of HPV infection in LEEP or cone surgery tissues had a positive predictive value of 80.0%, a negative predictive value of 82.3%, a specificity of 56.0%, and a sensitivity of 93.6%.ConclusionsIt is the first time that we have detected HPV genotype in the low‐grade SILs by the methods of manual microdissection with FFPE tissue specimens and the E6/E7 uniplex PCR. Patients with cervical biopsy tissue diagnosed with CIN1 and with a negative or only low‐risk HPV type result can be considered for follow‐up. Conversely, in cases of cervical biopsy tissue diagnosed with CIN1 positive for high‐risk HPV, surgery or a close follow‐up program can be selected.

A novel nomogram based on inflammation biomarkers for predicting radiation cystitis in patients with local advanced cervical cancer

AbstractBackgroundsPlatelet‐to‐albumin ratio (PAR) is a new systemic inflammatory prognostic indicator associated with many inflammatory diseases. However, its role in radiation cystitis (RC) is obscure. This study aimed to explore whether PAR could be used as an effective parameter for predicting the RC risk in local advanced cervical cancer (CC) treated with radiotherapy.MethodsA total of 319 local advanced CC patients who received radical radiotherapy at Fujian Cancer Hospital were enrolled between December 2018 and January 2021. Demographics and clinical parameters were retrospectively analyzed. Univariate and multivariate analyses were used to identify the risk factors for RC. Backward and stepwise regression was applied to construct two monograms‐one with primary significant factors and the other with extra inflammatory biomarkers. A DeLong test was applied to compare the prediction abilities of two nomograms. Calibration curves and decision curve analysis (DCA) evaluated its prediction consistency, discrimination ability, and clinical net benefit.ResultsUnivariate analysis showed that age, tumor size, stage, total radiation dose, pelvic radiation dose, Systemic Immune‐Inflammation Index (SII), platelet‐to‐lymphocyte ratio (PLR), and PAR were significantly associated with RC occurrence (all p < 0.05). Multivariate analyses indicated that age, tumor size, stage, total radiation dose, and PAR were independent factors (all p < 0.05). Then, the area under curve (AUC) value of the nomogramSII+PAR was higher (AUC = 0.774) compared to that of the baseline nomogram (AUC = 0.726) (pDelong = 0.02). Also, the five‐cross validation confirmed the stability of the nomogramSII+PAR. Moreover, the calibration curve and DCA exhibited the nomograms' good prediction consistency and clinical practicability.ConclusionsPAR and SII could be valued for CC patients who are treated with radiation therapy. The nomogram based on PAR and SII could stratify patients who need extra intervention and nursing care to prevent bladder radiation damage and improve patients' quality of life.

Efficacy and safety of low‐dose apatinib in ovarian cancer patients with platinum‐resistance or platinum‐refractoriness: A single‐center retrospective study

AbstractBackgroundThis study aimed to evaluate the efficacy and safety of apatinib with a low dose of 250 mg/d in the treatment of platinum‐resistant or platinum‐refractory ovarian cancer patients.MethodsPatients with platinum‐resistant or platinum‐refractory ovarian carcinoma treated with 250 mg/d apatinib in our institution from November 2016 to December 2017 were retrospectively reviewed. The tumor response and progression were evaluated according to the standard by incorporating the levels of CA125 and Response Evaluation Criteria in Solid Tumors 1.1. CTCAE 4.03 was used to evaluate adverse events (AEs).ResultsFifty‐two eligible patients were enrolled in per‐protocol (PP) analysis and 65 patients (including 13 lost to follow‐up) were included in the intention‐to‐treat (ITT) analysis. In PP analysis, 18 patients (34.6%) had partial response (PR), 22 patients (42.3%) had stable disease (SD), and the disease control rate (DCR) was 61.5%. Median progression‐free survival (PFS) was 4.0 months (95% CI, 2.83‐5.17 m), and median overall survival (OS) was 25.33 months (95% CI, 17.74‐32.92 m). The objective response rate and DCR for patients in ITT analysis were 27.7% and 49.2%, respectively. The top three treatment‐related AEs were hypertension, hand‐foot syndrome, and leukopenia. Eight patients (15.4%) in PP population had grade 3 treatment‐related AEs. Previous chemotherapy lines, number of recurrences, and AEs did not affect the efficacy of apatinib. Age older than 60 was associated with higher rates of disease control and prolonged PFS (P < .05).ConclusionApatinib 250 mg/d is a feasible treatment in platinum‐resistant or platinum‐refractory epithelial ovarian cancer (EOC) patients.

Associations of insulin resistance and inflammatory biomarkers with endometrial cancer survival: The Alberta endometrial cancer cohort study

AbstractBackgroundMetabolic dysfunction and inflammation have been associated with endometrial cancer risk; however, their influence on endometrial cancer survival is less understood.MethodsA prospective cohort study of 540 endometrial cancer cases diagnosed between 2002 and 2006 in Alberta were followed for survival outcomes to 2019. Baseline blood samples collected either pre‐ or post‐hysterectomy were analyzed for glucose, insulin, adiponectin, leptin, tumor necrosis factor‐α, interleukin‐6, and C‐reactive protein. Covariates were obtained during in‐person interviews and via medical chart abstraction. Cox proportional hazard regression models were used to estimate multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between each biomarker and disease‐free and overall survival.ResultsBlood samples were collected from 520 of the 540 participants (presurgical n = 235; postsurgical n = 285). During the median follow‐up of 14.3 years (range 0.4–16.5 years), there were 125 recurrences, progressions, and/or deaths with 106 overall deaths. None of the biomarkers were associated with disease‐free or overall survival in multivariable‐adjusted analyses. In an exploratory stratified analysis, the highest level of presurgical adiponectin, compared to the lowest level, was associated with improved disease‐free (HR = 0.42, 95% CI = 0.20–0.85) and overall (HR = 0.41, 95% CI = 0.18–0.92) survival, whereas no statistically significant associations were noted for postsurgical measures of adiponectin.ConclusionsOverall, there was no evidence of an association between biomarkers of insulin resistance and inflammation with mortality outcomes in endometrial cancer survivors. Future cohort studies with serial blood samples are needed to understand the impact of changes in insulin resistance and inflammatory markers on endometrial cancer survival.

PD‐L1, PARP1, and MMRs as potential therapeutic biomarkers for neuroendocrine cervical cancer

AbstractObjectiveNeuroendocrine cervical cancer (NECC) is a rare cervical cancer with high aggressivity that causes poor prognosis even in the early stage. Given other neuroendocrine carcinomas and other types of cervical cancer have been proved to have expression of programmed cell death protein 1 ligand 1(PD‐L1) and poly ADP‐ribose polymerase‐1(PARP1), we would measure and analyze these proteins in this invasive cancer. The purpose of this study is to investigate the application value of PD‐1/PD‐L1 and PARP1 inhibitors in NECC.MethodsThe NECC cases in our center with formalin‐fixed paraffin‐embedded tissue blocks were collected, and immunohistochemical (IHC) staining of PD‐L1, PARP1, Mismatch repair proteins (MMRs), and P53 was performed. Chi‐square test was used to analyze associations between various protein expressions. We analyzed the efficacy of immunotherapy in a recent patient with secondary recurrence after two courses of chemotherapy.ResultsAfter rigorous screening, 20 cases were finally included. Three cases did not undergo surgical treatment because of their advanced stage. Twelve (60%) developed distant metastases or relapsed within five years, and most of them within two years. The positive rate of PD‐L1 and PARP1 were 70% and 75% respectively. Among all the cases, microsatellite instability (MSI) was seen in six cases (30%) and abnormal p53 expression was in 15 patients (75%). PD‐L1 was associated with PARP1 expression in the MSI subgroup. The patient treated with chemotherapy + VEGF inhibitor (VEGFi) + programmed cell death protein 1(PD‐1) inhibitor had an excellent improvement in clinical symptoms, tumor markers, and mass size.ConclusionThe IHC results of PD‐L1, PARP1, and MMRs suggested that NECC was the target of immunotargeted therapy. Our case confirmed that immune checkpoint therapy was effective in patients with PD‐L1 positive and MMRs loss. Considering the clinical practicability, more cases should be collected, and effective biomarkers still need to be further searched.

Opportunistic Salpingectomy in Non‐Gynecologic Surgeries: Barriers and Facilitators From a Healthcare Provider Perspective

ABSTRACT Objective This study identifies barriers and facilitators for implementing opportunistic salpingectomy (OS) during non‐gynecological abdominal surgeries from a healthcare provider perspective. Methods From October 2023 to July 2024, a mixed‐method study was conducted. The qualitative phase involved semi‐structured focus group interviews and individual interviews with specialists in surgery (gynecologists, general surgeons, urologists, and residents) and policymakers to identify barriers and facilitators for implementing OS during non‐gynecological surgery. The quantitative phase consisted of a cross‐sectional web‐based survey assessing the importance of these barriers and facilitators. The study utilized the standardized implementation frameworks to categorize the factors into six domains: innovation, patient, healthcare professional, social setting, organization, and economic and financial context. Results In the qualitative phase, 38 healthcare professionals and policymakers identified 38 barriers and 28 facilitators. Barriers were found in all domains and mainly included increased workload, unclear invoicing, and variations in eligible surgeries. Facilitators included the poor prognosis of ovarian cancer, simplicity of OS, and availability of counseling materials. The quantitative survey revealed that 75% of gynecologists, 60% of surgeons, and 61% of urologists supported offering OS during non‐gynecological abdominal surgeries. Barriers identified included the ambiguity regarding which patients are eligible for OS, the perceived complication risks of OS, the increased workload as a result of adding OS, and the unclarity around invoicing an OS. Facilitators included the poor prognosis of ovarian cancer, the availability of uniform counseling materials, education on counseling and technical performance of OS, involvement of a gynecologist during the counseling, and clear agreements between the departments within hospitals. Conclusions Key barriers to OS implementation in non‐gynecological surgeries include unclear invoicing and increased workload, while significant facilitators are the availability of counseling materials and education on counseling and technical performance of OS. Addressing these barriers and leveraging facilitators could enhance OS adoption, potentially reducing ovarian cancer incidence.

High Prevalence of Human Papillomavirus in Vulvar Cancer Among Vietnamese Women: Implications for Vaccination Strategies

ABSTRACTBackgroundVulvar cancer (VC) is rare; however, its incidence has steadily increased, likely due to increased human papillomavirus (HPV) infections. HPV infection rates vary significantly with age and ethnicity. Data on the VC incidence in Vietnam are limited.ObjectivesThis study aimed to determine HPV infection rates and high‐risk HPV types (HR‐HPVs) and to model HPV causality in co‐infections using a Proportional Attribution (PropAttr) model in Vietnamese VC patients.MethodsWe investigated primary VC cases (invasive carcinoma) diagnosed at our hospital during 2020–2021. Tumor samples were tested for HPV using quantitative polymerase chain reaction. Recurrent cases and poor‐quality preserved tumor samples were excluded. HPV infection status, HR‐HPV status, and relevant clinicopathological features were analyzed. To estimate the most likely causative HPV genotype in co‐infected lesions, the PropAttr model was applied, attributing genotypes based on their prevalence in mono‐infections. Model reliability was validated using Spearman's correlation analysis.ResultsOf the 95 cases, 95% were squamous cell carcinoma, and 40% were clinical stage I. The HPV infection rate was approximately 77% (68.4–85.2), and HPV‐16 was the most common subtype. Patients infected with HPV (mean age: 62.8) were younger than those who were not infected (mean age: 71.4) in univariate (p = 0.004) and multivariate (p < 0.001) analyses. While the vulvar pathohistological type was significantly associated with HPV infection in multivariate analysis (p < 0.001), no significant relationship was observed with other factors in univariate and multivariate analyses. The PropAttr model showed significant correlations between attribution estimates and mono‐infection prevalence (HPV‐16: ρ = 0.806, p < 0.001; HPV‐18: ρ = 0.992, p < 0.001; 12 other HR‐HPVs: ρ = 0.880, p < 0.001). A strong negative correlation between HPV‐16 and 12 other HR‐HPVs (ρ = −0.751, p < 0.001) suggested competitive interactions in genotype assignment.ConclusionsThe HPV infection rate in Vietnamese VC cases was substantially higher than in other Asian populations, indicating a significant public health burden. Our findings reinforce the importance of expanding national HPV vaccination programs and incorporating advanced attribution models to improve HPV‐related cancer risk assessment.

Sensitivity of Platinum‐Based Chemotherapy and Efficacy of Arsenic Trioxide‐Based Non‐Platinum Chemotherapy Following the Progression of PARPi Maintenance Therapy: A Real‐World Study

ABSTRACT Background Cross‐resistance is observed between platinum and Poly (ADP‐ribose) polymerase inhibitors (PARPi). We aim to propose the definition of PARPi resistance and demonstrate the best therapeutic strategy for patients with PARPi resistance. Methods A retrospective analysis was performed on patients diagnosed with epithelial ovarian cancer from October 2015 to November 2022. Patients were treated with PARPi for more than 6 months and received chemotherapy after progression. Results Totally, 41 patients were enrolled, with 21 receiving PARPi for 6 to 12 months and 20 for more than 12 months. The median duration of PARPi was 12 months, and the median time to second progression (TTSP) was 3.45 months (range, 1.0–20.2 months). The Kaplan–Meier and Cox analysis revealed a significantly shorter TTSP for patients who received PARPi for more than 12 months compared to those for 6 to 12 months. After PARPi resistance, 34 (82.9%) received platinum‐based chemotherapy, with an overall response rate (ORR) of 26.5% (9/34). Seven patients (17.1%) received arsenic trioxide (ATO)‐based chemotherapy, with an ORR of 57.1% (4/7). During subsequent chemotherapy, 12/34 patients switched to ATO‐based chemotherapy due to progression, of which five cases were evaluated as effective (41.7%). Conclusion PARPi resistance has a negative impact on the subsequent chemotherapy. The progression of the disease beyond 6 to 12 months should be considered as acquired resistance. Non‐platinum chemotherapy, such as ATO‐based combined sequential chemotherapy, may emerge as the preferred option for patients with PARPi resistance.

A Review on Biomarker‐Enhanced Machine Learning for Early Diagnosis and Outcome Prediction in Ovarian Cancer Management

ABSTRACT Background Ovarian cancer (OC) remains the most lethal gynecological malignancy, largely due to its late‐stage diagnosis and nonspecific early symptoms. Advances in biomarker identification and machine learning offer promising avenues for improving early detection and prognosis. This review evaluates the role of biomarker‐driven ML models in enhancing the early detection, risk stratification, and treatment planning of OC. Methods We analyzed literature spanning clinical, biomarker, and ML studies, emphasizing key diagnostic and prognostic biomarkers (e.g., CA‐125, HE4) and ML techniques (e.g., Random Forest, XGBoost, Neural Networks). The review synthesizes findings from 17 investigations that integrate multi‐modal data, including tumor markers, inflammatory, metabolic, and hematologic parameters, to assess ML model performance. Findings Biomarker‐driven ML models significantly outperform traditional statistical methods, achieving AUC values exceeding 0.90 in diagnosing OC and distinguishing malignant from benign tumors. Ensemble methods (e.g., Random Forest, XGBoost) and deep learning approaches (e.g., RNNs) excel in classification accuracy (up to 99.82%), survival prediction (AUC up to 0.866), and treatment response forecasting. Combining CA‐125 and HE4 with additional markers like CRP and NLR enhances specificity and sensitivity. However, limitations such as small sample sizes, lack of external validation, and exclusion of imaging/genomic data hinder clinical adoption. Conclusion Biomarker‐driven ML represents a transformative approach for OC management, improving diagnostic precision and personalized care. Future research should prioritize multi‐center validation, multi‐omics integration, and explainable AI to overcome current challenges and enable real‐world implementation, potentially reducing OC mortality through earlier detection and optimized treatment.

Risk Assessment and Fertility Counseling for Hereditary Gynecological Cancer Syndromes

ABSTRACT Objective To review the genetic basis, clinical characteristics, and management strategies of hereditary gynecologic cancers associated with hereditary cancer syndromes. Methods Literature on germline mutations, inheritance patterns, clinical manifestations, and fertility preservation strategies was reviewed. Results Germline pathogenic mutations, predominantly inherited in an autosomal dominant manner, increase susceptibility to gynecologic tumors with varying risks. Genomic sequencing has facilitated identification of high‐risk individuals, underscoring the importance of tailored prevention, early detection, and treatment. Standardized counseling supports risk assessment, fertility preservation, and the formulation of individualized management strategies. Conclusion Comprehensive genetic counseling and precision‐based approaches are essential for effective prevention, diagnosis, and treatment of hereditary gynecologic cancers, while also addressing fertility preservation in affected patients.

TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation

AbstractBackgroundOvarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown.AimsThe aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer.Materials and MethodsWe used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co‐immunoprecipitation and western blotting.ResultsTRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression.DiscussionTRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer.ConclusionTRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.

Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In Vitro Analysis

ABSTRACTBackgroundOvarian cancer (OC) remains one of the most lethal gynecological malignancies, characterized by late‐stage diagnosis and high recurrence rates. Despite advances in treatment, the overall survival rate for OC patients remains low due to the lack of reliable biomarkers for early detection and prognosis. Thus, there is an urgent need for novel diagnostic and prognostic biomarkers to improve patient outcomes. In this study, we explored the potential role of the KCTD (Potassium Channel Tetramerization Domain‐containing) family genes in OC.MethodsThis study utilized comprehensive in silico and in vitro experiments.ResultsFirstly, we analyzed the expression patterns of KCTD genes across 12 OC cell lines and 6 normal control cell lines using RT‐qPCR, identifying significant upregulation of KCTD5, KCTD9, KCTD12, and KCTD16, while KCTD2, KCTD10, KCTD15, and KCTD21 were downregulated. ROC analysis revealed high diagnostic accuracy for KCTD2, KCTD5, KCTD9, and KCTD12. Further stage‐specific analysis indicated that KCTD2, KCTD5, KCTD15, and KCTD21 are associated with OC progression. Functional assays in SKOV3 and A2780 cells demonstrated that overexpression of KCTD2 and KCTD10 significantly inhibited cell proliferation, migration, and colony formation, suggesting their tumor‐suppressive roles. Immune and drug sensitivity analyses revealed that KCTD genes may influence immune evasion and chemoresistance in OC. Additionally, miRNA analysis identified potential regulatory mechanisms of KCTD expression.ConclusionCollectively, our findings indicate that KCTD family members serve as promising biomarkers, offering new insights into therapeutic strategies for OC management. Further validation in clinical settings is essential to establish their potential as therapeutic targets.

Development and Validation of Predictive Risk Scores for Ovarian Clear Cell Carcinoma: A Penalized Regression Model

ABSTRACT Background The precision management of ovarian clear cell carcinoma (OCCC) faces limitations due to the absence of personalized prognostic tools. This study aimed to establish predictive risk scores to enable effective stratification and tailored treatment of OCCC. Methods Retrospective data from 206 OCCC patients treated between 2004 and 2019 at two hospitals were analyzed. Penalized regression models were utilized to develop three risk scores based on preoperative laboratory results and intraoperative findings. These scores underwent internal and external validation. Results The median follow‐up periods were 65.7 and 44.0 months for the derivation and validation cohorts, respectively. In internal validation with the derivation cohort, all three risk scores effectively identified the high‐risk group for tumor recurrence. Upon validation with the external cohort, Risk Score 3, which incorporated variables selected in most cross‐validations by the penalized regression (Elastic Net), distinctly differentiated the high‐ and low‐risk groups ( p  = 0.03). Risk Score 2, consisting solely of preoperatively available variables, also demonstrated marginal significance ( p  = 0.08). Conclusion Our findings underscore the significance and utility of the developed risk scores in tailoring personalized treatments for patients with OCCC.

External Validation of Lung Cancer Prediction Models Combining Epidemiological Predictors in Chinese Ever and Never Smokers: Guangzhou Biobank Cohort Study

ABSTRACT Objective This study aimed to externally validate existing lung cancer models using data from the Guangzhou Biobank Cohort Study (GBCS) and compare their predictive performance for Chinese ever and never smokers. Methods We evaluated the discrimination and calibration of LCRAT (Lung Cancer Risk Assessment Tool), LLP version 2 (Liverpool Lung Project version 2), LLP version 3 (Liverpool Lung Project version 3), HUNT (HUNT was derived from the Nord‐Trøndelag Health Study), OWL (Optimized Early Warning Model for Lung Cancer Risk), LCRS (Lung Cancer Risk Score), PLCOm2012 (Prostate, Lung, Colorectal, and Ovarian 2012 model), PLCOall2014 (Prostate, Lung, Colorectal, and Ovarian 2014 model), NHIS (Korean National Health Insurance Service), LLPi (Liverpool Lung Project Risk Prediction Model for Lung Cancer Incidence), Pittsburgh, and Bach models. We compared the performance of models and Chinese lung cancer screening (T/CPMA 013‐2020), US Preventive Services Task Force 2021 (USPSTF‐2021) and Nederlands–Leuvens Longkanker Screenings Onderzoek (NELSON) criteria. Results The LLP version 2, LLP version 3, OWL, LCRS, PLCOall2014, and LLPi models showed better performance in ever smokers than in never smokers, with higher AUC (0.72–0.82 vs. 0.69–0.71) and E/O (expected to observed) ratios (0.57–0.79 vs. 0.60–0.69), while the LCRAT, HUNT, PLCOm2012, NHIS, Pittsburgh, and Bach models showed good performance in ever smokers, with AUC ranging from 0.70 to 0.79 and E/O ratios from 0.57 to 0.75. The T/CPMA 013‐2020, USPSTF‐2021, and NELSON criteria identified 56.52%–75.58% of high‐risk individuals at 5, 6, 6.6, 8.7, and 10 years, while the LCRAT, LLP version 2, LLP version 3, HUNT, OWL, LCRS, PLCOm2012, PLCOall2014, NHIS, LLPi, Pittsburgh, and Bach models identified 70.70%–89.72% of high‐risk individuals. Conclusions Most lung cancer risk prediction models showed good performance and identified more cases than screening criteria. Replacing screening criteria with risk prediction models may increase lung cancer screening efficiency.

Nationwide Genomic Data Analysis of Japanese Prostate Cancer Patients From C‐ CAT Database

ABSTRACT Purpose Prostate cancer is a leading malignancy among men, and genomic alterations are known to impact disease progression and treatment response. However, racial and ethnic differences may influence genomic profiles, necessitating population‐specific analyses. This study aimed to characterize the genomic landscape and its clinical significance in Japanese patients with treatment‐resistant, unresectable prostate cancer using data from the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) database. Methods We analyzed data from patients with advanced or metastatic prostate cancer who had progressed after standard therapies and underwent comprehensive genomic profiling between 2019 and 2022. We assessed the frequency of genomic alterations, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Associations between genomic features and clinical outcomes were also examined. Results A total of 2634 patients were included. Family history was reported in 12.5% for prostate cancer, 1.5% for breast cancer, 5.2% for pancreatic cancer, and 1.1% for ovarian cancer. AR gene alterations were observed in 18% of patients. TP53 and BRCA2 mutations were identified in 34% and 12% of cases, respectively. Mutations in TP53 , as well as alterations in genes related to the cell cycle, epigenetic regulation, MYC signaling, and the PI3K pathway, were associated with poorer overall survival. Conclusions This study provides a comprehensive overview of genomic alterations in advanced prostate cancer among Japanese patients and identifies key mutations linked to prognosis. These findings highlight the value of personalized prognostic assessment based on genomic profiling to guide clinical decision‐making in this population.

Tumor‐Infiltrating Lymphocytes in Breast and Female Genital Tract Cancers: Overlooked Potential and Unexplored Frontiers

ABSTRACTBackgroundThe growing success of cancer immunotherapies has led to significant advances in oncology. However, despite these promising developments, cancer‐related mortality remains high for common cancer types such as breast and lower female genital tract cancers.MethodHere, we synthesize recent findings on the prognostic relevance of tumor‐infiltrating lymphocytes (TILs) in breast, endometrial, tubo‐ovarian, and vulvar cancer. Our analysis covers the relationship between TIL counts and density, immune cell subtype combinations, immunotherapy approaches, and patient outcomes.ResultsHigh TIL infiltration, especially CD8+ T‐cells, generally correlates with improved outcomes such as in endometrial cancer (especially the POLE‐ultramutated subgroup), invasive breast cancer, and ovarian epithelial tumors. However, in ductal carcinoma in situ (DCIS) of the breast, elevated TIL counts are linked to a worse prognosis. Ethnicity, the tumor microenvironment (TME), and molecular profiles further complicate the prognostic utility of TILs.ConclusionsTIL‐based therapies have shown potential in personalized immunotherapy, particularly in recurrent, refractory ovarian cancer. Limited research on rarer gynecologic tumors hinders broader clinical applications.

Survivorship research in advanced gynecological cancer: A scoping review of cohort studies

AbstractBackgroundRecent calls to action highlight the need to address gaps in our understanding of survivorship for those living with advanced gynecological cancer to support optimal care. To ensure future research fills these knowledge gaps, we need to understand the breadth of existing survivorship research in this patient group, including the outcomes assessed, the populations included and the duration and retention in follow‐up.MethodsWe conducted a systematic scoping review searching PubMed, PsychINFO, and CINAHL during the month of November 2022 to identify prospective cohort studies measuring survivorship outcomes among participants with advanced (stage III–IV) gynecological cancer, or in cohorts in which ≥50% of participants had advanced cancer, or which provide results separately for patients with advanced cancer. Articles were screened, and data extracted using a standard form.ResultsWe assessed 33 articles from 21 unique studies, which overall included 6023 participants with gynecological cancer. Of these, 45% had cervical cancer, 44% ovarian, 10% endometrial/uterine, and 1% vaginal/vulvar cancer. The most frequently measured survivorship outcome was quality of life. Of the 33 articles, most reported on participant age (n = 31), but relatively few reported on comorbidities (n = 10), physical status (n = 6), ethnic background (n = 4), the country of birth (n = 2), or the area of participant residence (n = 2). None included details on indigenous status. Recruitment proportions ranged from 48% to 100%. Retention proportions ranged from 15% to 97%.ConclusionOur findings highlight gaps in survivorship research for advanced gynecological cancers and emphasize the need for future studies to include and describe the experiences of diverse and underrepresented groups.

Pan‐Cancer Single‐Cell Transcriptomic Analysis Reveals Divergent Expression of Embryonic Proangiogenesis Gene Modules in Tumorigenesis

ABSTRACT Background Angiogenesis is indispensable for the sustained survival and progression of both embryonic development and tumorigenesis. This intricate process is tightly regulated by a multitude of pro‐angiogenic genes. The presence of gene modules facilitating angiogenesis has been substantiated in both embryonic development and the context of tumor proliferation. However, it remains unresolved whether the pro‐angiogenic gene modules expressed during embryonic development also exist in tumors. Methods This study performed a pan‐cancer single‐cell RNA sequencing (scRNA‐seq) analysis on samples from 332 patients across seven cancer types: thyroid carcinoma, lung cancer, breast cancer, hepatocellular carcinoma, colorectal cancer, ovarian carcinoma, and prostate adenocarcinoma. Data processing was carried out using the Seurat R package, with rigorous quality control to filter high‐quality cells and mitigate batch effects across datasets. We used principal component analysis (PCA), shared nearest neighbor graph‐based clustering, and Uniform Manifold Approximation and Projection (UMAP) to visualize cell types and identify distinct cell clusters. Myeloid cell subpopulations were further analyzed for the expression of embryonic pro‐angiogenic gene modules (EPGM) and tumor pro‐angiogenic gene modules (TPGM). Results The analysis identified nine major cell types within the tumor microenvironment, with myeloid cells consistently exhibiting elevated expression of both tumor pro‐angiogenic gene modules (TPGM) and EPGM across all tumor types. In particular, myeloid cells, including macrophages and monocytes, showed high EPGM expression, indicating an active role of embryonic pro‐angiogenesis pathways in tumors. A subset analysis revealed 20 distinct myeloid subtypes with varying EPGM and TPGM expression across different cancers. Treatment and disease stage influenced these gene expressions, with certain subtypes, such as HSPAhi/STAT1+ macrophages in breast cancer, displaying reduced pro‐angiogenic gene activity post‐treatment. Conclusion This study provides evidence that tumors may exploit EPGM to enhance vascularization and support sustained growth, as evidenced by the elevated EPGM expression in tumor‐associated myeloid cells. The consistent presence of EPGM in TAMs across multiple cancer types suggests a conserved mechanism wherein tumors harness embryonic angiogenic pathways to facilitate their progression. Distinct EPGM expression patterns in specific myeloid cell subsets indicate potential therapeutic targets, particularly in cases where EPGM activation contributes to resistance against anti‐angiogenic therapies. These findings shed new light on the molecular mechanisms underlying tumor angiogenesis and highlight the prognostic relevance of EPGM expression in cancer, underscoring its potential as a biomarker for clinical applications.

KPNA5 Suppresses Malignant Progression of Ovarian Cancer Through Importing the PTPN4 Into the Nucleus

ABSTRACTBackgroundAbnormal protein localization due to disrupted nucleoplasmic transport is common in tumor cells, but its mechanisms are not well understood. Nuclear pore complexes and nuclear transporter proteins are crucial for protein transport between the nucleus and cytoplasm. Evidence increasingly shows that abnormal expression of karyopherin family proteins disrupts protein translocation, affecting processes like cell differentiation, proliferation, apoptosis, and transcriptional regulation. However, their functions and roles in ovarian cancer remain unclear.MethodsThe expression level of KPNA5 in ovarian cancer tissues and cells was detected by IHC, Western blot, and qPCR. CCK‐8 and colony formation assays were used to assess cell proliferation ability. Transwell assay was conducted to determine cell migration and invasion capacity. A xenograft model was used to assess the effect of KPNA5 on tumor growth in vivo.ResultsKPNA5 expression is downregulated in ovarian cancer (OC) tissues. Low KPNA5 levels were associated with poor survival in OC patients, validated by an OC tissue sample cohort. Overexpression of KPNA5 significantly suppressed OC cell proliferation, tumor growth, and invasion in both in vitro and in vivo studies. Mechanistically, KPNA5 recognizes nuclear localization signals (NLSs) in PTPN4, mediating its nuclear transport and inhibiting STAT3 phosphorylation and its downstream signaling pathway. Similarly, PTPN4 overexpression reduced OC cell viability and invasion, also suppressing STAT3 phosphorylation.ConclusionsOur findings identify KPNA5 as a tumor suppressor in OC, presenting a potential therapeutic target for OC treatment.

The Impact of Carboplatin Dosing Design Using Adjusted Serum Creatinine on Carboplatin Plus Paclitaxel Therapy for Ovarian Cancer

ABSTRACTBackgroundCarboplatin (CBDCA) is a mainstay of chemotherapy for ovarian cancer and its dose is determined in proportion to the estimated creatinine clearance (CCr). Serum creatinine (SCr) values necessary to estimate CCr vary by measurement method: adding 0.2 mg/dL to SCr by enzymatic methods commonly used in Japan equates to SCr calculated using the Jaffe method, which is widely adopted outside Japan. Although adjustment by adding 0.2 mg/dL to SCr by enzymatic methods may avoid the potential overdose of CBDCA, its impact on the dose intensity (DI) of chemotherapy is unclear.MethodsWe retrospectively studied patients with ovarian cancer treated with CBDCA + paclitaxel (PTX) (TC) after primary surgery. Patients were classified into Cohort A (dose‐dense [dd‐]TC, SCr‐adjusted, n = 18), B (dd‐TC, non‐adjusted, n = 8), C (tri‐weekly [tw‐]TC, SCr‐adjusted, n = 6), and D (tw‐TC, non‐adjusted, n = 15), and DI and DI‐related measures including average relative DI (ARDI, [RDI of CBDCA + RDI of PTX]/2]) known to correlate with patients’ prognoses were compared.ResultsAlthough the DI of CBDCA did not differ between Cohorts A and B, the DI of PTX and proportion of patients with ARDI ≥ 85% were higher in Cohort A than B (78 vs. 13%, p = 0.002) as a result of less frequent treatment modification. There was no difference in these measures between Cohorts C and D.ConclusionAdjustment of SCr when calculating the CBDCA dose did not compromise the DI of total CBDCA and may rather contribute to maintaining DI in patients receiving dd‐TC.

Anxiety and Depression Trajectories in Young Adults Up to 5 Years After Being Diagnosed With Cancer

ABSTRACTAimsThis study aimed to identify and characterize trajectories of anxiety and depression symptoms in a national cohort of young women and men up to 5 years after being diagnosed with cancer. Furthermore, potential sociodemographic, clinical, and psychosocial factors predictive of different trajectory groups were examined.MethodsA population‐based sample of 1010 young adults aged 18–39 at diagnosis with selected cancers/tumors (brain/breast/cervical/lymphoma/ovarian/testicular) completed a survey 1.5 years, 3 years (T2, n = 722) and 5 years (T3, n = 659) post‐diagnosis. Responses to the Hospital Anxiety and Depression Scale were computed using five trajectories as outcome groups: Stable cases, Stable non‐cases, Improving, Worsening, and Fluctuating. Multinomial logistic regression models were performed to identify predictive factors of different trajectories.ResultsThe most common trajectories for anxiety symptoms were Stable non‐cases (36%) and Stable cases (26%), followed by Improving (17%), Fluctuating (11%), and Worsening (10%). In contrast, the dominant trajectory for depression symptoms was Stable non‐cases (69%), with smaller groups identified as Improving (10%), Worsening (8%), Stable cases (7%), and Fluctuating (6%). Factors associated with several unfavorable trajectories were female sex, pre‐diagnosis support for emotional issues, fatigue, and financial problems (p < 0.05).ConclusionSymptoms of anxiety and depression follow five different developmental paths among young people with cancer. Within the first 5 years after a cancer diagnosis, a majority of young adults meet clinical levels of anxiety (64%) and a third meet clinical levels of depression (31%). It is important to consider risk factors for mental illness in the follow‐up care of people with cancer.

Navigating Metabolic Challenges in Ovarian Cancer: Insights and Innovations in Drug Repurposing

ABSTRACTBackgroundOvarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes.MethodsThis review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic‐targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways.ConclusionDrug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.

Retrospective Study of Genetic Testing Results Reveals Pathogenic Variants Beyond BRCA1/2 in Hereditary Breast and Ovarian Cancer Cases in New Brunswick: Implications for Future Care

ABSTRACTBackgroundIn Canada, founder variants in breast cancer susceptibility genes have been identified in populations residing in Québec and Newfoundland, thus demonstrating the value in characterizing the genetic profile of local populations for better clinical management. New Brunswick has a diverse, yet genetically unexplored population that includes founder Irish and Acadian ancestry, among others, and we hypothesized that this population could demonstrate potential enrichments for variants in breast cancer genes.MethodsHealth records were retrospectively analyzed for 445 cases referred to the genetics clinic in Moncton, New Brunswick, their molecular results were summarized and compared to allele frequencies from similar studies in Canada.ResultsNo ethnic or age‐related correlation for specific variants could be identified. However, BRCA1/2 variant frequency was lower than expected in the study group and variants in other susceptibility genes such as ATM and CHEK2 were higher when compared to similar studies.PerspectivesThis study demonstrates a distinct profile in hereditary breast cancer genetics in a previously uncharacterized population, thus adding to existing knowledge of population genetics in Atlantic Canada.

Transcriptome Concordance Between Borderline Tumors and Endometrioid Carcinoma: An Integrative Genomic Analysis

ABSTRACTBackgroundBorderline ovarian tumors (BOTs) differ from ovarian carcinomas in their clinical presentation and behavior, yet their molecular characteristics remain poorly understood. This study aims to address this gap by integrating whole‐exome sequencing (WES) and RNA sequencing (RNA‐seq) to compare BOTs with high‐grade serous carcinoma (HGSC), endometrioid carcinoma (EC), and clear‐cell carcinoma (CCC).ObjectiveTo elucidate the molecular features of BOTs and evaluate their similarities and differences in comparison to HGSC, EC, and CCC.MethodsThe study analyzed 44 ovarian tumor samples, employing WES to identify genomic alterations and RNA‐seq to examine transcriptomic profiles. Comparative analyses were conducted to investigate the molecular relationships among the tumor types.ResultsThe genomic analysis revealed that BOTs share significant similarities with EC. Furthermore, the transcriptomic data highlighted a novel and substantial similarity between BOTs and EC, suggesting deeper biological linkages, including potentially shared oncogenic pathways or tumor microenvironmental factors. These findings challenge traditional classifications and suggest a closer molecular alignment of BOTs with EC than previously understood.ConclusionsThis study provides new insights into the molecular characteristics of BOTs, demonstrating their significant resemblance to EC at both the genomic and transcriptomic levels. These results underscore the potential need to reconsider the molecular classification of ovarian tumors and open new avenues for research into the pathogenesis and treatment strategies for BOTs.

Targeted Genetic Sequencing Analysis of 223 Cases of Pseudomyxoma Peritonei Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Shows Survival Related to GNAS and KRAS Status

ABSTRACTBackground and AimPseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed.ResultsThe median follow‐up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co‐occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non‐appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi‐hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004).ConclusionsSurvival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.

Uptake of Risk‐Reducing Salpingo‐Oophorectomy and Gynaecologic Surveillance Among Germline BRCA Pathogenic Variants Carriers

ABSTRACTIntroductionRisk‐reducing salpingo‐oophorectomy (RRSO) is recommended by international guidelines in women with BRCA1/2 germline pathogenic variants (PV) to prevent ovarian cancer. Despite the solid recommendation, women frequently refuse surgery and uptake rates reported in the literature are diverse. This study analyses the uptake rate of RRSO in BRCA 1/2 PV‐carriers referred to a specialised referral centre for first counselling and investigate personal factors linked to the decision.MethodsThis is a single‐centre prospective study of BRCA1/2 PV‐carriers referred for the first counselling to IRCCS Fondazione San Gerardo de’ Tintori (Monza, Italy) between January 2010 and May 2023. Depending on individual characteristics, women were either proposed RRSO or surveillance, consisting of transvaginal ultrasound and CA125 measurement twice per year according to Regional guidelines. Women within the centre have access to a clinical psychologist, a nutritional consult and treatment of menopausal atrophy with diode vaginal laser. The primary endpoint of the study was the uptake rate of RRSO. The secondary objective was to evaluate the main reasons for refusing surgery.ResultsAmong the 287 women included, surgery was proposed to 205 women either at first counselling or during surveillance and was accepted by 197, with an uptake rate of 96.1%. 17.25% of women met the psychologist before or after surgery. The main reasons for refusing RRSO were fear of iatrogenic menopause and childbearing desire.ConclusionThis study shows a high uptake rate of RRSO in BRCA PV‐carriers. We believe that the presence of a dedicated outpatient clinic with a multidisciplinary team contributes decisively to our results. Gynaecologic surveillance, as though not beneficial in terms of oncological prevention, may play a significant role in encouraging women with BRCA PV to opt for risk‐reducing surgery.

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer

AbstractObjectiveThe TGF‐β superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin‐βA and INHBB/ Inhibin‐βB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC.MethodsPublicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA‐OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T‐cell markers CD8 and FoxP3 at the protein level. ELISA to activin‐A was used to assess levels in the ascites of advanced EOC patients. Kaplan–Meier curves were generated to visualize survival outcomes.ResultsGene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin‐A (inhibin‐βA) is significantly elevated in EOC patient ascites.ConclusionINHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin‐A may play a role in suppressing anti‐tumor immunity in EOC, highlighting its potential as a therapeutic target.

A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer

AbstractBackgroundMonoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear.MethodsHere, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk.ResultsThe frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations.ConclusionOur study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

Potentially functional variants of ERRFI1 in hypoxia‐related genes predict survival of non‐small cell lung cancer patients

AbstractBackgroundHypoxia is often involved in tumor microenvironment, and the hypoxia‐induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia‐related genes play in survival of patients with non‐small cell lung cancer (NSCLC).MethodsWe evaluated the associations between 16,092 single‐nucleotide polymorphisms (SNPs) in 182 hypoxia‐related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset.ResultsAn independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14–1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03–1.39, p = 0.014) and disease‐specific survival (HR = 1.21, 95% CI = 1.04–1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma.ConclusionOur findings suggest that genetic variants in the hypoxia‐related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.

Causal effects of hypertensive disorders of pregnancy on future gynecologic tumors: A two‐sample Mendelian randomization study

AbstractBackgroundNumerous observational studies have investigated the potential link between hypertensive disorders of pregnancy (HDPs) and the subsequent risks of gynecologic tumors, yet the findings have been inconsistent. In this study, we utilized Mendelian randomization (MR) approach to assess the influence of HDPs on the future risks of ovarian, cervical, endometrial, and breast cancer and uterine fibroids, controlling for confounding factors.MethodsThe genome‐wide association studies (GWAS) summary data relevant to HDPs was obtained from the FinnGen databases (10,736 cases and 136,325 controls). Gynecologic tumor outcomes were extracted from the IEU Open GWAS project and UK Biobank (47,690 cases and 1, 092,073 controls). The inverse variance weighted (IVW) approach was selected as the principal method for MR analysis, supplemented by MR‐Egger, weighted median, weighted model, simple model methods, MR pleiotropy residual sum and outlier (MR‐PRESSO) test, and leave‐one‐out method. Multivariate MR (MVMR) analysis was conducted after adjusting systolic blood pressure (SBP), body mass index (BMI) and type 2 diabetes mellitus (T2DM).ResultsOur univariate MR analysis (UVMR) results revealed no significant relationship between HDPs and the risks of ovarian cancer (odds ratio [OR] = 0.924, p = 0.360), cervical cancer (OR = 1.230, p = 0.738), endometrial cancer (OR = 1.006, p = 0.949), uterine fibroids (OR = 1.155, p = 0.158), and breast cancer (OR = 0.792, p = 0.241) by IVW test. Similar results were observed in gestational hypertension and preeclampsia/eclampsia. Additionally, our study detected neither heterogeneity nor pleiotropy. MVMR analysis also provided no evidence of a causal association between HDPs and common gynecologic tumors after adjusting SBP, BMI, and T2DM.ConclusionWe discovered no causal relationship between HDPs and ovarian, cervical, endometrial, breast cancer, and uterine fibroids in European populations. However, present analysis did not explore the effect of HDPs on the subtypes of gynecologic tumors across varied ethnic populations, which may require additional research.

Mechanism and rational combinations with GP‐2250, a novel oxathiazine derivative, in ovarian cancer

AbstractBackgroundGP‐2250, a novel analog of taurultam (TRLT), has emerged as a potent anti‐neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP‐2250 using in vitro and in vivo models.MethodsWe carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse‐phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP‐2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP‐2250 alone and in combination with standard‐of‐care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP‐ribose polymerase [PARP] inhibitors).ResultsWe investigated the cytotoxic effect of GP‐2250 in 10 ovarian cancer cell lines and found GP‐2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP‐2250 inhibited hypoxia‐inducible factor‐1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High‐resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP‐2250 exposure. Furthermore, GP‐2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP‐2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP‐2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups.ConclusionsTaken together, our data indicate that GP‐2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti‐tumor efficacy. These findings could have implications for the clinical development of GP‐2250.

Cervicovaginal specimen biomarkers for early detection of ovarian and endometrial cancer: A review

AbstractBackgroundIn the last decade, technical innovations have resulted in the development of several minimally invasive diagnostic cancer tools. Within women at high risk of developing ovarian cancer (OC) or endometrial cancer (EC) due to a hereditary cancer syndrome, there is an urgent need for minimally invasive and patient‐friendly methods to detect OC and EC at an early stage.Materials and MethodsWe performed a systematic search of studies using DNA methylation or mutation analysis, microbiome, or proteomics performed on cervicovaginal specimens (smear, swab, or tampon) intended to detect OC and EC published until January 2024.ResultsIncluded studies (n = 36) showed high heterogeneity in terms of biomarkers used and outcomes, and only a few studies reported on the detection of biomarkers in high‐risk subgroups.ConclusionBased on the findings in this review, DNA methylation techniques seem to be the most promising for detecting OC and EC at early stages in the general population. Future validation of cervicovaginal DNA methylation techniques is needed to determine whether this technique might be beneficial in hereditary high‐risk subgroups.

A prediction model based on deep learning and radiomics features of DWI for the assessment of microsatellite instability in endometrial cancer

AbstractBackgroundTo explore the efficacy of a prediction model based on diffusion‐weighted imaging (DWI) features extracted from deep learning (DL) and radiomics combined with clinical parameters and apparent diffusion coefficient (ADC) values to identify microsatellite instability (MSI) in endometrial cancer (EC).MethodsThis study included a cohort of 116 patients with EC, who were subsequently divided into training (n = 81) and test (n = 35) sets. From DWI, conventional radiomics features and convolutional neural network‐based DL features were extracted. Random forest (RF) and logistic regression were adopted as classifiers. DL features, radiomics features, clinical variables, ADC values, and their combinations were applied to establish DL, radiomics, clinical, ADC, and combined models, respectively. The predictive performance was evaluated through the area under the receiver operating characteristic curve (AUC), total integrated discrimination index (IDI), net reclassification index (NRI), calibration curves, and decision curve analysis (DCA).ResultsThe optimal predictive model, based on an RF classifier, comprised four DL features, three radiomics features, two clinical variables, and an ADC value. In the training and test sets, this model exhibited AUC values of 0.989 (95% CI: 0.935–1.000) and 0.885 (95% CI: 0.731–0.967), respectively, demonstrating different degrees of improvement compared with the clinical, DL, radiomics, and ADC models (AUC‐training = 0.671, 0.873, 0.833, and 0.814, AUC‐test = 0.685, 0.783, 0.708, and 0.713, respectively). The NRI and IDI analyses revealed that the combined model resulted in improved risk reclassification of the MSI status compared to the clinical, radiomics, DL, and ADC models. The calibration curves and DCA indicated good consistency and clinical utility of this model, respectively.ConclusionsThe predictive model based on DWI features extracted from DL and radiomics combined with clinical parameters and ADC values could effectively assess the MSI status in EC.

An explainable machine learning model to solid adnexal masses diagnosis based on clinical data and qualitative ultrasound indicators

AbstractBackgroundAccurate characterization of newly diagnosed a solid adnexal lesion is a key step in defining the most appropriate therapeutic approach. Despite guidance from the International Ovarian Tumor Analyzes Panel, the evaluation of these lesions can be challenging. Recent studies have demonstrated how machine learning techniques can be applied to clinical data to solve this diagnostic problem. However, ML models can often consider as black‐boxes due to the difficulty of understanding the decision‐making process used by the algorithm to obtain a specific result.AimsFor this purpose, we propose an Explainable Artificial Intelligence model trained on clinical characteristics and qualitative ultrasound indicators to predict solid adnexal masses diagnosis.Materials & MethodsSince the diagnostic task was a three‐class problem (benign tumor, invasive cancer, or ovarian metastasis), we proposed a waterfall classification model: a first model was trained and validated to discriminate benign versus malignant, a second model was trained to distinguish nonmetastatic versus metastatic malignant lesion which occurs when a patient is predicted to be malignant by the first model. Firstly, a stepwise feature selection procedure was implemented. The classification performances were validated on Leave One Out scheme.ResultsThe accuracy of the three‐class model reaches an overall accuracy of 86.36%, and the precision per‐class of the benign, nonmetastatic malignant, and metastatic malignant classes were 86.96%, 87.27%, and 77.78%, respectively. Discussion: SHapley Additive exPlanations were performed to visually show how the machine learning model made a specific decision. For each patient, the SHAP values expressed how each characteristic contributed to the classification result. Such information represents an added value for the clinical usability of a diagnostic system.ConclusionsThis is the first work that attempts to design an explainable machine‐learning tool for the histological diagnosis of solid masses of the ovary.

Real‐world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer

AbstractBackgroundThe optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real‐world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC.MethodsThis retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti‐HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use.ResultsOut of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001).ConclusionsThis is the first real‐world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.

Landscape of potential germline pathogenic variants in select cancer susceptibility genes in patients with adult‐type ovarian granulosa cell tumors

AbstractObjectiveThe objective of this study was to assess the frequency of potential germline pathogenic variants that may contribute to risk of development of adult granulosa cell tumors (AGCT) given the paucity of germline testing guidelines for these patients.MethodsThis was a retrospective cross‐sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022. Cases with a potential germline pathogenic variant were identified by filtering single nucleotide variants and short indels by variant allele frequency (VAF) and presence in ClinVar for select cancer susceptibility genes. Odds ratios for AGCT risk were calculated compared to a healthy population.ResultsPrior to analysis, 595 patients were screened and 516 with a somatic FOXL2 p.C134W mutation were included. Potential germline pathogenic variants in a DNA repair‐related gene (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, RAD51C, or RAD51D) were found in 6.6% of FOXL2‐mutated AGCT. Potential germline pathogenic CHEK2 variants were found in 3.5% (18/516) of AGCT patients, a rate that was 2.8‐fold higher than Genome Aggregation Database non‐cancer subjects (95% CI 1.8–4.6, p < 0.001). The founder variants p.I157T (38.9%, 7/18) and p.T367fs*15 (c.1100delC; 27.8%, 5/18) were most commonly observed. CHEK2 VAF indicated frequent loss of the wildtype copy of the gene.ConclusionsThese results support ongoing utilization of genomic tumor profiling and confirmatory germline testing for potential germline pathogenic variants. Further prospective investigation into the biology of germline variants in this population is warranted.

High expression of SLC7A1 in high‐grade serous ovarian cancer promotes tumor progression and is involved in MAPK/ERK pathway and EMT

AbstractOur previous studies have shown that upregulation of SLC7A1 in epithelial ovarian cancer (EOC) tumor cells significantly increases cancer cell proliferation, migration, and cisplatin resistance; however, the molecular mechanism by which SLC7A1 functions in EOC remains unknown. In later studies, we found that SLC7A1 is also highly expressed in the interstitial portion of high‐grade serous ovarian cancer (HGSOC), but the significance of this high expression in the interstitial remains unclear. Here, we showed the Interstitial high expression of SLC7A1 in HGSOC by immunohistochemistry. SLC7A1 enriched in cancer‐associated fibroblasts (CAFs) was upregulated by TGF‐β1. Transwell assay, scratch assay, cck8 assay and cell adhesion assay showed that SLC7A1 highly expressed in CAFs promoted tumor cells invasion, migration and metastasis in vitro. The effect of SLC7A1 on MAPK and EMT pathway proteins in ovarian cancer (OC) was verified by RNA sequencing and western blotting. Overexpression of SLC7A1 in OC is involved in MAPK/ ERK pathway and EMT. In general, in HGSOC, CAFs overexpressing SLC7A1 supported the migration and invasion of tumor cells; SLC7A1 is highly expressed in ovarian cancer and is involved in ERK phosphorylation and EMT signaling in MAPK signaling pathway. This suggests that SLC7A1 may be a potential therapeutic target for OC metastasis.

Exploring Cervical Adenocarcinoma: Epidemiological Insights, Diagnostic and Therapeutic Challenges, and Pathogenetic Mechanisms

ABSTRACTBackgroundCervical cancer poses a significant threat to women's health and encompasses various histological types, including squamous cell carcinoma (SCC), cervical adenocarcinoma (CA), and adenosquamous carcinoma. CA, in particular, presents a formidable challenge in clinical management due to its low early detection rate, pronounced aggressiveness, high recurrence rate, and mortality, compounded by the complexities associated with late‐stage treatment. There is limited understanding of the similarities and differences in the pathogenesis mechanisms between CA and SCC, such as tumor heterogeneity and the tumor immune microenvironment (TME).MethodsA literature search was carried out in the PubMed, Web of Science, and Google Scholar databases using the following research terms: “gynecological oncology,” “cervical cancer,” “cervical adenocarcinoma,” “epidemiology,” “diagnosis and treatment of cervical adenocarcinoma,” “Human papillomavirus,” “World Health Organization,” “tumor microenvironment,” “single‐cell RNA sequencing,” “molecular mechanism,” and “preclinical research model.”ConclusionThis review consolidates the epidemiological characteristics, diagnostic and therapeutic hurdles, and the latest advances in research on CA. It aims to highlight the significant heterogeneity of the TME characteristics exhibited by CA compared to SCC. Additionally, we also summarize the common preclinical models for CA and discuss the advantages and disadvantages of using various models in research. We aspire that the discussions presented herein will offer novel insights and directions for subsequent research, as well as clinical diagnosis and treatment strategies for CA.

Validating the 2023 FIGO staging system: A nomogram for endometrioid endometrial cancer and adenocarcinoma

AbstractBackgroundTo find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the 2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer.MethodsData were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C‐index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan–Meier curves.ResultsCox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C‐indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram‐predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis.ConclusionSeven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.

Application of interpretable machine learning algorithms to predict distant metastasis in ovarian clear cell carcinoma

AbstractBackgroundOvarian clear cell carcinoma (OCCC) represents a subtype of ovarian epithelial carcinoma (OEC) known for its limited responsiveness to chemotherapy, and the onset of distant metastasis significantly impacts patient prognoses. This study aimed to identify potential risk factors contributing to the occurrence of distant metastasis in OCCC.MethodsUtilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed with OCCC between 2004 and 2015. The most influential factors were selected through the application of Gaussian Naive Bayes (GNB) and Adaboost machine learning algorithms, employing a Venn test for further refinement. Subsequently, six machine learning (ML) techniques, namely XGBoost, LightGBM, Random Forest (RF), Adaptive Boosting (Adaboost), Support Vector Machine (SVM), and Multilayer Perceptron (MLP), were employed to construct predictive models for distant metastasis. Shapley Additive Interpretation (SHAP) analysis facilitated a visual interpretation for individual patient. Model validity was assessed using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and the area under the receiver operating characteristic curve (AUC).ResultsIn the realm of predicting distant metastasis, the Random Forest (RF) model outperformed the other five machine learning algorithms. The RF model demonstrated accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and AUC (95% CI) values of 0.792 (0.762–0.823), 0.904 (0.835–0.973), 0.759 (0.731–0.787), 0.221 (0.186–0.256), 0.974 (0.967–0.982), 0.353 (0.306–0.399), and 0.834 (0.696–0.967), respectively, surpassing the performance of other models. Additionally, the calibration curve's Brier Score (95%) for the RF model reached the minimum value of 0.06256 (0.05753–0.06759). SHAP analysis provided independent explanations, reaffirming the critical clinical factors associated with the risk of metastasis in OCCC patients.ConclusionsThis study successfully established a precise predictive model for OCCC patient metastasis using machine learning techniques, offering valuable support to clinicians in making informed clinical decisions.

Outcomes after fertility‐sparing surgery of early‐stage ovarian cancer: A nationwide population‐based study

Abstract Background Fertility‐sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early‐stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. Methods A total of 1297 patients aged between 20 and 44 years with newly diagnosed early‐stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site‐specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer‐specific survival (CSS) was evaluated using Kaplan–Meier method with log‐rank test and Cox regression model. Results There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high‐grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66–1.77, p  = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06–0.82, p  = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. Conclusion FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.

Real‐world data of poly (ADP‐ribose) polymerase inhibitor response in Japanese patients with ovarian cancer

AbstractBackgroundPoly (ADP‐ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored.MethodsThis retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined.ResultsHigh‐grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high‐grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non‐responders. Furthermore, neutrophil counts were significantly higher among responders than among non‐responders.ConclusionsInflammation‐related blood data, such as neutrophil count, obtained at the initial pre‐treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

A longitudinal study of symptom cluster latent profiles in ovarian cancer patients undergoing chemotherapy

AbstractBackgroundThis study aimed to identify distinct patterns within the symptom cluster of fatigue, pain, and sleep disturbance among ovarian cancer patients receiving chemotherapy, to determine the factors predicting these patterns and their impact on quality of life.MethodsThe longitudinal study collected data from 151 ovarian cancer patients at three time points: before chemotherapy (T0), after the first chemotherapy cycle (T1), and following the completion of four cycles of chemotherapy (T2). Latent profile analysis and latent transition analysis were used to identify symptom patterns and evaluate changes in symptom patterns. A bias‐adjusted three‐step approach was utilized to examine predictor variables and distal outcomes associated with latent class membership.ResultsThree symptom patterns emerged: “All Low,” “Moderate” (T0)/“Low pain and high sleep disturbance” (T1 and T2), and “All High.” Patients with lower educational attainment and higher levels of anxiety and depression were found to be at an elevated risk of belonging to the “All High” class. All quality‐of‐life domains showed significant differences among the three subgroups, following an “All Low” > “All High” pattern (p < 0.05). Membership in three classes remained relatively stable over time, with probabilities of 0.749 staying within their groups from T0 to T2.ConclusionsThis study underscores the existence of a diverse and heterogeneous experience within the symptom cluster of fatigue, pain, and sleep disturbance among ovarian cancer patients. Importantly, these patterns were stable throughout chemotherapy. Recognizing and understanding these patterns can inform the development of targeted interventions to alleviate the burden of symptom clusters in this population.

Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis

AbstractEndometrial cancer (EC) is a fatal female reproductive tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. In this study, GSE17025 and GSE40032 were obtained from Gene Expression Omnibus (GEO). “limma” package and Venn diagram tool were used to identify hub genes. FunRich was used for functional analysis. Retrieval of Interacting Genes Database (STRING) was used to analyze protein‐protein interaction (PPI) complex. Cancer Genome Atlas (TCGA), GEPIA, immunohistochemistry staining, and ROC curve analysis were carried out for validation. Univariate and multivariate regression analyses were performed to predict the risk score. Compound muscle action potential (CMap) was used to find potential drugs. GSEA was also done. We retrieved seven oncogenes which were upregulated and hypomethylated and 12 tumor suppressor genes (TSGs) which were downregulated and hypermethylated. The upregulated and hypomethylated genes were strikingly enriched in term “immune response” while the downregulated and hypermethylated genes were mainly focused on term “aromatic compound catabolic process.” TCGA and GEPIA were used to screen out EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1. Among them, ESPL1 and ROR2 were identified by Cox regression analysis and were used to construct prognostic risk model. The result showed that ESPL1 was a negative independent prognostic factor. Cmap identified aminoglutethimide, luteolin, sulfadimethoxine, and maprotiline had correlation with EC. GSEA results showed that “hedgehog signaling pathway” was enriched. This research inferred potential aberrantly methylated DEGs and dysregulated pathways may participate in EC development and firstly reported eight hub genes, including EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1 that could be used to predict EC prognosis. Aminoglutethimide and luteolin may be used to fight against EC.

Fertility counselling and fertility preservation among early onset female cancer patients—A Finnish register‐based study

AbstractIntroductionAdvances in multimodality cancer treatments have increased long‐term survival rates for early onset cancer patients, with 5‐year survival rates reaching 80% in Northern Europe. According to recent recommendations, clinicians should, as early as possible, inform cancer patients about the impact that cancer treatment may have on their fertility. Still, there is limited published data on fertility counselling (FC) and fertility preservation (FP) for cancer patients.MethodsThis register‐based study used hospital records to identify female cancer patients in the hospital district (n = 192) who received FC at the age of 16–42 years between 2011 and 2019.ResultsAltogether, 97 (50.5%) cancer patients were eligible for FP. Of these, 55 (56.7%) underwent FP, whereas 42 (43.3%) declined. Women undergoing FP were recommended cancer treatments with a higher risk of infertility (p = 0.01), and women with breast cancer were more prone to undergo FP than women with lymphoma (p = 0.043). In FP treatment cycles, the mean number of oocytes retrieved (13.9 ± 7.7 vs. 12.0 ± 6.5, p = 0.04) and transferrable embryos (4.7 ± 2.9 vs. 3.7 ± 2.8, p = 0.002) was higher among cancer patients compared to age‐matched comparisons with male or tubal factor infertility. The total mean gonadotropin dose used was higher among cancer patients (2243 ± 963 IU vs. 1679 ± 765 IU, p < 0.001).ConclusionWe conclude that a good ovarian response during FP can be achieved in female cancer patients.

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

AbstractBackgroundApproximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high‐grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss‐of‐function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression‐free survival and overall survival.MethodsThe study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.ResultsA total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression‐free survival.ConclusionFrequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non‐functional or non‐functional somatic variants, while eight 14.2% presented likely non‐functional or non‐functional somatic variants in BRCA1 or BRCA2.

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne

AbstractPurposeTumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li‐Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.MethodsThe German Consortium for Hereditary Breast and Ovarian Cancer (GC‐HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.ResultsTP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.ConclusionThe tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC‐HBOC criteria for genetic testing.

Detection rates and factors affecting thereof in endometrial hyperplasia, endometrial carcinoma, and cervical glandular lesions on cervical smear

AbstractIntroductionEndometrial lesions are morphologically diverse and uncommon on cervical smears, with its detection rate and associated diagnostic categories uncharacterized. In this study, cervical smears matched to histologically proven endometrial hyperplasias and carcinomas were reviewed and compared with cervical in‐situ‐carcinomas/carcinomas, aiming to detail the diagnostic performance of cervical smears for upper tract and glandular lesions.MethodsPathology reports of cervical smears, hysterectomies, endometrial and cervical biopsies from 1995 to 2021 were retrieved. Diagnoses of cervical smears were matched to endometrial hyperplasias and carcinomas, or cervical carcinomas and reviewed.ResultsTotally 832 cervical smears (272 cervical carcinomas, 312 endometrial carcinomas, and 248 hyperplasias) were included. Considering all cytologic glandular diagnosis as positive, the detection rate of cervical adenocarcinoma‐in‐situ was the highest (64.3%), followed by cervical adenocarcinoma (63.8%), endometrial carcinoma (31.7%), and hyperplasia (with atypia–8.5%; without atypia–2.3%) (p < 0.001). Endometrial hyperplasia was most often diagnosed as atypical squamous cells of undetermined significance (ASCUS) (5.0%) or atypical glandular cells, not otherwise specified (3.6%) without indication of endometrial origin. For endometrial carcinomas, higher FIGO grading and endocervical involvement were associated with higher detection rates across all diagnostic categories (p = 0.002–0.028). High FIGO grade was associated with suspicious/favor neoplastic (C4) (31.1%vs10.3%, p < 0.001) and carcinoma (C5) (17.8% vs. 5.6%, p = 0.005) categories, but not for all glandular diagnoses combined (33.3% vs. 31.0%, p = 0.761).ConclusionDetection rates for endometrial lesions are lower than cervical lesions but not insignificant. Endometrial hyperplasia should be recognized as a differential of human papilloma virus‐negative ASCUS and prompt consideration of investigation of the upper genital tract.

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

AbstractAimAs the second most prevalent subtype of epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) is known for its chemoresistance to conventional platinum‐based therapy. In this work, we examined the tryptophan (Trp) metabolism enzymes' differential expression in patients with OCCC to assess the potential for personalised treatment.MethodsA total of 127 OCCC tissues were used to construct tissue microarrays, and immunohistochemistry (IHC) staining of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 was performed. The correlations between Trp enzyme expression and clinical characteristics were analysed.ResultsPositive IDO1, IDO2, TDO2 and IL4I1 staining was identified in 26.8%, 94.5%, 75.6% and 82.7% of OCCC respectively. IDO1‐positive samples were more common in the chemoresistant group than in the platinum‐sensitive group (46.7% vs. 19.8%). Moreover, positive expression of IDO1, TDO2 and IL4I1 was related to advanced stage, metastasis, bilateral tumours, endometriosis and tumour rupture (p < 0.05) respectively. Univariate analysis revealed a significant association between bilateral tumours, lymph node metastasis, advanced stage, distant metastasis and aberrant cytology with a poor prognosis for OCCC, while the absence of residual tumour was correlated with a favourable outcome (p < 0.05). However, only bilateral tumours and lymph node metastases were related to a poor prognosis after multivariate analysis.ConclusionThis is the first study to investigate the expression of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 in OCCC tissues. IDO2, TDO2 and IL4I1 were detected in the majority of OCCC. Clinical traits were correlated with IDO1, IDO2, TDO2 and IL4I1 expression. IDO1 may be used as a therapeutic target given the large percentage of chemoresistant cases with IDO1 expression. These results will aid the development of personalised therapies for OCCC.

It is not the time to abandon intraoperative frozen section in endometrioid adenocarcinoma: A large‐scale, multi‐center, and retrospective study

AbstractIntroductionStage IB (deep myometrial invasion) high‐grade endometrioid adenocarcinoma (EA), regardless of LVSI status, is classified into high‐intermediate risk groups, requiring surgical lymph node staging. Intraoperative frozen section (IFS) is commonly used, but its adequacy and reliability vary between reports. Hence, we determined the utility of IFS in identification of high‐risk factors, including deep myometrial invasion and high‐grade.MethodWe retrospectively analyzed 9,985 cases operated with hysterectomy and diagnosed with FIGO stage I/II EA in postoperative paraffin section (PS) results at 30 Chinese hospitals from 2000 to 2019. We determined diagnostic performance of IFS and investigated whether the addition of IFS to preoperative biopsy and imaging could improve identification of high‐risk factors.ResultsIFS and postoperative PS presented the highest concordance in assessing deep myometrial invasion (Kappa: 0.834), followed by intraoperative gross examination (IGE Kappa: 0.643), MRI (Kappa: 0.395), and CT (Kappa: 0.207). IFS and postoperative PS presented the highest concordance for high‐grade EA (Kappa: 0.585) compared to diagnostic curettage (D&C 0.226) and hysteroscope (Hys 0.180). Sensitivity and specificity for detecting deep myometrial invasion were 86.21 and 97.20% for IFS versus 51.72 and 88.81% for MRI, 68.97 and 94.41% for IGE. These figures for detecting high‐grade EA were 58.21 and 96.50% for IFS versus 16.42 and 98.83% for D&C, 13.43 and 98.64% for Hys. Parallel strategies, including MRI‐IFS (Kappa: 0.626), D&C‐IFS (Kappa: 0.595), and Hys‐IFS (Kappa: 0.578) improved the diagnostic efficiencies of individual preoperative examinations. Based on the high sensitivity of IFS, parallel strategies improved the sensitivities of preoperative examinations to 89.66% (MRI), 64.18% (D&C), 62.69% (Hys), respectively, and these differences were statistically significant (p = 0.000).ConclusionIFS presented reasonable agreement rates predicting postoperative PS results, including deep myometrial invasion and high‐grade. IFS helps identify high‐intermediate risk patients in preoperative biopsy and MRI and guides intraoperative lymphadenectomy decisions in EA.

High TPX2 expression results in poor prognosis, and Sp1 mediates the coupling of the CX3CR1/CXCL10 chemokine pathway to the PI3K/Akt pathway through targeted inhibition of TPX2 in endometrial cancer

AbstractIntroductionApproximately 30% of individuals with advanced EC have unsatisfactory prognosis. Evidence suggests that TPX2 is frequently upregulated in malignancies and related to cancer progression. Its role and pathological mechanism in EC need further research.MethodsGSEA and TPX2 expression, GO, KEGG, and prognostic analyses were performed with TCGA data by bioinformatic approaches. Relationships between TPX2 expression and clinicopathological parameters were investigated immunohistochemically and statistically. shRNA and overexpression plasmids were constructed and transfected into AN3CA and Ishikawa cells to evaluate phenotypic changes and injected into nude mouse axillae. Coimmunoprecipitation and chromatin immunoprecipitation were used to identify interacting proteins and promoter‐binding sequences. Changes in TPX2 expression were identified by Western blotting and RT–qPCR.ResultsTPX2 expression was significantly higher in EC tissues than in normal tissues in TCGA and in‐house specimens (all p < 0.001). In survival analysis, high TPX2 expression was associated with poor prognosis (p = 0.003). TPX2 overexpression stimulated cancer cell proliferation, promoted the G0‐G1‐to‐G2/M transition, enhanced invasion and migration, and accelerated tumor growth in nude mice. TPX2 regulated the CX3CR1/CXCL10 chemokine pathway and activated the PI3K/Akt signaling pathway. Sp1 negatively regulated TPX2 expression, affecting the malignant progression of endometrial cancer cells by coupling the CX3CR1/CXCL10 chemokine pathway to the PI3K/Akt signaling pathway.ConclusionTPX2 could be a prognostic biomarker for EC and play an important role in the CX3CR1/CXCL10 chemokine pathway and PI3K/Akt pathway via Sp1.

Psychometric validation of the Functional Assessment of Cancer Therapy‐Endometrial among endometrial cancer patients

AbstractObjectiveTo evaluate a psychometric validation of the endometrial cancer subscales (EnCS) in the Functional Assessment of Cancer Therapy‐Endometrial (FACT‐EN) among patients with endometrial cancer.MethodsThis cross‐sectional study was conducted at a tertiary university‐based hospital in South Korea between April and October 2022. Participants completed a survey questionnaire that included the FACT‐EN. Exploratory and confirmatory factor analyses (EFA, CFA) and the reliability were measured using the intraclass correlation coefficient (ICC) under a two‐way mixed model. Pearson's correlations were used to evaluate the validity. We also tested known‐group validity.ResultsIn total, 240 patients with endometrial cancer participated in the survey. In EFA, we found EnCS included four domains. In CFA, four‐factor solution model was good: CFI = 0.659; SRMR = 0.066, and RMSEA = 0.073. The mean (SD) of total score of FACT‐EN was 122.84 (23.58). The floor and ceiling effects were 0.4% and 0.4%, respectively. Cronbach's α coefficients for the five scales of the EnCS ranged from 0.78 to 0.91. The ICC of EnCS was 0.76. The convergent and discriminant validity of EnCS was acceptable. In the group analysis, older age and lower ECOG performance scores were associated with higher EnCS scores. The stomach and vaginal domains in EnCS were higher in patients who had completed treatment for more than 1 year compared to those who were still undergoing treatment.ConclusionsFACT‐EN has demonstrated its validity as an assessment tool with significant implications for capturing various symptoms in patients with endometrial cancer.

Histopathology Images‐Based Deep Learning Prediction of Histological Types in Endometrial Cancer

ABSTRACT Background According to the new 2023 International Federation of Gynecology and Obstetrics staging system for endometrial cancer (EC), EC is classified into aggressive and nonaggressive histological types. Accurate diagnosis of the histological type of EC is crucial for optimizing treatment strategies and predicting patient outcomes. Objectives To develop and validate a deep convolutional neural network for predicting nonaggressive versus aggressive histological types from hematoxylin and eosin (H&E)‐stained images of EC specimens. Methods A deep convolutional neural network named EC‐AI HIS was developed to predict the nonaggressive or aggressive histological type from 1187 EC specimens. Its generalizability and clinical utility were assessed across multiple cohorts and benchmarked against pathological diagnoses. Furthermore, correlations between the model's predictions and molecular subtypes of EC were examined. Results EC‐AI HIS achieved an AUC of 0.911 (sensitivity 82%, specificity 83%). In fivefold cross‐validation, AUCs ranged from 0.865 to 0.909. External validation yielded an AUC of 0.859 (sensitivity 75%, specificity 83%). EC‐AI HIS maintained robustness on images from different scanners and of suboptimal quality. In clinical simulation settings, it showed higher sensitivity than pathologists and improved junior pathologists’ diagnostic accuracy. EC‐AI HIS scores were associated with molecular subtypes of EC and showed potential prognostic utility in the p53abn subtype. Conclusions EC‐AI HIS is an effective tool that can assist pathologists in classifying EC histological types.

Using Machine Learning to Predict the Prognosis in Endometrial Cancer Patients Undergoing Fertility‐Sparing Treatment

ABSTRACT Background Endometrial cancer is a significant gynecological malignancy with rising incidence among women of reproductive age, necessitating effective fertility‐sparing treatments. Machine learning offers potential in enhancing prognostic assessments through radiomics. Objective To develop and validate a machine learning‐based model integrating radiomics and clinical features to predict the prognosis of fertility‐sparing treatments in endometrial cancer patients. Methods This retrospective study included 102 endometrial cancer patients who received fertility‐sparing treatment at West China Second University Hospital from November 2017 to December 2023. Patients were randomly divided into training ( n  = 81) and testing ( n  = 21) cohorts. The primary outcome was 6 month treatment response evaluated by endometrial sampling. MRI‐based radiomic features and clinical data were analyzed using logistic regression and other machine learning algorithms. A combined model was constructed by incorporating radiomics and clinical features. Model performances were assessed by the area under the receiver operating characteristic curve (AUC) analysis, and decision curve analysis (DCA) was used to estimate the models' clinical values. Results Among 102 patients, 60 (58.8%) achieved complete remission (CR), whereas 42 (41.2%) did not (non‐CR). In total, 1197 radiomic features were extracted from MRI images. Thirteen radiomic features were deemed valuable by dimensionality reduction and selection. Among radiomic models, the logistic regression model was the most effective, showing high stability and accuracy, with AUCs of 0.875 in the training cohort and 0.852 in the test cohort. Ultimate clinical features selected by univariate and multivariable logistic regression constructed a clinical model. The combined model demonstrated superior performance with an AUC of 0.941 in the training cohort and 0.907 in the testing cohort. Combined model DCA revealed optimal clinical efficacy. Conclusion The integrated model effectively predicts fertility preservation outcomes, offering a reliable noninvasive tool for clinicians. This approach may enhance personalized treatment strategies for young endometrial cancer patients.

One‐Step Nucleic Acid Amplification Analysis of Sentinel Lymphatic Nodes in Endometrial Cancer Patients ( EU ‐ OSNA ): A European Multicenter Diagnostic Accuracy Study

ABSTRACT Objective This European multicenter study aimed to assess the diagnostic accuracy of one‐step nucleic acid amplification (OSNA) as the primary endpoint by comparing this method with ultrastaging for the detection of sentinel node metastases in endometrial cancer patients. Methods European multicenter prospective performance study including data from 10 centers across 5 European countries. Each node, upon removal of surrounding adipose tissue, was sliced in 2 mm thick sections and equally distributed between ultrastaging and OSNA. OSNA is based on cytokeratin‐19 detection, serving as a metastatic marker. Sensitivity, specificity, and concordance of OSNA versus ultrastaging were calculated at nodal and patient levels. Results Seven hundred forty‐three sentinel nodes from 366 patients were evaluated. Compared to ultrastaging, OSNA showed concordance, specificity, and sensitivity of 95%, 97.6%, and 41.2% at the nodal level and 93.2%, 96.2%, and 47.8% at the patient level, respectively. In reverse analysis, when compared to OSNA, the ultrastaging showed a sensitivity of 45.2% and 45.8% at the nodal and patient levels, respectively. Irrespective of the size of metastasis, both methods agreed in 14 positive and 692 negative nodes (95%). This resulted in 24 (6.56%) patients with a positive OSNA and 23 (6.28%) patients with a positive ultrastaging finding. The number of discordant nodes was 47 (6.33%), 40 (85.1%) of them were micrometastases. Benign epithelial inclusions occurred in 4 nodes (0.54%) and 4 patients (1.09%). Conclusion Compared with ultrastaging, OSNA showed high concordance and specificity, but sensitivity was low—similar to ultrastaging compared with OSNA as an index test in reverse analysis. The main limitation in comparing the two approaches by splitting the sentinel nodes was the tissue allocation bias. As reflected in the number of discordant cases, especially at the micrometastases level. The distribution of patients with node metastases was comparable between the two methods at both the nodal and patient levels. Trial Registration German Clinical Trial Register: Nr. DRKS00021520

Application of NGS molecular classification in the diagnosis of endometrial carcinoma: A supplement to traditional pathological diagnosis

AbstractObjectiveThis study aims to demonstrate the advantages of NGS molecular classification in EC diagnosis and to assess whether molecular classification could be performed on curettage specimens and its concordance with subsequent hysterectomy specimens.Methods80 patients with hysterectomy specimens and 35/80 patients with paired curettage specimens were stratified as POLE mut, MSI‐H, TP53 wt, or TP53 abn group by NGS panel. Histotype, tumor grade, IHC results, and other pathological details were taken from original pathological reports.ResultsThe correlation analysis of 80 patients with hysterectomy specimens between NGS molecular classification and clinicopathological characters displayed that the POLE mut group was associated with EEC (87.5%) and TP53 abn subtype was correlated to a later stage (Stage II–IV, 47.6%), G3 (76.2%), serous histology (61.9%) and myometrial invasion ≥50% (47.6%). A favorable concordance (31/32, 96.9%) was shown in MSI analysis and MMR IHC results, and the agreement rate of p53 IHC and TP53 mutation was 81.5% (53/65). Compared with the p53 IHC abnormal group, the TP53 mutation group had a higher correlation with high‐risk factors. A high level of concordance (31/35, 88.0%) of NGS molecular classification was achieved between curettage specimens and hysterectomy specimens while grade and histotype (including unclassified group) from curettage specimens and hysterectomy specimens showed only moderate levels of agreement, 54.3% (19/35) and 68.6% (24/35), respectively.ConclusionNGS molecular classification achieved on curettage samples showed high concordance with the final hysterectomy specimens, demonstrating superior to the conventional pathological assessment of grade and histotype and potential utilization in clinical practice.

Exploring the Relationship Between Adipocytokines and Endometrial Cancer: Identifying Correlations With Clinico‐Pathological Prognostic Factors

ABSTRACTBackgroundEndometrial cancer, a malignancy linked with obesity, may be influenced by adipocytokines signalling due to chronic inflammation. This study explores the molecular expression patterns of adiponectin, leptin, interleukin6 (IL6), tumor necrosis factor (TNF)α, and their receptors in endometrial cancer patients and associations with lymphovascular space invasion (LVSI) and other tumour characteristics.MethodsWe analysed mRNA expression levels of the above biomarkers in endometrial cancer tissue using quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR), comparing them to benign endometrial tissue controls. Additionally, expressions in adipose tissue and lymph nodes were assessed, with correlations drawn between biomarker expression, patient demographics, and tumor characteristics.ResultsUsing qRT‐PCR analysis, endometrial cancer tissues (n = 39) exhibited higher expression levels of adiponectin, leptin, IL6, TNFα, and their receptors, IL6R and TNFRSF1A/B, compared to the calibrator sample, which consisted of five pooled benign endometrial control samples. Intriguingly, the adiponectin receptors, ADIPOR1 and ADIPOR2 demonstrated opposing correlations with cancer characteristics such as grade, histology, LVSI, and microcystic elongated and fragmented (MELF) pattern. LVSI was linked to increased levels of markers such as IL6R and ADIPOR2, along with decreased expressions of OBR (leptin receptor) and ADIPOR1, suggesting their potential as surrogate markers for diagnosing LVSI. Notably, higher adiponectin expression was observed in the cancerous lymph nodes of patients with LVSI, contrasting with those without LVSI.ConclusionThis study provides novel insight into differential role of adiponectin receptors in endometrial cancer and the associations of various markers with LVSI, emphasizing the need for tissue‐specific biomarker assessments in determining treatment strategies.

Implementation of a Personalized Risk Model for Lymph Node Metastasis in Endometrial Carcinoma: Healthcare Providers' Perspectives on Use, Barriers, and Facilitators

ABSTRACT Background The ENDORISK model estimates the risk of lymph node metastases (LNM) in endometrial carcinoma (EC) patients using preoperative clinical variables and biomarkers. This qualitative study investigated healthcare providers' (HCP) perspectives on the use of the model and barriers and facilitators for clinical implementation. Methods Eight focus group interviews were performed among HCPs. A semi‐structured interview guide was used based on the Grol and Wensing implementation model. Results Focus groups included gynecologists, residents of gynecology, pathologists, radiation oncologists, and a nurse specialist ( n  = 41). ENDORISK was deemed supportive for counseling of patients and shared decision‐making for optimal surgical and adjuvant treatment. Barriers for implementation were difficulty in explaining the model and risk percentages to patients, differences in preoperative diagnostic tools used per hospital, and use of the model with the sentinel node procedure. Facilitators were a clear guideline for using the model with a predefined risk cutoff and making the model easily understandable for patients. A 10% risk cutoff was considered clinically relevant for lymph node assessment. Conclusion HCP found ENDORISK use in clinical practice supportive for patient counseling. Future implementation should focus on a user‐friendly interface, a cohesive guideline, and training to aid efficient use and counseling of patients.

Trends in breast, colon, pancreatic, and uterine cancers in women during the COVID‐19 pandemic in North Carolina

AbstractImportanceThe COVID‐19 pandemic led to reductions in primary care and cancer screening visits, which may delay detection of some cancers. The impact on incidence has not been fully quantified. We examined change in cancer incidence to determine how the COVID‐19 pandemic may have altered the characteristics of cancers diagnosed among women.MethodsThis study included female patients aged ≥18 years and diagnosed with breast (n = 9489), colon (n = 958), pancreatic (n = 669), or uterine (n = 1991) cancer at three hospitals in North Carolina. Using interrupted time series, we compared incidence of cancers diagnosed between March 2020 and November 2020 (during pandemic) with cancers diagnosed between January 2016 and February 2020 (pre‐pandemic).ResultsDuring the pandemic, incidence of breast and uterine cancers was significantly lower than expected compared to pre‐pandemic (breast—18%, p = 0.03; uterine −20%, p = 0.05). Proportions of advanced pathologic stage and hormone receptor‐negative breast cancers, and advanced clinical stage and large size uterine cancers were more prevalent during the pandemic. No significant changes in incidence were detected for pancreatic (−20%, p = 0.08) or colon (+14%, p = 0.30) cancers.Conclusion and RelevanceIn women, the COVID‐19 pandemic resulted in a significant reduction in the incidence of breast and uterine cancers, but not colon or pancreatic cancers. A change in the proportion of poor prognosis breast and uterine cancers suggests that some cancers that otherwise would have been diagnosed at an earlier stage will be detected in later years. Continued analysis of long‐term trends is needed to understand the full impact of the pandemic on cancer incidence and outcomes.

Pure and mixed clear cell carcinoma of the endometrium: A molecular and immunohistochemical analysis study

AbstractBackgroundUterine clear cell carcinoma (CCC) consists of either pure clear cell histology but can also display other histological components (mixed uterine CCCs). In this study, the molecular and immunohistochemical background of pure and mixed uterine CCC was compared. Secondly, it was evaluated whether histological classification and molecular background affected clinical outcome.MethodsA retrospective multicenter study was performed comparing pure uterine CCCs (n = 22) and mixed uterine CCCs (n = 21). Targeted next‐generation sequencing using a 12‐gene targeted panel classified cases as polymerase‐ε (POLE) mutated, microsatellite instable (MSI), TP53 wildtype or TP53 mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2.ResultsThe following molecular subgroups were identified for pure and mixed uterine CCCs, respectively: POLE mutated 0% (0/18) and 6% (1/18); MSI in 6% (1/18) and 50% (9/18); TP53 wildtype in 56% (10/18) and 22% (4/18); TP53 mutated in 39% (7/18) and 22% (4/18) (p = 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. Frequent TP53 mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome.ConclusionPure and mixed uterine CCCs are two entities with different clinical outcomes, which could be explained by different molecular backgrounds. These results underline the relevance of both morphological and molecular evaluation, and may assist in tailoring treatment.

OS and DFS are affected by different diagnostic methods and hysterectomy procedures in endometrial cancer patients: A single‐center retrospective study

AbstractPurposeWe aimed to evaluate whether hysteroscopy increases the risk of intraperitoneal dissemination or worsens the prognosis of endometrial carcinoma (EC) patients and whether radical hysterectomy (RH) improves overall survival (OS) or disease‐free survival (DFS) in patients with stage II to III EC and to investigate the effects of different procedures for identifying EC and the effects of different surgical methods on the OS and DFS of endometrial cancer patients.MethodsFour hundred sixty‐five women with EC were included in this retrospective study. Log‐rank tests and Kaplan–Meier analysis were used for the outcome comparisons of the effects of the EC diagnostic method and different hysterectomy procedures. A Cox proportional hazards model was used for univariate regression analysis.ResultsAmong the three procedures for diagnosing EC (diagnostic curettage, hysteroscopy, and hysterectomy), the incidences of fallopian tube and ovarian invasion were not significantly different (p = 0.506 and 0.066, respectively). The diagnostic methods for EC had no significant effect on OS (p = 0.577) or DFS (p = 0.294). In addition, type II RH and type III RH did not improve the prognosis of patients with FIGO stage II and III disease (log‐rank p = 0.914 and 0.810 for OS; log‐rank p = 0.707 and 0.771 for DFS, respectively).ConclusionBased on the current study evidence, the use of diagnostic hysteroscopy procedures is safe and does not increase the risk of fallopian tube and ovarian invasion of intraperitoneal dissemination or worsen the prognosis of EC patients. Type II and type III RH did not demonstrate a benefit for stage II‐III EC patients.

Significance of Gelsolin Superfamily Genes in Diagnosis, Prognosis and Immune Microenvironment Regulation for Endometrial Cancer

ABSTRACTBackgroundPreviously, anti‐CTLA4 and anti‐PD‐1/PD‐L1 immunotherapies have shown limited efficacy in MSI‐H/MMR‐D endometrial cancer, leading to poor clinical outcomes. The gelsolin superfamily, which includes GSN, SCIN, VILL, VIL1, CAPG, AVIL, SVIL, and FLII, plays crucial roles in cell motility and gene regulation.AimsThe objective of this study is to explore the potential therapeutic and prognostic implications of the gelsolin superfamily in EC.Materials & MethodsData from TCGA, GEPIA, THPA, UALCAN, and Kaplan–Meier plotter databases were analyzed to investigate the expression and clinical relevance of gelsolin superfamily members. Co‐expression networks of the gelsolin superfamily were assessed using LinkedOmics, GeneMANIA, and NetworkAnalyst. The relationship between gelsolin superfamily and immune cell infiltration was investigated using TIMER, ImmuCellAI, and GEPIA.ResultsWe found that high expressions of CAPG, AVIL, and SVIL were associated with poor prognosis, while high expressions of GSN and FLII were linked to better outcomes in EC. Functional enrichment analysis indicated the involvement of gelsolin superfamily members in pathways related to estrogen response, MYC targets, epithelial–mesenchymal transition, TGF beta signaling, MTORC1 signaling, oxidative phosphorylation, inflammatory response, and IL6‐JAK‐STAT3 signaling. Furthermore, gelsolin superfamily members demonstrated strong correlations with the levels of monocytes, natural killer T, naive CD4+ T, follicular helper T, and central memory T in EC. In vitro studies showed that silencing CAPG and FLII could inhibit proliferation and metastasis in endometrial cancer cell lines.ConclusionThese findings indicate the significant association of gelsolin superfamily members with prognosis and immunological status in endometrial cancer.

The Impact of High lncRNA Expression on Clinicopathological Characteristics and Prognosis of Endometrial Cancer Patients: A Meta‐Analysis

ABSTRACTBackgroundsA growing number of systematic bioinformatics analyses were conducted to investigate the mechanism of interaction between long non‐coding RNA (lncRNA) and endometrial carcinoma (EC) to predict the prognosis. However, there is no evidence‐based evidence that abnormal lncRNA expression is strongly associated with the pathological characteristics and prognosis of EC patients. In this meta‐analysis, we systematically evaluated the relationship between upregulated lncRNA expression levels and clinicopathological features, five‐year survival rate, and progression‐free survival (PFS).MethodsA systematic search was performed across seven reputable databases, namely the China National Knowledge Infrastructure, Wanfang, Wipu, PubMed, Web of Science, Cochrane Library, and Embase, encompassing the period from the inception of each database until November 27, 2022. Heterogeneity among the studies was assessed through the application of Cochran's Q and I2 statistics. All statistical analyses were conducted using Stata 14.0 software.ResultsThis study encompassed 30 clinical studies, involving a total of 2469 EC patients, and examined the expression of 24 lncRNAs, which were upregulated in EC samples. EC patients with higher expression of lncRNAs showed a later FIGO stage (OR = 1.94, 95% CI: 1.29 ~ 2.91), a poorer histological grade (OR = 3.40, 95% CI: 2.51 ~ 4.60), earlier deep myometrial invasion (OR = 2.57, 95% CI: 1.94 ~ 3.41), a higher likelihood of lymphatic vascular space infiltration (OR = 2.86, 95% CI: 1.15 ~ 7.14), an increased propensity for lymph node metastasis (OR = 2.89, 95% CI: 1.82 ~ 4.60), and a greater likelihood of distant metastasis (OR = 2.39, 95% CI: 1.33 ~ 4.30). All of these were statistically significant (p < 0.05). Furthermore, EC patients with a higher expression level of lncRNAs were significantly associated with five‐year survival (p < 0.05) and PFS (p < 0.05).ConclusionsHigh expression levels of upregulated lncRNAs in EC patients are associated with unfavorable clinicopathological features, a poor five‐year survival rate, and PFS. It serves as a detrimental prognostic factor and might be a biomarker and therapeutic target for EC.

The Multi‐Kinase Inhibitor GZD824 (Olverembatinib) Shows Pre‐Clinical Efficacy in Endometrial Cancer

ABSTRACT Objective Endometrial cancer is one of the few cancers for which mortality is still increasing. A lack of treatment options remains a major challenge, particularly for some subtypes of the disease. GZD824, also known as olverembatinib , is a multi‐kinase inhibitor previously investigated in clinical trials for chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia as a BCR‐ABL inhibitor. This study aimed to investigate the pre‐clinical efficacy of GZD824 for the treatment of EC. Methods Here, we undertook pre‐clinical evaluation of GZD824 in seven endometrial cancer cell lines (HEC‐1‐A, HEC‐1‐B, MFE296, RL95‐2, Ishikawa, KLE and ARK‐1), one normal immortalised endometrium derived cell line (E6E7hTERT) and primary mesothelial and fibroblast cells isolated from normal omentum samples. Results GZD824 inhibited the proliferation of all endometrial cancer cell lines, which were significantly more sensitive to GZD824 compared to normal cells ( p  = 0.030). GZD824 significantly inhibited migration in Ishikawa (endometrioid) and ARK1 (serous) endometrial cancer cell lines and significantly inhibited invasion in the ARK1 cells. Whole transcriptome regulation following two doses (0.1 and 1 μM) of GZD824 in Ishikawa and ARK1 cells was investigated via RNA‐seq, and key components of enriched pathways were investigated at the translational level. Key pathways altered included ROR1/Wnt, GCN2‐ATF4, epithelial to mesenchymal transition (EMT) and PI3K‐AKT. Conclusion Together, these studies support further investigation of GZD824 as a potential therapeutic agent in endometrial cancer, potentially in combination with immune checkpoint inhibitors.

Values of tumor volume on magnetic resonance imaging for a surgical approach to endometrial cancer

AbstractObjectiveTo analyze the relationship between tumor volume in Endometrial Cancer (EC) on Magnetic Resonance Imaging (MRI) and lymph node metastasis to establish which patients benefit from omitting the lymphadenectomy.MethodsA retrospective observational study with 194 patients with EC identified between 2016 and 2021 at the Juan Ramón Jiménez University Hospital, Huelva (Spain) was carried out. Preoperative MRI of 127 patients was assessed. The tumor volume was analyzed on MRI by the ellipsoid formula and another alternative method with a manual ROI in different sections. Risk factors for node metastases were analyzed to understand its relationship and to identify an optimum criterion for the tailored surgery.ResultsUnivariate analysis showed risk factors for lymph node metastases were histological grade (p = 0.001), tumor with a volume greater than >25 cm3 (p < 0.001), lymphovascular space invaded (p = 0.007), and preoperative Ca 125 serum >28 (p < 0.001). Multivariate analysis indicated that tumor volume index >25 cm3 was an independent risk factor for lymph node metastases. The patients without significant proposed risk factors (volume index >25 cm3 [OR = 0.64], Ca 125 > 28 [OR = 0.32], and high histological grade [OR = 2.6]) did not present lymph node metastases, independent of myometrial invasion.ConclusionsLymphadenectomy can be omitted in patients with Endometrioid carcinoma that do not have any of the following risk factors: high‐grade tumor, elevated Ca 125 (>28), and tumor volume on MRI greater than 25 cm3. Tumor volume might predict the state of lymph nodes in EC and it could give information regarding surgical management.

Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer

AbstractIntroductionEndometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism‐related prognostic model for EC and explore potential targets for cancer treatment.MethodTranscriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model.ResultsFive glutamine metabolism‐related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan–Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high‐risk patients whereas immune relevance analysis revealed low immune scores in the high‐risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT‐503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002).ConclusionOur work established and validated a glutamine metabolism‐related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High‐risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.

Concordance in detection of microsatellite instability by PCR and NGS in routinely processed tumor specimens of several cancer types

AbstractBackgroundMicrosatellite instability (MSI) occurs in several cancer types and is commonly used for prognosis and as a predictive biomarker for immune checkpoint therapy.MethodsWe analyzed n = 263 formalin‐fixed paraffin‐embedded (FFPE) tumor specimens (127 colorectal cancer (CRC), 55 endometrial cancer (EC), 33 stomach adenocarcinoma (STAD), and 48 solid tumor specimens of other tumor types) with a capillary electrophoresis based multiplex monomorphic marker MSI‐PCR panel and an amplicon‐based NGS assay for microsatellite instability (MSI+). In total, n = 103 (39.2%) cases with a known defect of the DNA mismatch repair system (dMMR), determined by a loss in protein expression of MSH2/MSH6 (n = 48, 46.6%) or MLH1/PMS2 (n = 55, 53.4%), were selected. Cases with an isolated loss of MSH6 or PMS2 were excluded.ResultsThe overall sensitivity and specificity of the NGS assay in comparison with the MSI‐PCR were 92.2% and 98.8%. With CRC cases a nearly optimal concordance was reached (sensitivity 98.1% and specificity 100.0%). Whereas EC cases only show a sensitivity of 88.6% and a specificity of 95.2%, caused by several cases with instability in less than five monomorphic markers, which could be difficult to analyze by NGS (subtle MSI+ phenotype).ConclusionsMSI analysis of FFPE DNA by NGS is feasible and the results show a high concordance in comparison with the monomorphic marker MSI‐PCR. However, cases with a subtle MSI+ phenotype, most frequently manifest in EC, have a risk of a false‐negative result by NGS and should be preferentially analyzed by capillary electrophoresis.

Micro‐histology combined with cytology improves the diagnostic accuracy of endometrial lesions

AbstractBackgroundIn the study, we aimed to evaluate the ability of micro‐histology combined with cytology to improve the quality of slides and diagnose endometrial lesions.MethodsEndometrial specimens were collected from Li Brushes. Every specimen was prepared for micro‐histological and cytological slides, using cell block (CB) and liquid‐based cytology (LBC) technologies. Semi‐quantitative scoring system was used to evaluate the qualities of slides. CB slides were assessed by 5‐category scoring system. Diagnostic accuracy was calculated in LBC, CB, and LBC + CB groups based on the histological gold standard. Endometrial atypical hyperplasia, and endometrial cancer were considered positive, whereas others were considered negative.ResultsA total of 167 patients were enrolled. CB slides were inferior to LBC slides only in cellularity (p < 0.001), but superior in the other six parameters (allp < 0.001). The satisfaction rate of micro‐histology accounted for 92.3%. The accuracy index in the CB group was higher than in the LBC group in terms of sensitivity (85.5% vs. 82.7%) and specificity (98.9% vs. 95.7%). The sensitivity and specificity in the LBC + CB group were increased to 94.2% and 99.0%, respectively.ConclusionsThe quality of micro‐histological slides was higher than that of cytological slides. By combining micro‐histology with cytology, higher accuracy was achieved for endometrial lesions diagnosis.

Serum cholesterol and the risk of developing hormonally driven cancers: A narrative review

AbstractAlthough cholesterol has been hypothesized to promote cancer development through several potential pathways, its role in the risk of developing hormonally driven cancer is controversial. This literature review summarizes evidence from the highest quality studies to examine the consistency and strength of the relationship between serum cholesterol parameters and incidence of hormonally driven cancer. Articles were identified using EMBASE. Longitudinal observational studies published between January 2000 and December 2020 were considered for inclusion. The endpoint of interest was incident prostate, ovary, breast, endometrium, and uterine cancers. In total, 2732 reports were identified and screened; 41 studies were included in the review. No associations were found for ovarian cancer. Most endometrial cancer studies were null. The majority (76.9%) of studies reported no association between cholesterol and prostate cancer. Data on breast cancer were conflicting, associations limited, and effect sizes modest. Our results do not provide evidence for a clear association between cholesterol and different types of incident, hormonally driven reproductive cancers. Future studies should investigate the impact of lipid‐lowering therapy.

Causes of death in endometrial cancer survivors: A Surveillance, Epidemiology, and End Result–based analysis

AbstractBackgroundIncreasing attention has been paid to the survival of endometrial cancer (EC) patients, but the non‐cancer causes of death from EC are rarely reported. This study primarily aimed to investigate the non‐cancer causes of death in patients with EC.MethodsThe study collected relevant data, including age, tumour stage and treatment mode, on patients diagnosed with endometrial malignancies from 2000 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) Programme. We analysed the standardised mortality ratio (SMR) to determine the cause of death.ResultsThe study included 135,831 patients with EC. During the follow‐up, 46,604 (34.3%) patients died, of whom 42.9%, 15.6% and 41.5% died of EC, other cancers and non‐cancer causes, respectively. As the diagnosis time increased, the number of EC‐associated mortalities gradually decreased. The most common non‐cancer causes of death were heart disease, cerebrovascular disease and diabetes. Regarding the general population of the United States, patients with EC died of heart disease (SMR: 1.06; 95% confidence interval [CI]: 1.03–1.09), diabetes (SMR: 1.56; 95% CI: 1.47–1.65) and septicaemia (SMR: 1.40; 95% CI: 1.28–1.52), which were statistically significant.ConclusionsFor patients with EC, the number of deaths from non‐cancer causes (mainly heart disease, cerebrovascular disease and diabetes mellitus) is equivalent to that of EC. In addition, compared with the general population, EC survivors have a higher risk of death from sepsis and diabetes. These discoveries support how survivors can avoid future‐related health risks. By doing this, clinicians can improve the quality of life and chances of the survival of patients with EC.

FAT2 mutation is associated with better prognosis and responsiveness to immunotherapy in uterine corpus endometrial carcinoma

AbstractBackgroundUterine corpus endometrial carcinoma (UCEC) ranks sixth among malignant tumors in women and the mortality is still rising. FAT2 gene has been considered to be related to the survival and prognosis of some certain diseases in previous studies, but the FAT2 mutation status in UCEC and its prognostic value has been rarely studied. Hence, the purpose of our study was to explore the role of FAT2 mutations for predicting prognosis and responsiveness to immunotherapy in patients with UCEC.MethodsUCEC samples from the Cancer Genome Atlas database were analyzed. We evaluated the impact of FAT2 gene mutation status and clinicopathological characteristics on the prognosis of UCEC patients and used univariate and multivariate Cox analysis risk scores to independently predict patient overall survival (OS). Tumor mutation burden (TMB) values of the FAT2 mutant and non‐mutant groups were computed by Wilcoxon rank sum test. The correlation of FAT2 mutation and half maximal inhibitory concentration (IC50) values of various anticancer drugs was analyzed. Gene Ontology data and Gene Set Enrichment Analysis (GSEA) were employed to examine the differential expression of genes between the two groups. Finally, a single‐sample GSEA arithmetic was utilized to measure the abundance of tumor‐infiltrating immune cells in UCEC patients.ResultsFAT2 mutations suggested better OS (p < 0.001) and disease‐free survival (DFS) (p = 0.007) in UCEC. The IC50 values of 18 anticancer drugs were upregulated in FAT2 mutation patients (p < 0.05). The TMB and microsatellite instability values of patients with FAT2 mutations were significantly higher (p < 0.001). Next, the Kyoto Encyclopedia of Genes and Genomes functional analysis and GSEA revealed the potential mechanism of FAT2 mutation on the tumorigenesis and progression of UCEC. In addition, in reference to the UCEC microenvironment, the infiltration levels of activated CD4/CD8 T cells (p < 0.001/p = 0.001) and plasmacytoid dendritic cells (p = 0.006) were upregulated in the non‐FAT2 mutation group, and Type 2 T helper cells (p = 0.001) were downregulated in the FAT2 mutation group.ConclusionsUCEC patients with FAT2 mutations have better prognosis and are more likely to respond to immunotherapy. FAT2 mutation may be a valuable predictor for prognosis and responsiveness to immunotherapy in UCEC patients.

Stratifying the risk of ovarian cancer incidence by histologic subtypes in the Korean Epithelial Ovarian Cancer Study (Ko‐EVE)

AbstractIntroductionThis study aimed to verify the association between ovarian cancer (OC) and reproductive‐ and lifestyle‐related risk factors stratified by the subtype of OC.MethodsIn this matched case–control study derived from the Korean epithelial ovarian cancer study (Ko‐EVE), we calculated the risk of OC subtypes using odds ratios (ORs) and 95% confidence intervals (95% CIs) in a logistic regression model.ResultsAs a result of matching, 531 cases and 2,124 controls were selected. Smoking had positive association with high‐grade serous (HGS) OC (OR = 2.69, 95% CI = 1.15–6.30), whereas alcohol consumption had positive association with mucinous type (MUC) (OR = 3.63, 95% CI = 1.39–9.49). Obesity (≥30 kg/m2) was associated with clear cell type (CLC) (OR = 4.57, 95% CI = 1.06–19.77). Spontaneous abortion was negatively associated with CLC (OR = 0.34, 95% CI = 0.13–0.90), in contrast to HGS (OR = 1.43, 95% CI = 0.96–2.15). Tubal ligation, hysterectomy, and oophorectomy were associated with decreased risk of HGS (OR = 0.14, 95% CI = 0.05–0.39; OR = 0.23, 95% CI = 0.07–0.73; OR = 0.28, 95% CI = 0.08–0.97, respectively). Early menarche was strongly associated with increased risk of CLC, but not MUC (OR = 6.11, 95% CI = 1.53–24.42; OR = 3.23, 95% CI = 0.98–10.86). Further, childbirth (≥2 times) was negatively associated with endometrioid type OC and CLC (OR = 0.11, 95% CI = 0.04–0.35; OR = 0.12, 95% CI = 0.02–0.37, respectively). Oral contraceptives and hormone replacement therapy were negatively associated with OC (OR = 0.61, 95% CI = 0.40–0.93; OR = 0.51, 95% CI = 0.32–0.80, respectively), and similar negative associations were also observed in HGS (OR = 0.69; OR = 0.60, respectively). Associations between family history of breast cancer and OC, regular exercise (≥5/week), and artificial abortion and OC were similar across all subtypes (OR = 3.92; OR = 0.41; OR = 0.72, respectively).ConclusionA heterogeneous association between some risk factors and the incidence of each subtype of epithelial OC was observed, suggesting that the carcinogenic mechanisms of each subtype may be partly different.

RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells

AbstractBackgroundProgestins are used as fertility‐sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). CD163+ macrophages promote estrogen‐dependent EEC development, but whether they induce progestin insensitivity remains unclear. This study aimed to investigate the possible effects of CD163+ macrophages on progestin response in AEH/EEC patients.MethodsThe number of infiltrating CD163+ macrophages in progestin‐insensitive and ‐sensitive endometrial lesions was compared. The effects of CD163+ macrophages on progestin responses and progesterone receptor (PR) expression in EC cells were evaluated in vitro. ATAC‐seq and RNA‐seq were combined to identify molecular/biological changes induced by CD163+ macrophages in progestin‐insensitive EC cells.ResultsIncreased CD163+ macrophage infiltration was significantly associated with progestin insensitivity and longer treatment durations in AEH/EEC patients. Additionally, the number of CD163+ macrophages was negatively correlated with PR expression in AEH/EEC tissues. Furthermore, the CD163+ macrophage‐mediated microenvironment and secreted cytokines downregulated PR expression and impaired the response of EC cells to medroxyprogesterone acetate (MPA). RNA‐seq analysis demonstrated that CD163+ macrophages antagonized PR signaling by blocking or even reversing MPA‐regulated differential gene expression. Based on RNA‐seq and ATAC‐seq analyses, extracellular matrix (ECM) signaling and ECM‐related transcription factors, FOXF2, POU1F1, and RUNX1were identified to potentially be involved in CD163+ macrophage‐induced progestin insensitivity in endometrial cancer patients.ConclusionsWe identified CD163+ macrophages as an important mediator of progestin desensitization and an unfavorable factor for the efficacy of fertility‐preserving treatment in AEH/EEC patients.

APOBEC3A/B deletion polymorphism and endometrial cancer risk

AbstractBackgroundA common 30 kb deletion affecting the APOBEC3A and APOBEC3B genes has been linked to increased APOBEC activity and APOBEC‐related mutational signatures in human cancers. The role of this deletion as a cancer risk factor remains controversial.Materials and MethodsWe genotyped the APOBEC3A/B deletion in a sample of 1,470 Norwegian endometrial cancer cases and compared to 1,918 healthy controls. For assessment across Caucasian populations, we mined genotypes of the SNP rs12628403, which is in strong linkage disequilibrium with the deletion, in a GWAS dataset of 4,274 cases and 18,125 healthy controls, through the ECAC consortium.ResultsWe found the APOBEC3A/B deletion variant to be significantly associated with reduced risk of endometrial cancer among Norwegian women (OR = 0.75; 95% CI = 0.62–0.91; p = 0.003; dominant model). Similar results were found in the subgroup of endometrioid endometrial cancer (OR = 0.64; 95% CI = 0.51–0.79; p = 3.6 × 10−5; dominant model). The observed risk reduction was particularly strong among individuals in the range of 50–60 years of age (OR = 0.51; 95% CI = 0.33–0.78; p = 0.002; dominant model). In the different populations included in the ECAC dataset, the ORs varied from 0.85 to 1.05. Although five out of six populations revealed ORs <1.0, the overall estimate was nonsignificant and, as such, did not formally validate the findings in the Norwegian cohort.ConclusionThe APOBEC3A/B deletion polymorphism is associated with a decreased risk of endometrial cancer in the Norwegian population.

Cervical Adenocarcinoma: What's Special About the Long‐Term Reproductive and Oncological Outcomes of Fertility‐Sparing Radical Trachelectomy in It?

ABSTRACT Objective To present reproductive and oncological outcomes of radical trachelectomy (RT) in patients with cervical adenocarcinomas (AC). Methods This retrospective study included 51 patients with cervical AC who underwent RT at Peking Union Medical Hospital from January 1, 2005 to June 1, 2023. Results Five patients (9.8%) experienced cervical stenosis following RT, which likely occurred in cases of abdominal RT (50%) and virginal prophylactic cerclage (33.33%) and those without copper T intrauterine devices during RT (20%). In total, 30 patients (58.82%) attempted to conceive, and 11 (36.67%) succeeded. Five patients (45.45%) achieved pregnancy with fertility assistance. The mean surgery–pregnancy interval was 27 months (range, 17–118). Two preterm and two full‐term births were achieved. With a median follow‐up of 50 months (range, 7–238), seven patients (13.73%) experienced recurrence and three (5.88%) died. Six of seven patients relapsed beyond the residual cervix. The cancer recurrence rate (CRR) was 5.88% for patients with pre‐cervical conization and 17.65% for those with biopsy ( p  = 0.250); 11.63% had human papillomavirus‐associated (HPVA) disease and 25% had non‐HPVA (NHPVA) ( p  = 0.313). The cancer death rate (CDR) was 4.65% with HPVA and 12.50% with NHPVA ( p  = 0.386); 13.63% had the endogenous type and 0 had the exogenous type ( p  = 0.04). Chemotherapy in patients with risk factors resulted in better CRR and CDR than in those without (5.88% vs. 17.65%, 0% vs. 8.82%). The cumulative 5‐year recurrence‐free survival (RFS) and overall survival rates were 82.03% and 94.39%, respectively. Conclusion RT in patients with AC led to an acceptable pregnancy rate but a higher CRR and lower 5‐year RFS. Careful patient selection for RT, combined with adjuvant chemotherapy when indicated, is crucial to optimize the balance between reproductive and oncological outcomes in AC.

Multi‐omics analysis of the oncogenic value of copper Metabolism‐Related protein COMMD2 in human cancers

AbstractBackgroundThe copper metabolism MURR1 domain (COMMD) protein family is involved in tumorigenicity of malignant tumors. However, as the member of COMMD, the role of COMMD2 in human tumors remains unknown.MethodsWe used The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA) database, Cancer Cell Line Encyclopedia (CCLE) platform, univariate Cox regression analysis, Kaplan–Meier curve, cBioPortal, UALCAN database, Sangerbox online platform, GSCA database gene set enrichment analysis (GSEA), and GeneMANIA to analyze the expression of COMMD2, its prognostic values, genomic alteration patterns, and the correlation with tumor stemness, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrates, drug sensitivity, and gene function enrichment in pan‐cancer. qRT‐PCR, CCK‐8, EdU, wound healing, and transwell migration assays were performed to confirm the function of COMMD2.ResultsCOMMD2 was strongly expressed in most cancer types. Elevated COMMD2 expression affects the prognosis, clinicopathological stage, and molecular or immune subtypes of various tumors. Moreover, promoter hypomethylation and mutations in the COMMD2 gene may be associated with its high expression and poor survival. Additionally, we discovered that COMMD2 expression was linked to tumor stemness, TMB, MSI, immune cell infiltration, immune‐checkpoint inhibitors, and drug sensitivity in pan‐cancer. Furthermore, the COMMD2 gene co‐expression network is constructed with GSEA analysis, displaying significant interaction of COMMD2 with E2F targets, G2‐M checkpoint, and mitotic spindle in bladder cancer (BLCA). Finally, RNA interference data showed suppression of COMMD2 prevented proliferation and migration of BLCA and uterine corpus endometrial carcinoma (UCEC) cells.ConclusionOur findings shed light on the COMMD2 functions in human cancers and demonstrate that it is a promising prognostic biomarker and therapeutic target in pan‐cancer.

Membranous and nuclear staining of CLDN18 in HPV‐independent and HPV‐associated endocervical adenocarcinomas

AbstractObjectivesA classification system for endocervical adenocarcinoma (ECA) based on high‐risk human papillomavirus (HPV) status has been established; however, the immunohistochemical markers distinguishing HPV‐independent and HPV‐associated ECAs have not been fully described. Here, we aimed to characterize ECA immunopathological features.MethodsWe evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV‐independent ECAs and 50 HPV‐associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed.ResultsMembranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV‐independent ECAs, including eight gastric‐type ECAs (G‐ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV‐independent ECAs. Among HPV‐associated ECAs, CLDN18 (M) expression levels in intestinal‐type (I‐ECAs) and usual‐type ECAs (U‐ECAs) were significantly different from those in invasive stratified mucin‐producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal‐type and 39.4% (13/33) of usual‐type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p < 0.001).ConclusionMembranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV‐independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new immunohistochemical marker for diagnosing Silva pattern A HPV‐associated ECAs and is associated with a good prognosis. Further studies should investigate the therapeutic and prognostic significance of membranous and nuclear CLDN18 expression and develop a related test that can be implemented in the clinical evaluation of ECAs.

Construction and validation of a prognostic model based on 11 lymph node metastasis‐related genes for overall survival in endometrial cancer

Abstract Background Endometrial cancer (EC) is one of the most common malignant tumors in female reproductive system. The incidence of lymph node metastasis (LNM) is only about 10% in clinically suspected early‐stage EC patients. Discovering prognostic models and effective biomarkers for early diagnosis is important to reduce the mortality rate. Methods A least absolute shrinkage and selection operator (LASSO) regression was conducted to identify the characteristic dimension decrease and distinguish porgnostic LNM related genes signature. Subsequently, a novel prognosis‐related nomogram was constructed to predict overall survival (OS). Survival analysis was carried out to explore the individual prognostic significance of the risk model and key gene was validated in vitro. Results In total, 89 lymph node related genes (LRGs) were identified. Based on the LASSO Cox regression, 11 genes were selected for the development of a risk evaluation model. The Kaplan–Meier curve indicated that patients in the low‐risk group had considerably better OS ( p  = 3.583e−08). The area under the ROC curve (AUC) of this model was 0.718 at 5 years of OS. Then, we developed an OS‐associated nomogram that included the risk score and clinicopathological features. The concordance index of the nomogram was 0.769. The survival verification performed in three subgroups from the nomogram demonstrated the validity of the model. The AUC of the nomogram was 0.787 at 5 years OS. Proliferation and metastasis of HMGB3 were explored in EC cell line. External validation with 30 patients in our hospital showed that patients with low‐risk scores had a longer OS ( p ‐value = 0.03). Finally, we revealed that the most frequently mutated genes in the low‐risk and high‐risk groups are PTEN and TP53, respectively. Conclusions Our results suggest that LNM plays an important role in the prognosis, and HMGB3 was potential as a biomarker for EC patients.

Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer

AbstractBackgroundMismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer.MethodsThis was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR‐D) tumors were identified as MLH1 methylated or nonmethylated by methylation‐specific multiplex ligation‐dependent probe amplification. Tumors with abnormal p53 staining or polymerase ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as “no specific molecular profile” (NSMP). Disease‐specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion.ResultsA total of 505 patients were included in the study. Median follow‐up time was 81 months (range 1–136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease‐specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease‐specific survival in the full MMR‐D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease‐specific survival in MMR‐D nonmethylated tumors (n = 70).ConclusionMMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy.

Adjuvant radiotherapy shows benefit in selected stage I uterine sarcoma: A risk scoring system based on a population analysis

AbstractBackgroundThe potential therapeutic benefit of adjuvant radiotherapy for patients with stage I uterine sarcoma has not been clear. In this study, we aimed to develop a risk scoring model to select the subgroup of patients with stage I uterine sarcoma who might benefit from adjuvant radiotherapy.MethodsPatients with stage I uterine sarcoma from the Surveillance, Epidemiology, and End Results program from 2010 to 2014 were retrospectively included in this analysis. Cox proportional hazards models were performed to identify risk factors.ResultsA total of 947 stage I uterine sarcoma patients were included. The 5‐year disease‐specific survival (DSS) of the overall cohort was 75.81%. Multivariate analysis identified stage (p = 0.013), tumor grade (p <0.001) and histology (p = 0.043) as independent prognostic factors for DSS, and these factors were used to generate the risk scoring model. The low‐risk group presented a better DSS than the high‐risk group (95.51% vs. 49.88%, p < 0.001). The addition of radiotherapy to surgery significantly increased the DSS in the high‐risk group compared with surgery alone (78.06% vs. 46.88%, p = 0.022), but no significant survival benefit was observed in the low‐risk group (98.36% vs. 100%, p = 0.766).ConclusionsOur risk scoring model based on stage, tumor grade, and histology predicted the outcome of patients with stage I uterine sarcoma cancer. This system may help to select stage I uterine sarcoma cancer patients who might benefit from adjuvant radiotherapy.

Survival for endometrial cancer as a second primary malignancy

AbstractBackgroundEndometrial cancer (EC) often occurs subsequently to a primary cancer arising from a different site. However, little is known regarding the survival experience of EC as a second primary (ECSP) malignancy, specifically in relation to the original primary site and prior treatment.MethodsUsing Florida's cancer registry, all EC cases (first, second, or higher‐order) diagnosed from 2005–2016 were analyzed. Kaplan–Meier methods and Cox Regression were used in a cause‐specific survival analysis.ResultsA total of 2879 clinically independent ECSPs and 42,714 first primary ECs were analyzed. The most common first primary sites for ECSPs were breast cancer (BC) (n = 1422) and colorectal cancer (CRC) (n = 359). Five‐year cause‐specific survival was 84.0% (95% CI: 83.6–84.3) for first primary ECs and 81.8% (95% CI: 80.0–83.4) for ECSPs. After adjusting for age, race/ethnicity, histology, and stage at diagnosis, ECSPs had a lower risk of EC mortality than first primary ECs (hazard ratios [HR] 0.88, 95% CI: 0.79–0.97). ECSPs with a first primary CRC had a higher risk of EC‐specific death (HR 1.47, 95% CI: 1.04–2.06) compared to ECSPs that followed BC in multivariable analysis. Finally, women who had chemotherapy for ECSP and preceding BC did not have a higher risk of death (HR 0.80, 95% CI: 0.49–1.31) compared to those who only received chemotherapy for first primary EC.ConclusionsECSPs present a complex clinical profile. ECSP survival is superior to that of first primary EC. However, ECSPs following CRC may constitute a population of interest for their worse prognosis. Chemotherapy for a previous BC does not seem to impact the effectiveness of chemotherapy for ECs.

Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C‐reactive protein, fasting insulin, and estradiol

AbstractBackgroundMechanisms underlying the adiposity–cancer relationship are incompletely understood. We quantified the mediating roles of C‐reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)‐positive breast, endometrial, and colorectal cancer risk in postmenopausal women.MethodsWe used a case–cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case–control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.ResultsFor breast cancer, the total effect RR for BMI ≥30 versus ≥18.5–<25 kg/m2 was 1.87 (95%CI,1.11–3.13). The indirect effect RRs were 1.38 (0.79–2.33) through leptin and CRP, 1.58 (1.17–2.43) through insulin, and 1.11 (0.98–1.30) through estradiol. The direct effect RR was 0.82 (0.39–1.68). For endometrial cancer, the total effect RR was 2.12 (1.12–4.00). The indirect effect RRs were 1.72 (0.85–3.98) through leptin and CRP, 1.42 (0.96–2.26) through insulin, and 1.24 (1.03–1.65) through estradiol. The direct effect RR was 0.70 (0.23–2.04). For colorectal cancer, the total effect RR was 1.70 (1.03–2.79). The indirect effect RRs were 1.04 (0.61–1.72) through leptin and CRP, 1.36 (1.00–1.88) through insulin, and 1.02 (0.88–1.17) through estradiol. The direct effect RR was 1.16 (0.58–2.43).ConclusionLeptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity‐associated cancer risk in postmenopausal women.

Preoperative magnetic resonance imaging predicts clinicopathological parameters and stages of endometrial carcinomas

ABSTRACTBackgroundWe investigated the agreement and accuracy of preoperative magnetic resonance imaging (MRI) with postoperative pathological characteristics and stages of endometrial endometrioid carcinoma (EEC).MethodsWe recruited 527 women with EEC who underwent staging surgery at a single medical institution. The preoperative MRI, stages, and clinical and pathological parameters, including myometrial invasion (MI), cervical invasion (CI), adnexal metastasis (AM), intra‐abdominal metastasis, and pelvic and/or para‐aortic nodal metastasis, were recorded and analyzed. The agreement and accuracy between the preoperative MRI findings and these parameters and stages were assessed.ResultsThe rate of the preoperative MRI‐based clinical stage matching the postoperative surgical stage was 85.2% in International Federation of Gynecology and Obstetrics stage IA, 51.9% in stage IB, 35.5% in stage II, 5.3% in stage IIIA, 33.3% in stage IIIB, 28.6% in stage IIIC1, 64.3% in stage IIIC2, and 93.8% in stage IVB. The consistency between radiologists and pathologists was 80.5% for deep MI, 91.5% for cervical invasion, 92.2% for adnexal metastasis, 98.9% for intra‐abdominal metastasis, and 87.5% and 92.2% for pelvic and para‐aortic nodal metastases, respectively. The negative predictive value of intra‐abdominal metastasis was the highest with 99.8%.ConclusionsPreoperative MRI could be an excellent tool for routine preoperative assessment to predict pathological parameters and stages of EEC, especially in excluding intra‐abdominal metastatic disease.

Identifying a molecular profile to predict the risk of recurrence in high‐intermediate risk endometrial cancer

AbstractBackgroundPatients with high‐intermediate risk endometrial cancer (H‐IR EMCA) have an elevated risk of recurrence compared to low‐risk counterparts. Many H‐IR EMCA patients are treated with radiation or chemotherapy, but their overall survival is not significantly impacted by treatment. The objective of this study was to compare molecular profiles of H‐IR EMCA patients with disease recurrence to those without to identify characteristics that could better predict patient outcomes.MethodsTissue was acquired from H‐IR EMCA patients with disease recurrence (n=15) and without disease recurrence (n=15) who had not received adjuvant therapy and performed DNA and RNA analyses.ResultsIn recurrent population, 5 patients had matchingrecurrent and initial tumor tissues. Of note, 5/7 (71%) African Americanpatients had disease recurrence compared to 10/23 (43%) White patients. Inaddition, several new mutations were found in individual patient’s recurrentcompared to initial tumors.ConclusionsCurrently the treatment ofendometrial cancer is rapidly changing with molecular profiling becoming partof the standard of care. Additionally, it and is being incorporated intoclinical trials in this group of patients. The specific gene mutations and RNAexpression signatures that were observed in our small cohort need to bevalidated in larger cohorts to determine their impact.

Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

AbstractGrade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

Increased risk of second primary malignancies among endometrial cancer survivors receiving surgery alone: A population‐based analysis

AbstractBackgroundWomen with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results.MethodsData from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated.ResultsAmong 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59–3.10) compared with the general female population. Women diagnosed with EC at age <50 years had a higher SIR for an SPC than those diagnosed at age ≥50 years (SIR = 4.38 vs. 1.28). The most frequent site of an SPC was the small intestine (SIR = 8.39, 95% CI 2.72–19.58), followed by the kidney (SIR = 4.84, 95% CI 1.78–10.54), and oral cavity (SIR = 4.52, 95% CI 2.17–8.31). Women, regardless of age at EC diagnosis, had significantly higher SIRs for subsequent breast, colorectal, lung, and thyroid cancer, and lymphoma. Women with an SPC had shorter overall survival than those without (5‐year: 88.9 vs. 94.2%, 10‐year: 71.3 vs. 89.8%, 15‐year: 62.3 vs. 86.1%, and 20‐year: 47.6 vs. 81.1%, all ps<0.001).ConclusionsEven women treated for EC with surgery alone, especially young EC survivors, had an increased risk of SPCs. Genetic counseling/testing is recommended for young EC patients, and all are recommended to receive regular surveillance and screening for breast, colorectal, and lung cancers.

Sensitivity of cervical cytology in endometrial cancer detection in a tertiary hospital in Spain

AbstractIntroductionCervical cytology is a well‐stablished cervical cancer screening method. However, due to the anatomical continuity of the genital tract, it can also detect signs of endometrial disease. Our aim was to estimate the sensitivity of cervical cytology in endometrial cancer detection and prognosis in a large population over a 30‐year period in a large academic tertiary hospital in Spain.MethodologyWe performed a search for women diagnosed with endometrial cancer from 1990 to 2020, who were surgically treated and had a previous cervical cytology result. Information Technologies Department databases from Bellvitge University Hospital and the Screenwide case–control study's database were used. Cervical cytology results were classified as abnormal when squamous lesions, glandular atypia or malignant cells were identified.ResultsOverall, we evaluated 371 women with endometrial cancer and a documented cervical cytology performed within 3 years previous to surgical treatment. Overall, the sensitivity of cervical cytology for endometrial cancer detection was 25.6%. Several clinico‐pathological characteristics, such as non‐endometrioid histology and a higher stage, were correlated with higher sensitivity.DiscussionWe observed a low sensitivity of cervical cytology to effectively diagnose endometrial cancer. However, recent technological advances using genomics and epigenomics may offer a promising perspective to detect endometrial cancer with high sensitivity in these cervical specimens.

Establishment and validation of a prognostic nomogram based on a novel five‐DNA methylation signature for survival in endometrial cancer patients

AbstractBackgroundThis study aimed to explore the prognostic role of DNA methylation pattern in endometrial cancer (EC) patients.MethodsDifferentially methylated genes (DMGs) of EC patients with distinct survival from The Cancer Genome Atlas (TCGA) database were analyzed to identify methylated genes as biomarkers for EC prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) analysis was used to construct a risk score model. A nomogram was built based on analysis combining the risk score model with clinicopathological signatures together, and then verified in the validation cohort and patients in our own center.ResultsIn total, 157 DMGs were identified between different prognostic groups. Based on the LASSO analysis, five genes (GBP4, OR8K3, GABRA2, RIPPLY2, and TRBV5‐7) were screened for the establishment of risk score model. The model outperformed in prognostic accuracy at varying follow‐up times (AUC for 3 years: 0.824, 5 years: 0.926, and 7 years: 0.853). Multivariate analysis identified four independent risk factors including menopausal status (HR = 3.006, 95%CI: 1.062–8.511, p = 0.038), recurrence (HR = 2.116, 95%CI: 1.061–4.379, p = 0.046), lymph node metastasis (LNM, HR = 3.465, 95%CI: 1.225–9.807, p = 0.019), and five‐DNA methylation risk model (HR = 3.654, 95%CI: 1.458–9.161, p = 0.006) in training cohort. The performance of the nomogram was good in the training (AUC = 0.828), validation (AUC = 0.866) and the whole cohorts (AUC = 0.843). Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan–Meier survival curve also proved to be significantly different (p < 0.01). The subgroup analysis in different stratifications indicated that the accuracy was high in different subgroups for age, histological type, tumor grade, and clinical stage (all p < 0.01).ConclusionsBriefly, our work established and verified a five‐DNA methylation risk model, and a nomogram merging the model with clinicopathological characteristics to facilitate individual prediction of EC patients for clinicians.

Weight and weight control behaviors during long‐term endometrial cancer survivorship: Results of the Laparoscopic Approach to Cancer of the Endometrium long‐term follow‐up study

AbstractBackgroundOverweight or obesity is common in endometrial cancer (EC). This study aimed to examine sociodemographic, clinical, and psychosocial characteristics associated with being discontent with current weight and use of weight control methods among long‐term EC survivors.MethodsWomen diagnosed with early‐stage EC who participated in the Laparoscopic Approach to Cancer of the Endometrium (LACE) trial (n = 516) were invited to complete a long‐term follow‐up survey at least 4.5 years after treatment. Chi‐square test and multivariate logistic regression models adjusted for time since surgery were used to determine factors associated with being discontent with current weight.ResultsOn average 9 years after surgery, 190/259 (73%) of participants were currently discontent with their weight, and 146 (56%) had used one or more weight loss methods during the past 12 months. Women who were discontent with their weight were more likely to be younger than 70 years (p < 0.000), and used one or more weight loss methods ever or during the past 12 months (p < 0.000). Among the weight loss methods used, exercise (40.1%), meal reductions (52.7%), or fat/sugar reductions (48.5%) were much more commonly reported than fasting (2.6%) or designated weight loss programs (2.3%).ConclusionsOur study provides evidence that the majority of long‐term EC survivors in this clinical trial population are discontent with their weight and over half continue to use multiple methods to lose weight each year. These data indicate that health professionals and lifestyle educators need to assess weight issues, and develop a tailored plan to address the specific needs of long‐term survivors to assist them become content with their weight after treatment for EC.

Competing risk nomogram predicting cancer‐specific mortality for endometrial cancer patients treated with hysterectomy

AbstractBackgroundThe incidence of endometrial cancer has tended to increase in recent years. However, competing risk nomogram combining comprehensive factors for endometrial cancer patients treated with hysterectomy is still scarce. Therefore, we aimed to build a competing risk nomogram predicting cancer‐specific mortality for endometrial cancer patients treated with hysterectomy.MethodsPatients diagnosed with endometrial cancer between 2010 and 2012 were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database. Competing risk model was performed to select prognostic variables to build the competing risk nomogram to predict the cumulative 3‐ and 5‐year incidences of endometrial cancer‐specific mortality. Harrell's C‐index, receiver operating characteristic (ROC) curve, and calibration plot were used in the internal validation. And decision curve analysis was applied to evaluate clinical utility.ResultsA total of 10,447 patients were selected for analysis. The competing risk nomogram identified eight prognostic variables, including age at diagnosis, race, marital status at diagnosis, grade, histology, tumor size, FIGO stage, and number of regional nodes positive. The C‐index of the competing risk nomogram was 0.857 (95% confidence interval [CI]: 0.854–0.859), and the calibration plots were adequately fitted. When the threshold probabilities were between 1% and 57% for 3‐year prediction and between 2% and 67% for 5‐year prediction, the competing risk nomogram was of good clinical utility.ConclusionsA competing risk nomogram for endometrial cancer patients treated with hysterectomy was successfully built and internally validated. It was an accurately predicted and clinical useful tool, which could play an important role in consulting and health care management of endometrial cancer patients.

Development of a Mitochondrial Permeability Transition‐Driven Necrosis‐Related Prognostic Signature in Cervical Cancer: Integrating Bulk Transcriptomic and Single‐Cell Data

ABSTRACT Background Cervical cancer (CC) is a prevalent gynecological malignancy with notable heterogeneity. The role of mitochondrial permeability transition (MPT)‐driven necrosis, a form of cell death due to mitochondrial dysfunction, in CC progression and prognosis is poorly understood and represents a promising therapeutic target for cancers. This study aimed to create a new prognostic signature linked to MPT‐driven necrosis, improving CC prediction and prognosis. Methods This study utilized the GSE63514, TCGA‐CESC, CGCI‐HTMCP‐CC, and GSE197641 transcriptome datasets. Firstly, the GSE63514 dataset was utilized to identify differentially expressed genes (DEGs). Differentially expressed MPT‐driven necrosis‐related genes (DE‐MRGs) were obtained by intersecting DEGs with MRGs. Regression analyses were performed to identify genes significantly associated with prognosis. A prognostic model was established in TCGA‐CESC, followed by independent validation and nomogram construction. Additional analyses included immune infiltration, enrichment analysis, and drug susceptibility based on high‐ and low‐risk groups. Finally, cell communication analysis was performed to investigate interactions between key cell types. Results A total of 156 DE‐MRGs were identified. Regression analyses identified three prognostic genes ( ICOS , MMP3 , and POSTN ) to construct a prognostic risk signature. Then, risk score was an independent prognostic factor for CC, and a nomogram demonstrated effective predictive accuracy for CC survival outcomes. The risk signature was linked to immune‐associated processes such “Antigen processing and presentation” and immune cell infiltration, especially M0 macrophages and CD8 T cells. Cell communication analysis uncovered a strong interaction between endothelial cells and monocytes. To validate the molecular mechanisms, qRT‐PCR, cell proliferation, and wound healing assays were performed. Functional tests showed that MMP3 and POSTN knockdown drastically reduced CC cell growth and migration. Conclusion This study developed a novel prognostic risk signature based on ICOS , MMP3 , and POSTN . MMP3 and POSTN knockdown significantly decrease CC cell growth and migration, highlighting their potential as therapeutic targets.

Jupiter microtubule‐associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers

AbstractPreoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre‐ and post‐metformin‐treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)‐based proteomic and immunohistochemical analyses. Jupiter microtubule‐associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95‐2 and ACI‐181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95‐2 and ACI‐181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response.

Prevalence of Lynch syndrome in women with mismatch repair‐deficient ovarian cancer

AbstractBackgroundThere are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR‐D) by immunohistochemistry (IHC).Materials and MethodsThree hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR‐D by IHC. The incidence of LS in this cohort was evaluated.ResultsMMR‐D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%–8.3%) primary ovarian‐related cancers. Most cases with MMR‐D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%–86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%–72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%–50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%–86.5%) were confirmed to have LS.ConclusionsMost ovarian cancers with somatic MMR‐D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non‐Lynch germline mutation identified in this cohort.

The fallopian tube as origin of ovarian cancer: Change of diagnostic and preventive strategies

AbstractOvarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high‐grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk‐reducing bilateral salpingo‐oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high‐risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients’ quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches.

A Critical Analysis of the Impact of Etoposide as a Topoisomerase II Inhibitor in Cervical Cancer Treatment: A Review

ABSTRACT Background Etoposide is a semisynthetic derivative of podophyllotoxin and an FDA‐approved topoisomerase II inhibitor that induces DNA strand breaks leading to cancer cell death. Cervical cancer remains the fourth most common cancer among women worldwide, with platinum‐based chemotherapy constituting the standard of care. Although etoposide has demonstrated broad anticancer activity, its role in cervical cancer therapy is considered secondary and is mainly explored in combination regimens. Methods This review summarizes published clinical and preclinical studies evaluating the use of etoposide in cervical cancer, both as monotherapy and in combination with other chemotherapeutic agents. Emphasis is placed on treatment regimens, disease stages, routes of administration, limitations, and emerging strategies aimed at improving therapeutic outcomes. Results The etoposide has been administered orally or intravenously and has shown clinical benefit primarily when used in combination therapies, including cisplatin, topotecan, mitomycin, epirubicin, doxorubicin, vincristine, cyclophosphamide, bevacizumab, and adriamycin. Its application is mainly observed in FIGO stage IA2–IB2, as well as in recurrent or metastatic cervical cancer. However, platinum‐based regimens, particularly cisplatin or carboplatin combined with paclitaxel, topotecan, fluorouracil, or bevacizumab, remain superior in efficacy. Limitations such as drug resistance and systemic toxicity have restricted the widespread use of etoposide. Recent research has focused on nanocarriers, dual inhibitors, and polymeric implants to enhance its therapeutic index and reduce adverse effects. Conclusion While etoposide is an effective topoisomerase II inhibitor with proven anticancer activity, its role in cervical cancer remains adjunctive rather than primary. Combination‐based strategies and advanced drug‐delivery systems hold promise for improving its clinical utility. Continued research is essential to overcome resistance and toxicity, potentially expanding the therapeutic relevance of etoposide in cervical cancer management.

Theory‐based behavior change intervention to increase uptake of risk‐reducing salpingo‐oophorectomy in women with a BRCA1 or BRCA2 pathogenic variant: The PREVENT randomized controlled trial

AbstractObjectiveTo evaluate the effect of a theory‐based behavioral intervention delivered by genetic counselors on the uptake of risk‐reducing salpingo‐oophorectomy (RRSO) at 12 and 24 months by women with a BRCA1 or BRCA2 pathogenic variant (PV) compared to women who received usual care.MethodsIn this two‐arm, multi‐site randomized controlled trial participants were randomized to receive a theoretically‐guided behavioral telephone intervention or usual care. Outcome data were collected at 12 and 24 months. Participants in the usual care arm were offered the intervention after 12 months.ResultsData on 107 participants were included in the analysis. There was no significant difference in the proportion of women who had a RRSO by 1 year (28.6%‐ intervention; 22.9%‐ usual care (p = 0.54)). At 1 year, women who received the intervention had significantly lower mean decisional conflict (pinteraction <0.001) and a higher mean knowledge score at one‐year compared to usual care (pinteraction <0.001). At 2 years, 53.9% of participants in the intervention arm had RRSO compared to 32.6% in usual care (p = 0.05).ConclusionsA theory‐based behavioral intervention delivered by genetic counselors to women with a BRCA PV who chose not to have the recommended RRSO was effective at reducing decisional conflict and increasing knowledge in women with a BRCA1 or BRCA2 PV.

Development and Validation of Prediction Models for the Prognosis of Clear Cell Adenocarcinoma of the Cervix: A Population‐Based Cohort Study

ABSTRACT Aims Clear cell adenocarcinoma of the cervix (CCAC) is a rare and aggressive malignancy with poor prognosis. This study aimed to develop and validate nomograms and risk‐stratification scores for predicting overall survival (OS) and cancer‐specific survival (CSS) in CCAC patients. Methods Data from 429 CCAC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2019). Patients were randomly assigned to training and validation sets. Cox regression analysis identified five independent prognostic factors for OS and CSS, which were used to construct nomograms for predicting 1‐, 3‐, and 5‐year OS and CSS. The models were evaluated using receiver operating characteristic (AUC) analysis, calibration curves, and decision curve analysis (DCA). The clinical utility of the nomograms was compared with the 2018 FIGO Stage System using C‐index, NRI, and IDI. Patients were stratified into low‐ and high‐risk groups based on predicted risk scores, and Kaplan–Meier survival analysis was performed. Results Multivariate Cox regression identified age at diagnosis, tumor size, and surgery as independent prognostic factors for both OS and CSS, while chemotherapy and radiotherapy were specifically associated with OS and CSS. The C‐index for OS and CSS in the training set was 0.83 and 0.84, respectively. The AUC for 1‐, 3‐, and 5‐year OS and CSS in the training set was 0.95, 0.95, and 0.88, respectively, with similar results in the validation set. Calibration curves showed good agreement between predicted and actual outcomes. DCA, NRI, and IDI analyses indicated that the nomogram outperformed the 2018 FIGO Stage System. Survival analysis revealed that high‐risk patients had worse prognosis compared to low‐risk patients. Conclusion This study developed and validated nomograms for predicting OS and CSS in CCAC patients using SEER data. These models offer a more accurate prognostic tool, enhancing clinical decision‐making and enabling individualized treatment planning.

Development of a Culturally Sensitive Intervention for Cervical Cancer Screening Promotion for Latinx Transgender Individuals

ABSTRACT Introduction Trans men and non‐binary people face some of the most challenging cancer health disparities. Primary care physicians could play a key in addressing these, but many clinicians' lack the necessary skill to discuss cervical screening with trans people as these are not routinely taught in medical school. Thus, the objective of this study was to develop an intervention to foster medical students' skills for cervical cancer screening and to examine its initial impact and feasibility. Methods Our research team is comprised of academic researchers, clinicians, and community members. Together, we developed a 2‐h intervention which we implemented using Standardized Patient Simulations (TM actors portraying the role of a TM patient) to observe provider behaviors (general care behaviors, gender affirming behaviors and cervical cancer preventive behaviors) and self‐reported measures to examine study outcomes. The total sample consisted of 37 third‐year medical students. Welch's t ‐test was used to compare the intervention effects on all outcomes. Results Results suggest the intervention had medium to large effects on all examined behaviors. Behaviors improved in the experimental group compared to the control group and all changes were statistically significant. In general, the intervention was seen as feasible and appropriate with participants mentioning it was “very helpful” and emphasizing the importance of discussing trans health care as part of their medical training as this improves their “confidence.” Discussion Although the sample size was small, results show a potentially promising intervention. We provide an overview of the content of the intervention and discuss future research directions.

Native American Women's Willingness to Screen for Both Cervical and Colorectal Cancer at Home

ABSTRACT Introduction Fewer than 50% of Native American (NA) women screen for both cervical and colorectal (CRC) cancer. We aim to explore the perspectives of NAs around cervical and colorectal cancer home‐based self‐screening options. Methods The NA community provided review and approval for this cross‐sectional survey on cancers in general, and specifically on cervical and colorectal cancer screening. We invited screen‐eligible Native American women, aged 45–65 years, who attended the Lakota Nation Invitational tournament in December 2023, to complete the survey. Results One hundred women, with a mean age of 54.1 (SD 6.3), completed the survey. Respondents reported visiting their doctor once a year, rarely (10%), with 66% experiencing a poor experience accessing healthcare—only 16% self‐reported screening for both cervical and colorectal cancers within the last 5 years. If the participant could screen for both cervical and CRC cancer at home, 83.0% said they would be willing to do both, compared to 9% who would do neither at home. The doctor's recommendation for how to screen for cervical and CRC cancer was the most important factor in screening decision‐making. The other two very important reasons were how easy or convenient the screening is, how comfortable I am with the screening process/what happens to me during the test. Conclusions With the recommendation of their doctors, and convenience and comfort being important, Native American women are enthusiastic to participate in home‐based cervical and colorectal cancer screening. While the home‐based CRC screening has been available for many years, with minimal effect on screening uptake, the advent of self‐sampling for primary HPV testing for cervical cancer appears to create interest for both tests at home. These options may increase both cancer screening rates and access to care in this underserved population.

Overexpressed CD24 and CD47 Indicate a Worse Prognosis in Cervical Cancer

ABSTRACT Background Two antiphagocytic (“don't eat me”) signals that allow tumor immune evasion have been discovered, including CD24 and CD47. This study explored the association between CD24/CD47 expression and macrophage infiltration and clinical outcomes in cervical cancer. Methods RNA expression and survival data of the Cancer Genome Atlas (TCGA) cohort were extracted from OncoLnc. The macrophage infiltration level was calculated using xCell, TIMER, and ImmuCellAI. The expression of CD24 and CD47 was detected by immunohistochemistry in tissue microarrays composed of 130 clinical cervical cancer specimens from Fudan University Shanghai Cancer Center (FUSCC). Patients' medical records were also retrospectively assessed to correlate demographic and survival data. Results Expression levels of both CD24 and CD47 in the cancer population were higher than those in the normal population. Patients with high CD24 expression had poorer survival than those with low CD24 expression in the TCGA and FUSCC cervical cancer cohorts. Although CD47 alone was not statistically significant in predicting outcomes, patients with high CD47 and low CD11c expression, a specific marker of M1‐polarized macrophages, exhibited worse survival in the TCGA cohort. Conclusions Our study implies that high CD24 expression is an important predictor of a worse prognosis, and CD24 blockade might have therapeutic potential for the treatment of cervical cancer. High expression levels of CD47 and low M1‐polarized macrophage infiltration predict a worse prognosis.

Clinical evaluation of primary human papillomavirus (HPV) testing with extended HPV genotyping triage for cervical cancer screening: A pooled analysis of individual patient data from nine population‐based cervical cancer screening studies from China

AbstractObjectiveTo assess the clinical values of extended human papillomavirus (HPV) genotyping in triage of high‐risk HPV‐positive women, focusing on the trade‐off between cervical precancer detections and colposcopy referrals.MethodsA bivariate random‐effects model was used to estimate the diagnostic accuracy of primary HPV screening with following triage strategies to detect cervical precancers: (i) partial genotyping for HPV16/18 combined with cytological testing at atypical squamous cells of undetermined significance threshold (used as the comparator), (ii) genotyping for HPV16/18/58/52, (iii) genotyping for HPV16/18/58/52/33, (iv) genotyping for HPV16/18/58/33/31, (v) genotyping for HPV16/18/58/52/33/31, and (vi) genotyping for HPV16/18/58/52/33/31/39/51. Internal risk benchmarks for clinical management were used to evaluate the risk stratification of each triage strategy.ResultsA total of 16,982 women (mean age 46.1 years, range 17–69) were included in this analysis. For CIN3+ detection, triage with HPV16/18/58/33/31 genotyping achieved lower positivity (6.85% vs. 7.35%, p = 0.001), while maintaining similar sensitivity (91.35% vs. 96.42%, p = 0.32) and specificity (94.09% vs. 93.67%, p = 0.56) compared with the comparator strategy. Similar patterns were observed for CIN2+ detection. Women with a positive HPV16/18/58/33/31 genotyping test had high enough risk for CIN3+ for colposcopy referral, while the risk for women with a negative test was below the 1‐year return decision threshold according to internal benchmarks.ConclusionsOur findings suggested extended HPV genotyping is of potential to be used as a triage technique integrated into HPV‐based cervical cancer screening, leading to reduced need for colposcopy referral while maintaining similar disease detection and efficient risk stratification.

A Pilot Study: Adaptation Phase of the PROMIS Women Education Program—Promoting Cervical Cancer Prevention Methods Among Muslim Women in Virginia

ABSTRACT Purpose The purpose of this comprehensive research project is to address the notable disparities in cervical cancer prevention experienced by Muslim women in Virginia, compared with non‐Muslim women. Low participation in prevention and control activities, such as cervical cancer screening and HPV vaccination, often leads to their diagnosis with late‐stage cervical cancer. The long‐term research goal is to develop a culturally appropriate and religiously adapted intervention program to promote cervical cancer screening and prevention among Muslim women. Driven by an integrative conceptual model, the primary aim is to adapt existing evidence‐based educational materials to create a religiously adapted and culturally appropriate intervention program to improve cancer screening rates among Muslim women in the U.S. Methods The study adapted existing evidence‐based educational materials to fit religious and cultural contexts, facilitated through focus group sessions with 10 Muslim women aged 18 and older. Additionally, interviews with five Muslim religious leaders provided feedback on the materials. The PEN‐3 model was employed to categorize and analyze cultural factors influencing health behaviors. Results Preliminary findings from the thematic analysis, structured around the three domains of cultural identity, relationships, and expectations, and cultural empowerment, indicated a strong positive reception and increased awareness among participants. Key themes identified include the importance of culturally sensitive health messages, the influential role of community leaders, and the need for educational materials that consider cultural and gender dynamics. Data saturation was reached after the second focus group session, as no new themes emerged in participating discussions. Additionally, the Community Advisory Board (CAB) actively participated in the refinement process by reviewing the educational materials alongside the research team, ensuring that the content was culturally appropriate and aligned with community needs. Participants demonstrated a heightened readiness to engage in preventive behaviors, highlighting the effectiveness of a culturally tailored educational approach.

Ethnic and racialized disparities in the use of screening services for pap smears and mammograms in Canada

AbstractBackgroundBreast and cervical cancers pose significant health challenges for women globally, emphasizing the critical importance of effective screening programs for early detection. In Canada, despite the implementation of accessible healthcare systems, ethnic and racialized disparities in cancer screening persist. This study aims to assess ethnic and racialized disparities in breast and cervical cancer screening in Canada.MethodsUsing 2015–2019 data from the Canadian Community Health Survey, we analyzed women aged 18–70 in distinct ethnic and racial groups. The primary outcome was mammography or Papanicolaou test (pap smear). The secondary outcome was time since the last screening. We used weighted multivariable logistic regression to estimate the odds of having a pap smear or mammography across the ethnic and racialized groups, adjusted for relevant covariates. Results were reported as odds ratios (ORs) with 95% confidence intervals (CIs).ResultsWe included 14,628,067 women of which 72.5% were White, 8.4% Southeast Asian, 4.7% South Asian, 3.4% Indigenous, 2.7% Black, 2.0% West Asian, and 1.6% Latin American. In comparison with the White reference group, a higher odds ratio of not having a pap smear was estimated for the West Asian (5.63; CI 3.85, 8.23), South Asian (5.19; CI 3.79, 7.12), Southeast Asian (4.35; CI 3.46, 5.46), and Black groups (2.62; CI 1.82, 3.78). Disparities in mammography screening were found only for the Southeast Asian group with higher odds of not having screening (1.85; CI 1.15, 2.98) compared to the White reference group.ConclusionThis study reveals significant disparities in pap smear and mammography screenings affecting various ethnic groups, particularly in West Asia, South Asian, and Black communities. These findings underscore the urgent need for targeted interventions, policies, and healthcare strategies to address these gaps and ensure equitable access to essential breast and cervical cancer prevention across all ethnicity.

Assessment of organization of cervical and breast cancer screening programmes in the Latin American and the Caribbean states: The CanScreen5 framework

AbstractBackgroundIn the Community of Latin American and Caribbean States (CELAC), breast cancer and cervical cancer are the first and third causes of cancer death among females. The objectives are to assess the characteristics of the cervical and breast cancer screening programmes in CELAC, their level of organization, and the association of screening organization and coverage of essential health services.MethodsRepresentatives of the Ministries of Health of 33 countries were invited to the CanScreen5 project. Twenty‐seven countries participated in a “Train The Trainers” programme on cancer screening, and 26 submitted data using standardized questionnaires. Data were discussed and validated.The level of organization of the screening programmes was examined adapting the list of essential elements of organized screening programmes identified in a recently published IARC study.ResultsTwenty‐one countries reported a screening programme for cervical cancer and 15 for breast cancer. For cervical cancer, 14 countries dedicated budget for screening (66.7%), and women had to pay in 3 countries for screening (14.3%), 9 for diagnosis (42.9%) and 8 for treatment (38.1%). Only 4 countries had a system to invite women individually (19.0%). For breast cancer, 8 countries dedicated budget for screening (53.3%), and women had to pay for screening in 3 countries (20.0%), diagnosis in 7 (46.7%) and treatment in 6 (40.0%). One country (6.7%) invited women individually.There was variability in the level of organization of both cancer screening programmes. The level of organization of cervical cancer screening and coverage of essential health services were correlated.ConclusionLarge gaps were identified in the organization of cervical and breast cancer screening services. CELAC governments need pragmatic public health policies and strengthened health systems. They should guarantee sustainable funding, and universal access to cancer diagnosis and treatment. Moreover, countries should enhance their health information system and ensure adequate monitoring and evaluation.

Resveratrol: Sensitising CD44+ Cervical Cancer Cells to Carboplatin and Mitigating Metastasis

ABSTRACT Background Cervical cancer remains a leading cause of cancer‐related mortality among women globally. Persistent infection with high‐risk human papillomavirus drives cervical carcinogenesis, and treatment outcomes are frequently challenged by metastasis and chemoresistance. The transmembrane glycoprotein cluster of differentiation 44 (CD44), a marker associated with cancer stem cells (CSCs), has emerged as a critical mediator of both processes in cervical cancer. Objective This review aims to critically evaluate current evidence on the role of CD44 in cervical cancer progression, metastasis, and treatment resistance. It also explores the potential of resveratrol, a naturally occurring polyphenol with known anticancer properties, as a chemo‐sensitizing agent to carboplatin therapy. Methods A comprehensive review of the literature was conducted using databases such as PubMed, Google Scholar, and Scopus to identify studies that investigate CD44‐mediated mechanisms in cervical cancer, as well as the modulatory and mechanistic effects of resveratrol on CD44 and chemoresistance across various cancer types. Results CD44 has been consistently implicated in promoting drug resistance, epithelial‐to‐mesenchymal transition (EMT), and stemness in cervical cancer. Resveratrol has demonstrated antimetastatic and chemo‐sensitizing effects in several malignancies, such as colorectal and breast cancers, often through modulation of CD44 and associated pathways. However, direct evidence in cervical cancer remains limited. Conclusion Current findings suggest a promising therapeutic avenue for combining resveratrol with carboplatin to overcome CD44‐mediated treatment resistance and metastasis in cervical cancer. Nonetheless, further cervical‐specific studies are needed to validate this approach. A clearer understanding of this relationship may facilitate lower chemotherapy dosing, reduced toxicity, and improved clinical outcomes.

Efficacy of chemotherapy combined with surgical resection for gastric cancer with synchronous ovarian metastasis: A propensity score matching analysis

AbstractBackgroundOvarian metastasis from gastric cancer (GC) is characterized by aggressive biological behavior and poor outcome. Currently, there is no standard treatment mode for such patients. Thus, we evaluated the efficacy of conversion therapy in patients with synchronous ovarian metastasis from GC in this study.MethodsAbout 219 GC patients with ovarian metastasis in 2011–2020 were enrolled. Two groups were established based on the different treatment: the conversion therapy group (chemotherapy combined with surgical resection, CS group) and the non‐conversion therapy group (NCS group). Propensity score matching (PSM) was used to analyze the efficacy of different treatment modes on the prognosis of these patients.ResultsNinety‐two patients were included according to PSM results, with 46 patients each in CS and NCS groups. The median overall survival (OS) in the CS group was notably better than that in the NCS group (p < 0.001). Twenty‐six patients (56.52%) in the CS group achieved R0 resection, and they had a better prognosis (p = 0.003). Compared with patients who underwent simultaneous gastrectomy and ovarian metastasectomy (CSb group), those who underwent ovarian metastasectomy before systemic chemotherapy (CSa group) had a higher R0 resection rate (p = 0.016) and longer survival time (p = 0.002). A total of 38 patients (41.30%) across both groups received hyperthermic intraperitoneal chemotherapy (HIPEC), and these patients had a better survival (p = 0.043).ConclusionThe conversion therapy is safe and effective for patients with synchronous ovarian metastasis from GC and can improve their prognosis. However, our results need to be confirmed by more randomized controlled clinical studies.

Personalised Medicine in Cervical Cancer: Evaluating Therapy Resistance Through Multi‐Model Approaches

ABSTRACTIntroductionCervical cancer remains a leading cause of malignancy among women globally, disproportionately affecting women from low‐to‐middle‐income countries, including South Africa. The high prevalence in impoverished communities places significant pressure on the public healthcare system. In these regions, human papillomavirus (HPV); the primary risk factor for cervical cancer—along with co‐occurring immunosuppressive conditions such as HIV, is common. Compounding this burden is the widespread development of treatment resistance to conventional therapies like cisplatin and carboplatin. Resistance is frequently associated with therapy‐induced cellular senescence, underscoring the need for more personalised treatment strategies tailored to individual patient profiles.Methods and MaterialsThis study aimed to assess ex vivo methods' utility in predicting patient‐specific therapy responses. Biopsy samples from cervical cancer patients were cultured and subjected to various chemotherapies. Cell viability, senescence markers and treatment resistance pathways were analysed to determine optimal treatment outcomes.ResultsThe findings revealed significant variability in optimal treatment responses, with ex vivo methods demonstrating limitations in fully capturing the complexity of patient‐specific reactions to therapy. No single experimental model provided comprehensive predictive insights into treatment outcomes.ConclusionThis study underscores the need for integrative and multidisciplinary approaches when evaluating treatment strategies for cervical cancer. While ex vivo models offer valuable insights, combining multiple experimental methods is crucial for a more reliable and comprehensive understanding of treatment response and resistance mechanisms. Standardiszing approaches or employing method combinations may enhance personalised medicine efforts, particularly in resource‐limited settings.

Bayesian and deep‐learning models applied to the early detection of ovarian cancer using multiple longitudinal biomarkers

AbstractBackgroundOvarian cancer is the most lethal of all gynecological cancers. Cancer Antigen 125 (CA125) is the best‐performing ovarian cancer biomarker which however is still not effective as a screening test in the general population. Recent literature reports additional biomarkers with the potential to improve on CA125 for early detection when using longitudinal multimarker models.MethodsOur data comprised 180 controls and 44 cases with serum samples sourced from the multimodal arm of UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Our models were based on Bayesian change‐point detection and recurrent neural networks.ResultsWe obtained a significantly higher performance for CA125–HE4 model using both methodologies (AUC 0.971, sensitivity 96.7% and AUC 0.987, sensitivity 96.7%) with respect to CA125 (AUC 0.949, sensitivity 90.8% and AUC 0.953, sensitivity 92.1%) for Bayesian change‐point model (BCP) and recurrent neural networks (RNN) approaches, respectively. One year before diagnosis, the CA125–HE4 model also ranked as the best, whereas at 2 years before diagnosis no multimarker model outperformed CA125.ConclusionsOur study identified and tested different combination of biomarkers using longitudinal multivariable models that outperformed CA125 alone. We showed the potential of multivariable models and candidate biomarkers to increase the detection rate of ovarian cancer.

‘I Don't Think There Is a One‐Size‐Fits‐All’: A Qualitative Study Exploring Healthcare Professional and Service Provider Perspectives of Using Innovative Models of Cervical Screening to Improve Equitable Access to Self‐Collection

ABSTRACTIntroductionIn the Australian National Cervical Screening Program (NCSP), self‐collection can be performed in any setting deemed appropriate by the healthcare professional who orders the test, creating opportunities to develop innovative cervical screening models that can address known barriers to access for under‐ and never‐screened women and people with a cervix. This study explored the acceptability and appropriateness of innovative models and key considerations for their design and implementation from the perspectives of clinical and non‐clinical providers.MethodsWe conducted online, semi‐structured interviews with healthcare professionals, pathology providers and community service providers (June–October 2023). Data were analyzed using template analysis, a form of thematic analysis.ResultsThere were 132 participants from across Australia (82 clinical providers [e.g., doctors, nurses, midwives]; 34 non‐clinical providers [e.g., health/community service staff, disability support workers, bicultural workers]; and 16 pathology sector professionals). Four overarching themes were identified: acceptability, appropriateness, screening quality and safety, and implementation considerations. Most found innovative models acceptable when appropriately tailored to the needs of different population groups, particularly through community outreach, home in‐reach and peer‐supported services. Embedding clinical governance and oversight in the cervical screening pathway was a high priority to ensure that screening participants received adequate information about cervical screening and appropriate follow‐up care. Participants identified the need for clearly defined roles in the cervical screening pathway, sustainable funding and professional development opportunities to expand the role of nurses and optimize the roles of non‐clinical providers.ConclusionsInnovative models of cervical screening using self‐collection can offer more accessible, inclusive, and convenient care, especially for under‐ and never‐screened populations. Clinical governance and oversight must be embedded in the cervical screening pathway to maintain high‐quality screening services and to support the implementation of tailored and targeted innovative screening models.

Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management

Abstract Background BRCA1 :c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2 . Results Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion Pathogenicity of BRCA1 :c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.

Changes in Breast and Cervical Cancer Incidence by Stage at Diagnosis During the COVID‐19 Pandemic in Utah

ABSTRACTPurposeThe COVID‐19 pandemic caused unprecedented disruptions in healthcare access, resulting in significant delays in breast and cervical cancer screening and diagnostic services. This study examined whether there were changes in the stage of diagnosis for breast and cervical cancers diagnosed among Utah women during the pandemic compared to years prior to the pandemic.MethodsPatients included adult females with a new breast or cervical cancer diagnosis reported to the Utah Cancer Registry, diagnosed from January 2020 to December 2021 (pandemic time period) or between January 2018 and December 2019 (pre‐COVID‐19). We calculated age‐adjusted incidence rates and incidence rate ratios (IRRs) with 95% confidence intervals (CI) to compare stage at diagnosis and sociodemographic factors between time periods.ResultsA total of 308 cervical cancer cases and 8215 breast cancer cases were diagnosed throughout the duration of the study. Overall incidence of cervical cancer was higher during the pandemic, driven primarily by distant‐stage disease incidence, which was more than three times higher than before the pandemic (IRR, 3.11; 95% CI, 1.67–5.79). Non‐Hispanic (NH) White women were significantly more likely to be diagnosed with late‐stage cervical cancer (IRR, 1.60; 95% CI, 1.12‐2.30) during the pandemic compared to pre‐pandemic. Local‐stage breast cancer incidence decreased slightly during the pandemic compared to pre‐pandemic (IRR, 0.93; 95% CI, 0.88–0.99). Hispanic women saw a slight increase in late‐stage breast cancer incidence during the pandemic compared to before the pandemic (IRR, 1.31; 95% CI, 1.03–1.67).ConclusionsWe saw a significant increase in the incidence of late‐stage cervical cancer during the pandemic compared with pre‐pandemic. Conversely, while local‐stage breast cancer incidence was slightly lower during COVID‐19 compared with pre‐COVID‐19, no difference was observed among all other stages. More time is needed to assess the full impact of COVID‐19 on breast and cervical cancer trends.

Evaluation of Efficacy of Neoadjuvant Immunochemotherapy for Cervical Metastatic Squamous Cell Carcinoma of Unknown Primary

ABSTRACT Purpose This study aims to evaluate the antitumor activity of neoadjuvant immunochemotherapy in patients with cervical metastatic squamous cell carcinoma of unknown primary (CMSCCUP), providing a new idea for its treatment. Method We retrospectively examined the medical records from Sun Yat‐sen University Cancer Center to identify patients with CMSCCUP from July 2020 to November 2023. CMSCCUP's diagnoses are based on the results of biopsy and imaging examination. All patients received PD‐1 inhibitors combined with chemotherapy: paclitaxel (Albumin‐bound) 260 mg/m 2 and cisplatin 60 mg/m 2 every 3 weeks for two or more cycles as their initial treatment. Clinical response after neoadjuvant immunochemotherapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Surgery, radiotherapy, or chemoradiotherapy was performed subsequently based on the imaging evaluation results. Outcomes included overall survival (OS) and disease‐free survival (DFS). Result After neoadjuvant immunochemotherapy, the objective response rate (ORR) was 84.2%; complete response (CR), partial response (PR), and stable disease (SD) were 36.8%, 47.4%, and 15.8%, respectively. Of the 9 patients (42.9%) who underwent surgery after neoadjuvant immunochemotherapy, 7 (77.8%) achieved pathological complete response (pCR). No severe treatment‐related adverse events occurred. The most common treatment‐related adverse events were Grade 1–2 fatigue (11/14, 78.6%), decreased appetite (11/15, 73.3%), and increased aspartate transaminase (12/20, 60.0%). One (1/20, 5.0%) patient experienced Grade 3 anemia. The 2‐year overall survival (OS) and 2‐year disease‐free survival (DFS) rates were 94.4% and 89.4%, respectively. Conclusion Neoadjuvant immunochemotherapy showed favorable efficacies, anticipated outcomes, and tolerable toxicity for patients with CMSCCUP. More clinical practice and clinical studies are still needed to confirm further.

Prognostic Differences and Survival Predictive Models for Mucinous Versus Usual‐Type Adenocarcinoma of the Uterine Cervix

ABSTRACT Background There is significant histological heterogeneity between the endocervical adenocarcinoma (EA) subtypes. Usual‐type carcinoma (adenocarcinoma) and mucinous carcinoma (mucinous adenocarcinoma, MA) are the most common types of EA. Methods Demographic and clinical variables were collected from the SEER database for selected patients between 2004 and 2021. The effect of confounding variables was reduced by propensity score matching (PSM). Survival data were analyzed using the Kaplan–Meier method and Cox regression models. A risk prediction model nomogram for MA was developed and validated. Results The median age for MA patients was 46 years compared to 45 years for adenocarcinoma ( p  = 0.021). The 1‐, 3‐, and 5‐year overall survival (OS) rates for MA were 88.2%, 74.5%, and 68.4%, respectively, significantly lower than those for adenocarcinoma (89.0%, 79.0%, and 74.9%, p  < 0.0001). Cancer‐specific survival (CSS) showed a similar trend ( p  < 0.0001). Seven variables, including age, primary site, T, N, combined stage, surgery, and chemotherapy, were selected to create the nomograms for predicting OS, while age, primary site, tumor size, T, N, combined stage, and surgery were selected for CSS. The validations of all predictive models were satisfactory. Conclusion This study revealed MA's poorer prognosis compared to adenocarcinoma using the SEER database. It developed predictive models for OS and CSS of MA, offering a more accurate prognosis assessment tool for clinical practice.

FTO Facilitates Cervical Cancer Malignancy Through Inducing m6A‐Demethylation of PIK3R3 mRNA

ABSTRACTBackgroundThe incidence rate and mortality of cervical cancer rank the fourth in the global female cancer. N6‐methyladenosine (m6A) always plays an important role in tumor progression, and fat mass and obesity‐associated gene (FTO) works as the m6A demethylase.AimsOur study aimed to narrate the biological function and potential mechanisms for FTO in cervical cancer malignancy.Materials & MethodsWe analyzed potential clinical value of FTO in cervical cancer patients. The relative protein levels of FTO in cervical cancerous tissue and paracancerous tissue were verified by IHC. After changing the FTO expression level by lentivirus transfection, the proliferation and metastasis ability of cervical cancer cells were detected both in vitro and in vivo. Further, Merip‐seq and Merip‐qPCR are used to profile m6A transcriptome‐wide. Finally, western blot were performed to identify the regulatory mechanism.ResultsBased on TCGA‐CESC cohort and GEO dataset, FTO expression levels in HPV‐positive cancer patients were significantly higher than those in HPV‐negative cancer patients and could predict advanced FIGO stage. The protein level of FTO in cervical cancerous tissue was higher than that in paracancerous tissue. Functional assays indicated that FTO promoted the proliferation, migration and invasion of cervical cancer cells both in vitro and in vivo. The Merip‐seq and Merip‐qPCR evoked that relative PIK3R3 m6A level was significantly increased after FTO knockdown, which effected the activation of FoxO pathway. After knocking down FTO, upregulation of PIK3R3 can restore the malignancy of cervical cancer.ConclusionAll in all, these data suggest a vital role for FTO in occurrence and development of cervical cancer.

Risk Factor Analysis and Prediction of Para‐Aortic Lymph Node Metastases in Locally Advanced Cervical Cancer

ABSTRACTBackground and PurposeThe indications of prophylactic extended‐field radiotherapy (EFRT) remain uncertain. This study aims to identify the risk factors for para‐aortic lymph node (PALN) metastases in locally advanced cervical cancer (LACC) and determine which part of patients may benefit from prophylactic EFRT.Materials and MethodsBetween January 2015 and July 2023, a single‐center retrospective analysis was performed on patients with stages IB3 and IIA2‐IVA cervical cancer. Lymph node involvement was assessed using positron emission tomography/computed tomography (PET/CT). Risk factors were evaluated by logistic regression. A prediction nomogram model was developed and validated.ResultsAmong 329 patients, 64 (19.5%) had PALN metastases. Univariate analysis indicated that tumor size > 5.3 cm, tumor maximum standardized uptake value (SUVmax) > 9.8, bilateral pelvic lymph node (PLN) metastases, the number of positive PLNs ≥ 3, and T3–T4 stages were related to PALN metastases. After multivariate logistic analysis, it was found that tumor size > 5.3 cm (odds ratio [OR] = 3.129, 95% confidence interval [CI] = 1.536–6.374, p = 0.002), and the number of positive PLNs ≥ 3 (OR = 11.260, 95% CI = 3.506–36.158, p < 0.001) were independent risk factors. The C‐index of the nomogram was 0.886 (95% CI = 0.844–0.927). The calibration plot showed that the nomogram was well‐fitted. Decision curve analysis (DCA) exhibited excellent clinical utility.ConclusionTumor size > 5.3 cm and the number of positive PLNs ≥ 3 are independent risk factors of PALN metastases. The nomogram shows pretty good accuracy, which may provide a valuable reference for guiding patients who are very likely to develop PALN metastases to receive prophylactic EFRT.

Advances in the Prevention of Cervical Cancer by Anti‐Human Papillomavirus Agents

ABSTRACTBackgroundCervical cancer remains a major global health threat for women, primarily driven by human papillomavirus (HPV) infection. While HPV vaccination serves as the cornerstone of prevention, disparities in vaccine accessibility persist across low‐income countries. Secondary prevention through screening faces challenges in public engagement, often leading to late‐stage diagnoses. Recent advancements in novel anti‐HPV drugs offer expanded opportunities for cervical cancer management.AimThis review examines emerging anti‐HPV therapeutics to provide insights into innovative strategies for cervical cancer prevention and treatment.MethodsWe conducted a systematic analysis of published studies investigating anti‐HPV agents, focusing on their molecular mechanisms and clinical efficacy in cervical cancer prevention.Results & ConclusionsMultiple promising anti‐HPV agents have been identified, including 3‐hydroxyphthalic anhydride‐modified bovine β‐lactoglobulin (3HP‐β‐LG), carrageenan, defensins, and 25‐hydroxycholesterol (25HC). These compounds exert antiviral effects through distinct mechanisms: 3HP‐β‐LG competitively inhibits viral attachment, carrageenan blocks HPV entry via heparan sulfate mimicry, defensins inhibit the dissociation of viral capsid, and 25HC activates cholesterol‐mediated antiviral pathways. They have demonstrated strong inhibitory effects on HPV infection, making them novel therapeutic candidates for the prevention and treatment of cervical cancer.

Optimizing the Follow‐Up Interval After Successful Cold Knife Conization of CIN3: A 10‐Year Retrospective Cohort Study

ABSTRACTBackgroundThis study was conducted to identify the risk of residual or recurrent high‐grade squamous intraepithelial lesions or worse (HSIL+) in patients with successful conization and to develop a customized management strategy.MethodsThis retrospective study included 939 patients who underwent cold knife conization (CKC) for cervical intraepithelial neoplasia 3 at a hospital in China between January 1, 2013 and December 31, 2020. Demographic characteristics and test results were obtained before and 6, 12, and 24 months after CKC and annually thereafter. Human papillomavirus (HPV) persistence was defined as HPV positive at both 6 and 12 months after CKC, and the primary endpoint was residual or recurrent HSIL+ after CKC.ResultsThe mean follow‐up period was 68.8 months. In total, 61 (6.5%) patients had HPV persistence, and 19 (2.0%) had residual or recurrent HSIL+. The risk of residual or recurrent HSIL+ was increased in patients with HPV infection at 6 months (hazard ratio [HR], 84.6; 95% confidence interval [CI], 11.2–641) and 12 months (HR, 214; 95% CI, 28.1–1625) after CKC, and HPV persistence after CKC (HR, 244; 95% CI, 32.2–1854). Comparing two different colposcopic referral criteria for HPV persistence and HPV positive 6 months post‐CKC, substantially fewer colposcopies were performed per case of residual or recurrent HSIL+ detected in patients with HPV persistence after CKC (3.39 vs. 8.28).ConclusionsThe risk of residual or recurrent HSIL+ was higher in patients with HPV persistence after CKC. In patients with negative margins, extending the follow‐up interval to 12 months may reduce the number of HPV tests and colposcopy referral rates while maintaining HSIL+ detection.

Patient Perspectives on Impact of Weight and Weight Stigma on Breast and Cervical Cancer Treatment: A Qualitative Study

ABSTRACTBackgroundHigher weight individuals report experiencing weight‐based stigma in the healthcare setting; within the cancer continuum, the most robust evidence exists for cancer screening. More research is needed to understand whether and how higher weight patients experience weight stigma during cancer treatment.MethodsWe conducted semi‐structured interviews with 15 breast and 15 cervical cancer survivors diagnosed 2017–2019 in Iowa who had a pre‐diagnosis body mass index of 30+ kg/m2 calculated from their driver's license height and weight. Interviews focused on whether individuals perceived being treated differently because of their weight in daily life, in healthcare, or during cancer treatment. Data were coded using a combination of inductive and deductive approaches, and analyzed using a multi‐phase thematic analysis.ResultsAlmost all interviewees reported positive experiences during cancer treatment; several described their weight as never being an issue. Some identified weight stigma during cancer diagnosis or treatment that resulted in delayed diagnoses or changes in treatment. Many interviewees described situations where their weight was discussed negatively during cancer treatment, but most did not identify these as stigmatizing because their providers were only “concerned about [their] health.” Additional themes developed included experiencing environmental stigma, the discussion of cancer recurrence by providers only as it related to weight, and misconceptions of the causes and consequences of obesity.ConclusionsWhile several participants did not feel that their weight impacted cancer treatment, some reported experiences of weight stigma pre‐diagnosis and during treatment. When individuals noted their weight was discussed during treatment, internalized bias may have impacted whether they considered these discussions stigmatizing.

The Role of Lymphocyte Recovery Index in Prognosis Prediction for Locally Advanced Cervical Cancer With Radiation‐Induced Lymphopenia

ABSTRACTBackgroundIn patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT), the high incidence of radiation‐induced lymphopenia significantly affects prognosis. There are significant variations in lymphocyte count (ALC) recovery patterns among patients, and their impact on prognosis remains unclear. This study aims to quantify the lymphocyte recovery patterns by the lymphocyte recovery index (LRI) and evaluate its prognostic value.MethodsThis study reviewed patients with LACC who had ALCs available within 6 months post‐CCRT. Lymphopenia was graded using CTCAE 5.0, and lymphocyte recovery patterns were quantified using LRI (the ratio of ALCs at 6 months post‐treatment to baseline ALCs). Cox regression analysis was conducted to assess the correlation between LRI, other clinical factors, and survival. The dose–volume of bone marrow (BM) following pelvic radiotherapy was collected, and measurements of spleen standardized uptake value (SUV) and spleen‐to‐liver SUVmax ratio (SLR) were obtained from pre‐treatment 18F‐FDG PET/CT. Logistic regression analysis was used to identify independent risk factors for LRI.ResultsA total of 180 patients were included retrospectively. During CCRT, 53 patients (29.4%) experienced G4 lymphopenia. The median LRI was 53.4% (range 13.2%–159.4%). Multivariable analysis revealed that LRI, G4 lymphopenia, and FIGO stage were associated with progression‐free survival (PFS) and overall survival (OS). Subgroup analysis revealed that the degree of lymphopenia (G4 and G1‐3) did not affect the correlation between LRI and PFS (P: 0.001 and 0.011) or OS (P: 0.003 and 0.043). Regarding FIGO stage, the impact of LRI on PFS (p < 0.001) and OS (p < 0.001) was primarily observed in patients with FIGO stage > II. Logistic analysis identified BM‐V10 > 96.0% and SLR > 0.90 as independent risk factors for LRI.ConclusionIn patients with LACC after CCRT, the LRI is associated with prognosis. Splenic metabolism and BM irradiation are associated with lymphocyte recovery.

Phenome‐wide association study of ovarian cancer identifies common comorbidities and reveals shared genetics with complex diseases and biomarkers

AbstractBackgroundOvarian cancer (OC) is commonly diagnosed among older women who have comorbidities. This hypothesis‐free phenome‐wide association study (PheWAS) aimed to identify comorbidities associated with OC, as well as traits that share a genetic architecture with OC.MethodsWe used data from 181,203 white British female UK Biobank participants and analysed OC and OC subtype‐specific genetic risk scores (OC‐GRS) for an association with 889 diseases and 43 other traits. We conducted PheWAS and colocalization analyses for individual variants to identify evidence for shared genetic architecture.ResultsThe OC‐GRS was associated with 10 diseases, and the clear cell OC‐GRS was associated with five diseases at the FDR threshold (p = 5.6 × 10−4). Mendelian randomizaiton analysis (MR) provided robust evidence for the association of OC with higher risk of “secondary malignant neoplasm of digestive systems” (OR 1.64, 95% CI 1.33, 2.02), “ascites” (1.48, 95% CI 1.17, 1.86), “chronic airway obstruction” (1.17, 95% CI 1.07, 1.29), and “abnormal findings on examination of the lung” (1.51, 95% CI 1.22, 1.87). Analyses of lung spirometry measures provided further support for compromised respiratory function. PheWAS on individual OC variants identified five genetic variants associated with other diseases, and seven variants associated with biomarkers (all, p ≤ 4.5 × 10−8). Colocalization analysis identified rs4449583 (from TERT locus) as the shared causal variant for OC and seborrheic keratosis.ConclusionsOC is associated with digestive and respiratory comorbidities. Several variants affecting OC risk were associated with other diseases and biomarkers, with this study identifying a novel genetic locus shared between OC and skin conditions.

Depleting the 19S proteasome regulatory PSMD1 subunit as a cancer therapy strategy

AbstractBackgroundProteasome inhibitors are in use in treating certain types of cancers. These drugs inhibit the catalytic activity of the 20S proteasome, shared by all the different proteasome complexes. Inhibitors of the 26S‐associated deubiquitinating activity explicitly inhibit the 26S proteasomal degradation of ubiquitinylated substrates. We have previously reported an alternative strategy that is based on reducing the 26S/20S ratio by depleting PSMD1, 6, and 11, the subunits of the 19S proteasome regulatory complex. Given the addiction of the many cancer types to a high 26S/20S ratio, the depletion strategy is highly effective in killing many aggressive cancer cell lines but not mouse and human immortalized and normal cells.MethodsWe used two aggressive cell lines, MDA‐MB‐231, a triple‐negative breast tumor cell line, and OVCAR8, a high‐grade ovary adenocarcinoma. Cell culture, mouse MDA‐MB‐231, OVCAR8 xenografts, and patient‐derived ovarian cancer xenograft (PDX) models were transduced with lentivectors expressing PSMD1 shRNA. Tumor size was measured to follow treatment efficacy.ResultsUsing different experimental strategies of expressing shRNA, we found that PSMD1 depletion, either by expressing PSMD1 shRNA in an inducible manner or in a constitutive manner, robustly inhibited MDA‐MB‐231, and OVCAR8 xenograft tumor growth. Furthermore, the PSMD1 depletion strategy compromised the growth of the PDX of primary ovarian cancer.ConclusionOur results suggest that reducing the 26S/20S ratio might be a valuable strategy for treating drug‐resistant aggressive types of cancers.

Practitioners support and intention to adopt universal access to self‐collection in Australia's National Cervical Screening Program

AbstractObjectivePrimary care practitioners are crucial to engaging people in Australia's national cervical screening program. From July 2022, practitioners have been able to offer all screen‐eligible people the choice to collect their own self‐collected sample; an option introduced to increase equity. This study explored how practitioners are intending to incorporate universal access to self‐collection into their clinical care.MethodsSemi‐structed interviews with 27 general practitioners, nurses, and practice managers from 10 practices in Victoria, Australia conducted between May and August 2022. Interviews were deductively coded, informed by the Consolidated Framework for Implementation Research. The Diffusion of Innovations theory was used to categorise intention to provide self‐collection.ResultsParticipants were supportive of universal access to self‐collection, citing benefits for screen‐eligible people and that it overcame the limited adaptability of the previous policy. Most participants' practices (n = 7, 70%) had implemented or had plans to offer the option for self‐collection to all. Participants deliberating whether to provide universal access to self‐collection held concerns about the correct performance of the self‐test and the perceived loss of opportunity to perform a pelvic examination. Limited time to change practice‐level processes and competing demands within consultations were anticipated as implementation barriers.ConclusionsThe extent to which self‐collection can promote equity within the program will be limited without wide‐spread adoption by practitioners. Communication and education that addresses concerns of practitioners, along with targeted implementation support, will be critical to ensuring that self‐collection can increase participation and Australia's progression towards elimination of cervical cancer.

Establishment of a Novel Risk Stratification System Integrating Clinical and Pathological Parameters for Prognostication and Clinical Decision‐Making in Early‐Stage Cervical Cancer

ABSTRACTBackgroundHighly heterogeneity and inconsistency in terms of prognosis are widely identified for early‐stage cervical cancer (esCC). Herein, we aim to investigate for an intuitional risk stratification model for better prognostication and decision‐making in combination with clinical and pathological variables.MethodsWe enrolled 2071 CC patients with preoperative biopsy‐confirmed and clinically diagnosed with FIGO stage IA‐IIA who received radical hysterectomy from 2013 to 2018. Patients were randomly assigned to the training set (n = 1450) and internal validation set (n = 621), in a ratio of 7:3. We used recursive partitioning analysis (RPA) to develop a risk stratification model and assessed the ability of discrimination and calibration of the RPA‐derived model. The performances of the model were compared with the conventional FIGO 2018 and 9th edition T or N stage classifications.ResultsRPA divided patients into four risk groups with distinct survival: 5‐year OS for RPA I to IV were 98%, 95%, 85.5%, and 64.2%, respectively, in training cohort; and 99.5%, 93.2%, 85%, and 68.3% in internal validation cohort (log‐rank p < 0.001). Calibration curves confirmed that the RPA‐predicted survivals were in good agreement with the actual survivals. The RPA model outperformed the existing staging systems, with highest AUC for OS (training: 0.778 vs. 0.6–0.717; internal validation: 0.772 vs. 0.595–0.704; all p < 0.05), and C‐index for OS (training: 0.768 vs. 0.598–0.707; internal validation: 0.741 vs. 0.583–0.676; all p < 0.05). Importantly, there were associations between RPA groups and the efficacy of treatment regimens. No obvious discrepancy was observed among different treatment modalities in RPA I (p = 0.922), whereas significant survival improvements were identified in patients who received adjuvant chemoradiotherapy in RPA II–IV (p value were 0.028, 0.036, and 0.024, respectively).ConclusionWe presented a validated novel clinicopathological risk stratification signature for robust prognostication of esCC, which may be used for streamlining treatment strategies.

Identification and Experimental Validation of Prognostic miRNA Signature and Ferroptosis‐Related Key Genes in Cervical Squamous Cell Carcinoma

ABSTRACT Objectives This study aimed to investigate the prognostic value of miRNAs and ferroptosis‐related genes in cervical squamous cell carcinoma. Methods We mined data from public databases for differentially expressed miRNAs, ferroptosis‐related genes, and clinical parameters and constructed a prognostic risk model. The predictive performance of the model was evaluated using survival and receiver operating characteristic curve analyses. We combined the clinicopathological features to construct a nomogram and evaluated its efficacy using calibration and clinical decision curves. The correlation between miRNA characteristics, risk score, and the tumor microenvironment was also studied. Next, consensus and key genes were screened, and their biological functions were analyzed using KEGG, GO, GSEA, and drug sensitivity analysis. Finally, the expression of miRNAs and key genes was detected using qRT‐PCR and western blotting to verify the prediction results. Results Seven miRNA signatures (miR‐100‐3p, miR‐301a‐5p, miR‐331‐3p, miR‐425‐5p, miR‐502‐3p, miR‐505‐5p, and miR‐629‐3p) were generated, and prognostic risk and nomogram models were successfully constructed. These models exhibited good accuracy. miRNA signatures correlated with the tumor microenvironment. Twelve consensus genes and three key genes (SLC2A1, ANO6, and TXNIP) were screened and their biofunctional diversity was identified using various analytical methods. qRT‐PCR and western blotting were used to verify the expression of miR‐301a‐5p, miR‐505‐5p, SLC2A1, and TXNIP in cervical squamous carcinoma. The results were consistent with those of bioinformatics analyses. Conclusions Seven miRNAs may serve as prognostic biomarkers of cervical squamous cell carcinoma. SLC2A1, ANO6, and TXNIP are associated with cervical squamous cell carcinoma and may serve as ferroptosis‐related markers of the disease.

Associations between prediagnostic aspirin use and ovarian tumor gene expression

AbstractBackgroundAspirin use has been associated with reduced ovarian cancer risk, yet the underlying biological mechanisms are not fully understood. To gain mechanistic insights, we assessed the association between prediagnosis low and regular‐dose aspirin use and gene expression profiles in ovarian tumors.MethodsRNA sequencing was performed on high‐grade serous, poorly differentiated, and high‐grade endometrioid ovarian cancer tumors from the Nurses' Health Study (NHS), NHSII, and New England Case–Control Study (n = 92 cases for low, 153 cases for regular‐dose aspirin). Linear regression identified differentially expressed genes associated with aspirin use, adjusted for birth decade and cohort. False discovery rates (FDR) were used to account for multiple testing and gene set enrichment analysis was used to identify biological pathways.ResultsNo individual genes were significantly differentially expressed in ovarian tumors in low or regular‐dose aspirin users accounting for multiple comparisons. However, current versus never use of low‐dose aspirin was associated with upregulation of immune pathways (e.g., allograft rejection, FDR = 5.8 × 10−10; interferon‐gamma response, FDR = 2.0 × 10−4) and downregulation of estrogen response pathways (e.g., estrogen response late, FDR = 4.9 × 10−8). Ovarian tumors from current regular aspirin users versus never users were also associated with upregulation in interferon pathways (FDR <1.5 × 10−4) and downregulation of multiple extracellular matrix (ECM) architecture pathways (e.g., ECM organization, 4.7 × 10−8).ConclusionOur results suggest low and regular‐dose aspirin may impair ovarian tumorigenesis in part via enhancing adaptive immune response and decreasing metastatic potential supporting the likely differential effects on ovarian carcinogenesis and progression by dose of aspirin.

Cost‐Effectiveness of Computer‐Assisted Cytology in a Primary hrHPV‐Based Cervical Cancer Screening Programme

ABSTRACTBackgroundComputer‐assisted screening (CAS) shows equal performance compared to manual screening, although results are heterogeneous. Furthermore, using CAS may save costs through a potentially increased screening productivity of technicians, therefore also offering a solution for temporary and structural capacity shortage. We evaluated the circumstances under which CAS will be cost‐effective compared to manual cytology triage in a primary HPV‐based cervical screening programme.MethodsMicrosimulation model MISCAN‐Cervix was used to evaluate 198 different CAS scenarios with varying probabilities to detect cervical intraepithelial neoplasia grade 1 (CIN1) and CIN3 and cost reductions per test, compared to manual cytology triage. Cost‐effectiveness was evaluated by costs per (quality‐adjusted) life year ((QA)LY) gained.ResultsCAS will be cost‐effective in all scenarios, except for the following combinations: (1) no cost reduction and an increased probability of detecting CIN1, (2) a cost reduction of €2 per test and an increased probability of detecting CIN1 from 4% onwards or (3) a cost reduction of €4 per test and an increased probability of detecting CIN1 from 6% onwards, compared to manual cytology triage. All CAS scenarios with any reduction in the probability of detecting CIN1 (i.e., increased CIN2+ specificity), or a reduction in costs from €6 per test onwards suggested a more cost‐effective strategy compared to manual cytology triage.ConclusionAs we based our analysis on a realistic range in costs and test performance, the implementation of CAS is likely to be cost‐effective. Our results can be used as a guideline to advise when to choose CAS instead of manual cytology triage.

Prevalence and Description of High‐Grade Intraepithelial Lesions of Cervical Mucosa Cells in a Screening Programme for Cervical Cancer in Isère, France

ABSTRACTObjectiveThis study aims to analyse high‐grade intraepithelial lesions (LIEHG) observed in a screening programme from 2010 to 2018 to more accurately describe them and formulate recommendations for best practices in the context of screening evolution following the introduction of an HPV test in primary cervical cancer screening in 2020.MethodsThis study included 305,940 asymptomatic women aged 25–65 years. The eligible population was invited to undergo a screening cervico‐uterine‐smear every 3 years. If this smear was normal, the woman received a new invitation. In the case of a positive screen, the patient underwent further diagnostic procedures, such as colposcopy and biopsy to confirm the diagnosis. Only those diagnosed with LIEHG and above proceeded to treatment. The diagnoses associated with LIEHG were those related to the WHO Classification of tumours of the uterine cervix.ResultsPositive smears led to the diagnosis of 3230 LIEHG. The prevalence of LIEHG in the screened population was 0.4%. The LIEHG distribution varied significantly according to the age of the women. The probability of diagnosing LIEHG in young women was 12.2% at 25–29 years. This probability decreased by half after 50 years. We observed that the type of smear was significantly associated with LIEHG detection. The positive predictive value for diagnosing LIEHG was 70.3% for high‐grade squamous intraepithelial lesion (HSIL) smears and 35.1% for atypical squamous cells cannot exclude HSIL (ASC‐H) smears.ConclusionIn the study population, the prevalence of LIEHG was high in women under 35 years. Low‐grade smears were correlated with the risk of LIEHG and should prompt screening facilities to allocate resources to ensure active follow‐up of LSIL and ASC‐US smears. Adherence to cytological screening recommendations was associated with a reduced risk of LIEHG in multivariate analysis.

The efficacy of first and second immunotherapy exposure in patients with recurrent or metastatic cervical cancer

AbstractObjectiveImmunotherapy has led to changes in cervical cancer guidelines. Therefore, additional biomarkers to identify the ideal patient who would experience the most benefit may be important.MethodsWe retrospectively collected 208 patients with R/M CC and recorded clinicopathologic information, peripheral blood markers and treatments to analyze the prognostic factors of clinical outcomes. Response rate comparison, univariate, and multivariate analyses were performed to assess the efficacy of different factors.ResultsA total of 43.27% patients achieved objective responses, including 18 with complete response and 72 with partial response. Patients receiving first‐line immunotherapy had much higher objective response rate (ORR) than the remaining patients (53.8% vs. 34.8%, p = 0.006). CRP >3 ECOG ≥1 and recurrence in 6 months predicted shorter progression free survival (PFS). CRP >3, GLU >6.1 independently predicted unfavorable overall survival (OS). Compared with no antiangiogenic therapy, previous antiangiogenic therapy reduced the median OS by nearly 14 months. Immunotherapy rechallenge was still effective after first immunotherapy failure, and combined with dual‐immunotherapy or bevacizumab combined with chemoradiotherapy resulted in a 60.00% or 62.50% ORR, respectively. Patients with squamous cell carcinoma, with stable disease or objective response in the first immunotherapy or without chemotherapy in second immunotherapy had favorable clinical outcome.ConclusionThe baseline CRP levels in serum was an independent factor for PFS and OS of R/M CC patients treated with immunotherapy, and previous antiangiogenic therapy was associated with poor OS. Patients still show response to immunotherapy rechallenge and combined treatment with bevacizumab or candonilimab showed higher response rate than anti‐PD‐1 after immunotherapy failure.

Cemiplimab monotherapy in Japanese patients with recurrent or metastatic cervical cancer

AbstractBackgroundIn the phase 3 EMPOWER‐Cervical 1/GOG‐3016/ENGOT‐cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first‐line platinum‐based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan.MethodsPatients were enrolled regardless of programmed cell death‐ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single‐agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression‐free survival (PFS) and objective response rate (ORR).ResultsOverall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow‐up was 13.6 (6.0–25.3) versus 18.2 (6.0–38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0‐not evaluable) and 9.4 (5.4–14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43–1.68). Median PFS (95% CI) was 4.0 (1.4–8.2) versus 3.7 (1.8–4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50–1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44–13.99). Incidence of treatment‐emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively.DiscussionWhile acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6‐month shorter median duration of follow‐up versus the overall study population.

Prevalence and genotype distribution of HPV combined with cervical pathological results in women from Sichuan, China: A cross‐sectional study based on post‐vaccination period 2019 to 2023

AbstractBackgroundHuman papillomavirus (HPV) screening and vaccination exert efficacy in controlling the progression of cervical cancer. Thus, examinations into HPV prevalence, age‐stratified specificity, genotype distribution, and their correlation with pathological outcomes can furnish robust evidence for customizing high‐quality population screening and management.MethodsA cohort of 17,923 women attending clinics in the Jintang area, Sichuan, from January 2019 through August 2023 were enrolled in the study. Genotyping of HPV was conducted using real‐time polymerase chain reaction (RT‐PCR). The epidemiology and the relationship between HPV infection and histologic/cytologic abnormalities were subjected to analysis.ResultsHPV infection was identified in 4387 women. The outpatient group exhibited a significantly higher HPV infection rate compared to the healthy examination group (26.5% vs. 17.5%, p < 0.05). The distribution of infection rates across different age groups exhibited a U‐shaped pattern, with the highest infection rate in the group ≤20 years of age, succeeded by those >60 years of age. The 31–40 age group demonstrated the lowest prevalence of infection, but upon infection, its prevalence of the precancerous lesion CIN2‐3 reached a maximum of 29.0%, constituting a novel finding. The most prevalent genotype was HPV52, followed by HPV16, 58, 53, 68, and 18. In the cytologic and histologic abnormalities group, the most common types were HPV52, 16, and 58. HPV16 predominantly appeared in high‐grade intraepithelial neoplasia and carcinoma in situ, constituting over 60% of cases. While HPV type 52 was not individually detected in cervical cancer cases. And some other non‐vaccine‐covered HPV subtypes also showed high prevalence in Sichuan. The single infection rates of NH9‐HPV (high‐risk HPV subtypes covered by the non‐nine‐valent vaccine) in CIN2‐3 and cervical cancer patients were 6.5% and 2.6%, respectively. Among them, HPV51, HPV53, HPV59, and HPV35 exhibited a significant preponderance, which even higher than HPV45 and HPV31 covered by the nine‐valent vaccine types. And in NL9‐HPV (low‐risk HPV subtypes covered by the non‐nine‐valent vaccine), HPV42 accounted for the highest percentage in CIN2‐3. A similar decreasing trend was observed in annual infection rates in the healthy examination population and in the 31–40 and 51–60 age groups, while the ≤20 age group showed an increase. Regarding type‐specificity, HPV16 and HPV58 exhibited the most rapid declines.ConclusionThis study furnishes the latest insights into the characteristics of HPV infection rate, age distribution, and genotype prevalence in Sichuan.

Trends in HPV‐associated cancer incidence in Texas medically underserved regions

AbstractBackgroundWhile cervical cancer incidence rates (IR) in the United States have dropped in the last 20 years, non‐cervical human papillomavirus (HPV) associated cancers increased. Many people in Texas (TX) live in medically underserved areas and have higher risk of developing HPV‐associated cancers. Since previous studies of these regions focused on cervical cancer, we included other HPV‐associated cancers in our analysis of IR in East TX and the TX‐Mexico Border compared to other TX regions.MethodsCancer data from 2006 to 2019 were obtained from the TX Cancer Registry. Cases of HPV‐associated cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers and corresponding patient‐level demographic data were included. We calculated IR per 100,000 and drew heat maps to visualize cancer IR by county. To control potential confounders, we added county‐level risk factors: rates for smoking, excessive drinking, obesity, STIs, primary care provider availability and dentist availability, from the County Health Rankings and Roadmaps program. We reported IRs by region and time and estimated unadjusted and adjusted risk ratio (RR) for association of each type of cancer and region. Lastly, we created adjusted models for each cancer by period to see time trends of regional differences.ResultsRisk of anal, cervical, and oropharyngeal cancer was lower at parts of the Border than in the rest of TX in the adjusted model. We also observed increasing anal and oropharyngeal cancer risk and decreasing cervical and vaginal cancer risk over time.ConclusionPatient sociodemographics, behavioral risk factors, and access to care may contribute to some observed differences in cancer IR across regions. This indicates that targeted prevention efforts towards these regions, especially in low socioeconomic status communities, may benefit future generations.

Long non‐coding RNA NEAT1 promotes aerobic glycolysis and progression of cervical cancer through WNT/β‐catenin/PDK1 axis

AbstractBackgroundCervical cancer is one of the most common gynecological cancers. Accumulated evidence shows that long non‐coding RNAs (lncRNAs) play essential roles in cervical cancer occurrence and progression, but their specific functions and mechanisms remain to be further explored.MethodsThe RT‐qPCR assay was used to detect the expression of NEAT1 in cervical cancer tissues and cell lines. CCK‐8, colony formation, flow cytometry, western blotting, and Transwell assays were used to evaluate the impact of NEAT1 on the malignant behavior of cervical cancer cells. Glucose consumption, lactate production, ATP levels, ROS levels, MMP levels, and the mRNA expressions of glycolysis‐related genes and tricarboxylic acid cycle‐related genes were detected to analyze the effect of NEAT1 on metabolism reprograming in cervical cancer cells. The expressions of PDK1, β‐catenin and downstream molecules of the WNT/β‐catenin signaling pathway in cervical cancer cells and tissues were detected by western blotting, RT‐qPCR, immunofluorescence and immunohistochemistry assays.ResultsThis study investigated the role and possible molecular mechanism of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in cervical cancer. Our results showed that NEAT1 was highly expressed in cervical cancer tissues and cell lines. Downregulation of NEAT1 inhibited the proliferation, migration, invasion and glycolysis of cervical cancer cells, while overexpression of NEAT1 led to the opposite effects. Mechanistically, NEAT1 upregulated pyruvate dehydrogenase kinase (PDK1) through the WNT/β‐catenin signaling pathway, which enhanced glycolysis and then facilitated cervical cancer metastasis. Furthermore, NEAT1 maintained the protein stability of β‐catenin but did not affect its mRNA level. We also excluded the direct binding of NEAT1 to the β‐catenin protein via RNA pull‐down assay. The suppressive impact of NEAT1 knockdown on cell proliferation, invasion, and migration was rescued by β‐catenin overexpression. The WNT inhibitor iCRT3 attenuated the carcinogenic effect induced by NEAT1 overexpression.ConclusionIn summary, these findings indicated that NEAT1 may contribute to the progression of cervical cancer by activating the WNT/β‐catenin/PDK1 signaling axis.

Causes of death analysis and the prognostic model construction in neuroendocrine carcinoma of the cervix: A SEER‐based study

AbstractPurposeNeuroendocrine carcinoma of the cervix (NECC) is rare but results in poor prognosis. The causes of death (CODs) in NECC patients are rarely reported. Our study aimed to explore the distributions of death causes of NECC patients compared with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) and to develop a validated survival prediction model.MethodsPatients diagnosed with NECC, SCC, or ADC were identified from the Surveillance, Epidemiology, and End Results Program database from 1975 to 2019. We analyzed the standardized mortality ratio (SMR) to determine each cause of death for each survival time category. The Kaplan–Meier method was used for survival analysis. Univariate and multivariate Cox regression analyses were used to establish a nomogram model.ResultsA total of 358 NECC patients were included in this study, and 270 (75.4%) died during the follow‐up period. Patients with NECC had 5.55 times (95% CI, 4.53–6.79, p < 0.0001) higher risk of death compared with patients with SCC and 10.38 times (95% CI, 8.28–13.01, p < 0.0001) higher compared with ADC. Cervical cancer is the main cause of death in NECC. As the diagnosis time increased, the risk of death from all causes and cervix cancer gradually decreased. While after at least 10 years of follow‐up time, the highest and most dramatical SMR values were observed for metastasis (SMR, 138.81; 95% CI, 37.82–355.40; p < 0.05) and other cancers as the reason for death has an over 7‐fold higher SMR (SMR: 7.07; 95% CI: 2.60–15.40, p < 0.05) more than 5 years after the cancer diagnosis. Race, FIGO stage, and surgery were independent risk factors for the overall survival (OS) of NECC patients. For the predictive nomogram, the C‐index was 0.711 (95% CI: 0.697–0.725) and was corrected to 0.709 (95% CI: 0.680, 0.737) by bootstrap 1000 resampling validation.ConclusionCompared with SCC and ADC, NECC patients have an elevated risk of mortality due to cervical cancer and metastasis. We successfully constructed a prognostic nomogram for patients with NECC. Based on refractoriness and high mortality of NECC, targeted treatment strategies and follow‐up plans should be further developed according to the risk of death and distribution characteristics of CODs.

Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores

ABSTRACTIntroductionBRCA2 is a causal gene for hereditary breast and ovarian cancer (HBOC) syndrome. However, its association with other cancers and interplay with polygenic scores (PGS) remains unclear.MethodsAn observational cohort study for the diagnosis of various cancers in the UK Biobank (UKB, N = 453,541) were recruited at ages of 40–69 years Association of germline pathogenic variants (PVs) in BRCA2 and published cancer‐specific PGS with cancer risk was tested using Cox proportional hazards model.ResultsThe median age and interquartile range (IQR) of participants at the analysis was 58.34 (50.60–63.74) years. Carriers of BRCA2 PVs (N = 1629) had a significantly increased risk for four core HBOC‐associated cancers (breast, ovarian, pancreatic, and prostate) and six additional types of cancer (lung, oral, small intestine, larynx, liver, and mesothelioma), hazard ratio (HR) > 2.37, all ps < 0.001. For eight cancers where cancer‐specific PGS is available, each PGS was significantly associated with its respective cancer risk and independent of BRCA2, HR > 1.25 for 1 unit increase in standard deviation, all ps < 0.001. For female breast and prostate cancer, a significant interaction between BRCA2 and PGS was found (HR < 0.83, p < 0.05); the effect of PGS on cancer risk was weaker in carriers than noncarriers. The probability of cancer by age 75 years (P75) for these 10 cancers increased with higher PGS deciles in both carriers and noncarriers. For several cancers, the P75 in carriers with the lowest PGS decile was lower than that of noncarriers with the highest PGS decile.ConclusionsBRCA2 PVs increase risk beyond core HBOC cancers and their risks are modified by cancer‐specific PGS. These results suggest that genetic counseling of BRCA2 PV carriers may extend to cancers beyond core HBOC syndrome and incorporate cancer‐specific PGS in estimating their penetrance.

Perspective of obstetric care‐providers on being involved in cervical cancer screening during antenatal care in the Netherlands

AbstractBackgroundThe aim of this study was to determine attitude of Dutch midwifes, gynecologists and general practitioners (GPs) towards involvement in antenatal cervical cancer screening (CCS) in the Netherlands.MethodsIn 2021, Dutch midwives, gynecologists, and GPs were offered a single digital questionnaire assessing perceived feasibility, benefits, and harms of antenatal CCS.ResultsA total of 6943 Questionnaires were send and response rate was 18% (N = 1260). Of all respondents, 78% considered antenatal CCS via obstetric care providers feasible. Most respondents (85%) agreed that offering CCS in person can increase motivation to attend. Most midwives (93%) considered that women would feel less encumbered if cervical sampling would be performed by obstetric care providers, rather than by GPs.ConclusionResults indicate that introduction of antenatal CCS is considered feasible by a majority of Dutch midwifes, gynecologists, and GPs. Considered benefits include improved motivation to attend and reduced test related barriers.

Correlation between hematological parameters and outcome in patients with locally advanced cervical cancer treated by concomitant chemoradiotherapy

AbstractBackgroundHemoglobin (Hb), white blood cell (WBC), and polymorphonuclear neutrophil (PMN) blood counts may be correlated with outcomes in patients with locally advanced cervical cancer.MethodsHb, WBC, and PMN counts were measured at diagnosis and during concomitant cisplatin‐based chemoradiotherapy (CCRT) in a retrospective sample of 103 patients between 2010 and 2017. Red blood cell (RBC) transfusions were also recorded. The associations between hematological variables and patient overall survival (OS) and recurrence‐free survival (RFS) were assessed by Cox regression models.ResultsThe 3‐year OS and RFS rates were 81.4% and 76.8%, respectively. In addition to tumor size and smoking, OS and RFS were found to be significantly associated with changes in WBC and PMN counts from the first to the last cisplatin cycle. Hb count throughout the treatment and RBC transfusions were not predictive of outcome.ConclusionsThis study found no association between Hb count or RBC transfusions and outcome. The daily practice of maintaining the Hb count above 12 g/dL during CCRT should be weighed against the potential risks of transfusions. Drops in WBC and PMN counts during treatment positively impacted OS and RFS and could, therefore, serve as biomarkers during CCRT to adapt the follow‐up and consider the need for adjuvant systemic treatments.

The Sonic Hedgehog signaling pathway regulates autophagy and migration in ovarian cancer

AbstractBackgroundThe Sonic Hedgehog (SHH) signaling pathway plays an important role in various types of human cancers including ovarian cancer; however, its function and underlying mechanism in ovarian cancer are still not entirely understood.MethodsWe detected the expressions of SHH and SQSTM1 in borderline ovarian tumor tissues, epithelial ovarian cancer (EOC) tissues and benign ovarian tumor tissues. Cyclopamine (Cyp, a well‐known inhibitor of SHH signaling pathway) and chloroquine (CQ, the pharmaceutical inhibitor of autophagy) were used in vivo and in vitro (autophagic flux, CCK‐8 assay, wound healing assay, transwell assay, tumor xenograft model). The mechanism of action was explored through Quantitative RT‐PCR and Western Blot.ResultsWe found up‐regulation of SHH and accumulation of SQSTM1/P62 in epithelial ovarian cancer. Cyp induced autophagy through the PI3K/AKT signaling pathway. Moreover, low‐dose Cyp and chloroquine (CQ) significantly promoted the migratory ability of SKOV3 cells.ConclusionsOur findings suggest that inhibition of the SHH pathway and autophagy may be a potential and effective therapy for the treatment of ovarian cancer.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

AbstractBackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk.Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

Immune correlates of therapy outcomes in women with cervical cancer treated with chemoradiotherapy: A systematic review

AbstractBackgroundImmune markers have been correlated with prognosis in a variety of solid tumors, including cervical cancer.ObjectiveTo review the literature on hematologic and immune markers and their association with recurrence and survival among patients with cervical cancer treated with chemoradiation.Evidence reviewThis systematic review was conducted in accordance with PRISMA guidelines via searches of Ovid MEDLINE, Ovid Embase, and the Cochrane Library using keywords regarding cervical cancer, immune markers, and HIV. Studies involving patients treated with cisplatin‐based chemoradiotherapy were selected and reviewed by at least two independent reviewers, with disagreements resolved by a third reviewer.FindingsA total of 737 studies were identified, of which 314 assessed immune biomarkers in immunocompetent patients (30 included in the final analysis) and 327 studies in immunosuppressed patients (5 included in the final analysis). The strongest prognostic indicators were lymphopenia and elevated neutrophil‐to‐lymphocyte ratio. Other potential markers included HPV‐specific lymphocyte response, cytokine profile, expression of immune‐blocking antigens on cell surfaces, and tumor‐associated lymphocyte, macrophage, and neutrophil infiltration. Studies of immunosuppressed patients described more severe cytopenic changes overall and concluded that viral suppression led to improved outcomes.ConclusionsThe immunologic interplay at work in cervical cancer development, progression, and treatment is complex. Strong evidence was found in favor of lymphopenia and elevated neutrophil‐to‐lymphocyte ratio being prognostic for worse outcomes with other markers showing potential associations as well. Although the interpretation of immune status with regard to treatment approach remains unclear, future studies should aim to tailor treatment that minimizes possible detrimental immune effects.

The association between single nucleotide polymorphisms and ovarian cancer risk: A systematic review and network meta‐analysis

AbstractBackgroundThe relationship between single nucleotide polymorphisms (SNPs) and ovarian cancer (OC) risk remains controversial. This systematic review and network meta‐analysis was aimed to determine the association between SNPs and OC risk.MethodsSeveral databases (PubMed, EMBASE, China National Knowledge Infrastructure, Wanfang databases, China Science and Technology Journal Database, and China Biology Medicine disc) were searched to summarize the association between SNPs and OC published throughout April 2021. Direct meta‐analysis was used to identify SNPs that could predict the incidence of OC. Ranking probability resulting from network meta‐analysis and the Thakkinstian’s algorithm was used to select the most appropriate gene model. The false positive report probability (FPRP) and Venice criteria were further tested for credible relationships. Subgroup analysis was also carried out to explore whether there are racial differences.ResultsA total of 63 genes and 92 SNPs were included in our study after careful consideration. Fok1 rs2228570 is likely a dominant risk factor for the development of OC compared to other selected genes. The dominant gene model of Fok1 rs2228570 (pooled OR = 1.158, 95% CI: 1.068–1.256) was determined to be the most suitable model with a FPRP <0.2 and moderate credibility.ConclusionsFok1 rs2228570 is closely linked to OC risk, and the dominant gene model is likely the most appropriate model for estimating OC susceptibility.

Identification of a novel nine‐SnoRNA signature with potential prognostic and therapeutic value in ovarian cancer

AbstractBackgroundIncreasing evidence has been confirmed that small nucleolar RNAs (SnoRNAs) play critical roles in tumorigenesis and exhibit prognostic value in clinical practice. However, there is short of systematic research on SnoRNAs in ovarian cancer (OV).Material/Methods379 OV patients with RNA‐Seq and clinical parameters from TCGA database and 5 paired clinical OV tissues were embedded in our study. Cox regression analysis was used to identify prognostic SnoRNAs and construct prediction model. SNORic database was adopted to examine the copy number variation of SnoRNAs. ROC curves and KM plot curves were applied to validate the prognostic model. Besides, the model was validated in 5 paired clinical tissues by real‐time PCR, H&E staining and immunohistochemistry.ResultsA prognostic model was constructed on the basis of SnoRNAs in OV patients. Patients with higher RiskScore had poor clinicopathological parameters, including higher age, larger tumor size, advanced stage and with tumor status. KM plot analysis confirmed that patients with higher RiskScore had poorer prognosis in subgroup of age, tumor size, and stage. 7 of 9 SnoRNAs in the prognostic model had positive correlation with their host genes. Moreover, 5 of 9 SnoRNAs in the prognostic model correlated with their CNVs, and SNORD105B had the strongest correction with its CNVs. ROC curve showed that the RiskScore had excellent specificity and accuracy. Further, results of H&E staining and immunohistochemistry of Ki67, P53 and P16 confirmed that patients with higher RiskScore are more malignant.ConclusionsIn summary, we identified a nine‐SnoRNAs signature as an independent indicator to predict prognosis of OV, providing a prospective prognostic biomarker and potential therapeutic targets for ovarian cancer.

A 5‐year survival status prognosis of nonmetastatic cervical cancer patients through machine learning algorithms

AbstractBackgroundPrediction models with high accuracy rates for nonmetastatic cervical cancer (CC) patients are limited. This study aimed to construct and compare predictive models on the basis of machine learning (ML) algorithms for predicting the 5‐year survival status of CC patients through using the Surveillance, Epidemiology, and End Results public database of the National Cancer Institute.MethodsThe data registered from 2004 to 2016 were extracted and randomly divided into training and validation cohorts (8:2). The least absolute shrinkage and selection operator (LASSO) regression was employed to identify significant factors. Then, four predictive models were constructed, including logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The predictive models were evaluated and compared using Receiver‐operating characteristics with areas under the curves (AUCs) and decision curve analysis (DCA), respectively.ResultsA total of 13,802 patients were involved and classified into training (N = 11,041) and validation (N = 2761) cohorts. By using the LASSO regression method, seven factors were identified. In the training cohort, the XGBoost model showed the best performance (AUC = 0.8400) compared to the other three models (all p < 0.05 by Delong's test). In the validation cohort, the XGBoost model also demonstrated a superior prediction ability (AUC = 0.8365) than LR and SVM models (both p < 0.05 by Delong's test), although the difference was not statistically significant between the XGBoost and the RF models (p = 0.4251 by Delong's test). Based on the DCA results, the XGBoost model was also superior, and feature importance analysis indicated that the tumor stage was the most important variable among the seven factors.ConclusionsThe XGBoost model proved to be an effective algorithm with better prediction abilities. This model is proposed to support better decision‐making for nonmetastatic CC patients in the future.

Systematic review of patients’ and healthcare professionals’ views on patient‐initiated follow‐up in treated cancer patients

AbstractBackgroundCurrent follow‐up models in cancer are seen to be unsustainable and inflexible, and there is growing interest in alternative models, such as patient‐initiated follow‐up (PIFU). It is therefore important to understand whether PIFU is acceptable to patients and healthcare professionals (HCPs).MethodsStandard systematic review methodology aimed at limiting bias was used for study identification (to January 2022), selection and data extraction. Thematic synthesis was undertaken for qualitative data, and survey findings were tabulated and described.ResultsNine qualitative studies and 22 surveys were included, mainly in breast and endometrial cancer. Women treated for breast or endometrial cancer and HCPs were mostly supportive of PIFU. Facilitators for PIFU included convenience, control over own health and avoidance of anxiety‐inducing clinic appointments. Barriers included loss of reassurance from scheduled visits and lack of confidence in self‐management. HCPs were supportive of PIFU but concerned about resistance to change, unsuitability of PIFU for some patients and costs.ConclusionPIFU is viewed mostly positively by women treated for breast or endometrial cancer, and by HCPs, but further evidence is needed from a wider range of cancers, men, and more representative samples.A protocol was registered with PROSPERO (CRD42020181412).

Randomized trial of exercise on cancer‐related blood biomarkers and survival in women with ovarian cancer

AbstractBackgroundIn randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer‐related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer.MethodsThis secondary analysis of a published randomized controlled trial examined the impact of a 6‐month exercise intervention versus attention‐control on change in prespecified circulating biomarkers (cancer antigen 125 (CA‐125), C‐reactive protein (CRP), insulin‐like growth factor‐1(IGF‐1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention‐control on all‐cause mortality included all (N = 144) participants. All statistical tests were two‐sided.ResultsParticipants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post‐diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF‐1 (group difference in change: −14.2 (−26.1 to −2.3) ng/mL (least squared means (95% CI))) and leptin (−8.9 (−16.5 to −1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention‐control (N = 51). No group difference in change was seen for CA‐125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow‐up of 70 months [range 6.6–105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention‐control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99).ConclusionsFurther studies are needed to determine the clinical significance of exercise‐induced changes in cancer‐related circulating biomarkers in women with ovarian cancer.

18F‐Fluoro‐2‐Deoxyglucose Positron Emission Tomography/Computed Tomography Measures of Spatial Heterogeneity for Predicting Platinum Resistance of High‐Grade Serous Ovarian Cancer

ABSTRACTBackgroundThe purpose of this study is to construct models for predicting platinum resistance in high‐grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18F‐FDG PET/CT images.MethodsA retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki‐67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki‐67 and p53 was assessed by Spearman's correlation coefficient (ρ).ResultsA total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU_Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki‐67 scores with ρ = 0.753.ConclusionsAdding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki‐67 and p53 scores.

BIRC5 facilitates cisplatin‐chemoresistance in a m6A‐dependent manner in ovarian cancer

AbstractCisplatin‐based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat‐containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti‐apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin‐resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6‐methyladenosine (m6A) binding sites. The modification of m6A was found to enhance the expression of BIRC5 by recognizing and binding to the 3′‐UTR of mRNA. Additionally, the insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co‐silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m6A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.

A qualitative assessment of the acceptability of human papillomavirus self‐sampling and informational materials among diverse populations

AbstractBackgroundDisparities in cervical cancer screening rates among marginalized groups is a driver of inequalities in cervical cancer. Self‐sampling for human papillomavirus (HPV) testing is a newly emerging alternative to clinician‐performed testing to screen for cervical cancer, and has high potential to reduce screening barriers in under‐screened and marginalized groups. We study the acceptability in of HPV self‐sampling and informational materials among Black/African American, Hispanic/Spanish speaking, American Indian/Alaska Native and transgender/nonbinary populations.MethodsWe conducted qualitative interviews with patients, ages 30–65, who were Black/African American, Hispanic, American Indian, and/or transgender/nonbinary individuals assigned female at birth. Telephone interviews were conducted in English or Spanish. Patients did not complete the test, rather were asked about the attractiveness, comprehensibility, and acceptability of the HPV self‐test, instructions, and messaging.ResultsAmong 23 completed interviews (5 American Indian/Alaska Native, 7 Hispanic [2 bilingual, 5 Spanish‐speaking], 5 Black/African American, and 6 transgender/nonbinary), patients from all groups thought the test was straightforward and convenient, and they would complete the test at home or in clinic. The transgender/nonbinary patients preferred at‐home testing. American Indian and transgender/nonbinary patients liked that the test might avoid pain, discomfort, and invasiveness. All patients liked the letter and instructions. All groups had specific suggestions for making the materials more culturally acceptable.ConclusionsThe HPV self‐test and the instructions and materials for use were acceptable for a diverse group of patients. Tailored outreach and messaging should be considered to reduce screening disparities among groups that have been historically underserved by the medical system.

ANKRD62 Modulates NF ‐ κB Signaling to Promote Proliferation and Migration in UCEC

ABSTRACT Members of the ankyrin repeat domain (ANKRD) family are involved in multiple cellular functions, including cell cycle regulation, cell adhesion, and signaling, and have been implicated in the pathogenesis of various cancers. However, the function of ANKRD62, a recently identified member of this family, remains largely unexplored. This study investigated the clinical significance and biological function of ANKRD62 in uterine corpus endometrial carcinoma (UCEC). Through gene expression profiling, we identified ANKRD62 upregulation in UCEC tissues compared to paired adjacent normal tissues. Using overexpression and shRNA‐mediated knockdown in cell lines and mouse models, we demonstrated that ANKRD62 is significantly upregulated in UCEC tissues, with expression levels positively correlated with tumor grade and inversely associated with patient survival. In vitro functional assays revealed that ANKRD62 overexpression markedly enhanced UCEC cell proliferation and migration, whereas ANKRD62 knockdown suppressed these malignant phenotypes without significantly affecting apoptosis. Consistent with these findings, in vivo experiments showed that ANKRD62‐overexpressing cells exhibited accelerated tumor growth and increased metastatic potential. Mechanistically, ANKRD62 was found to be associated with NF‐κB pathway modulation, promoting p65 nuclear translocation and phosphorylation, thereby affecting cellular function. In summary, this study provides the first evidence that ANKRD62 acts as a critical oncogenic driver in UCEC progression and unveils its functional association with NF‐κB signaling. These findings highlight the potential of ANKRD62 as a novel therapeutic target and offer new insights into the molecular mechanisms underlying UCEC pathogenesis.

Epigenetic Compound Library Screen Identifies Ibrutinib as an Inhibitor of Ovarian Clear Cell Carcinoma Viability

ABSTRACT Background Ovarian clear cell carcinoma (OCCC) is an endometriosis‐associated ovarian cancer subtype. Somatic mutations in OCCC are reported in ARID1A , PIK3CA , and the TERT promoter ( TERTp ), as well as less commonly in KRAS and TP53 among other genes. OCCC is typically resistant to standard‐of‐care chemotherapy, especially after relapse. While recent studies have seen favourable responses to immunotherapy, patients with OCCC face limited therapeutic options. Methods With the objective of discovering new drug treatments for OCCC, we screened OCCC (RMG‐1, JHOC‐5, OV207, OVISE, OVMANA, OVTOKO, and TOV‐21G) and non‐OCCC cell lines with a commercially available epigenetic drug compound library at two concentrations. Based on specified selection criteria, drugs were sought that preferentially inhibited viability of OCCC versus non‐OCCC cells, with subsequent validation in 2D and 3D bioprinted models and exploration of a relevant signalling pathway. Results Taken together, OCCC cell lines were more sensitive to the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib than non‐OCCC cells, with some variation in response observed between cell lines in 2D and 3D bioprinted cultures. Furthermore, ibrutinib inhibited PI3K/AKT/mTOR cell survival signalling in some but not all OCCC cell lines, suggesting that this drug functions on additional pathways. Conclusions Ibrutinib is used clinically to treat specific B cell disorders; however, it is not currently approved to treat solid tumours. Data presented in OCCC cell lines complements clinical observations of a therapeutic response to ibrutinib in low‐grade serous ovarian cancer. Ibrutinib demonstrates potential for the treatment of certain rare subtypes of ovarian cancer and should be further investigated.

Efficacy and Safety of Multivisceral Resection for Ovarian Cancer: A Comparative Study of Gynecologic Oncologists and Multidisciplinary Surgeons

ABSTRACT Background Advanced ovarian cancer often presents with extensive pelvic and abdominal metastases, even malignant pleural effusion. Consequently, multivisceral resection has become the common surgical approach to achieve optimal resection of ovarian cancer. The present study aimed to evaluate postoperative complications and prognosis of multivisceral resection performed by the independent gynecologic oncologist team (GOT) or multidisciplinary team (MDT). Methods The retrospective cohort study enrolled ovarian cancer patients who underwent surgery with multivisceral resection in Jiangsu Cancer Hospital. Patients were divided into two groups depending on the surgical team: the GOT and MDT groups. Patient baseline characteristics, surgical outcomes, postoperative complications, and long‐term prognosis were compared between the GOT and MDT groups. Results Between January 2017 and June 2024, 299 ovarian cancer patients were included in this study: 83 in the GOT and 216 in the MDT group. The GOT group had shorter operating times (235 vs. 290 min; p  < 0.001) and less blood loss (400 vs. 600 mL; p  < 0.001) compared with the MDT group. There were no significant differences in postoperative complications and median progression‐free survival (PFS) (not reached (NR) vs. 22.8 months; HR = 0.818, 95% CI 0.507–1.320; p  = 0.410) between the GOT and MDT groups. In multivariate analysis, HRD positive status was an indicator of a favorable prognosis (HR = 0.453; 95% CI 0.243–0.844; p  = 0.013). Conclusion The results suggest that ovarian cancer patients who underwent multivisceral resection performed by the independent gynecologic oncologist team are safe and feasible. Our team will continue to follow up to obtain more comprehensive survival data to validate this finding.

The Role of Gut Microbiota and Their Derived Metabolites in Chemotherapy‐Induced Nausea and Vomiting in Ovarian Cancer

ABSTRACT Objective This study aimed to investigate the relationship between gut microbiota and chemotherapy‐induced nausea and vomiting (CINV) in patients with ovarian cancer undergoing platinum‐based chemotherapy (carboplatin or cisplatin combined with paclitaxel). Methods Clinical data and fecal samples were collected from patients with ovarian cancer after admission but prior to the initiation of their first chemotherapy cycle. Patients were divided into the CINV ( n  = 25) and non‐CINV ( n  = 25) groups on the basis of symptoms occurring after chemotherapy. No additional samples were collected during chemotherapy. Integrated metagenomic sequencing and untargeted metabolomic profiling identified CINV‐associated microbial taxa and metabolites. Additionally, fecal microbiota transplantation (FMT) in SD rats validated causal links between gut dysbiosis and CINV pathogenesis. Results Bacteroides caccae , Corynebacteriales, and Corynebacterium were significantly enriched in the CINV group. KEGG enrichment revealed upregulated pathways in CINV, including focal adhesion, lysosome function, and eukaryotic cellular communities. Metabolomic analysis identified 19 significantly increased metabolites in the fecal samples of CINV patients versus 10 in non‐CINV controls. KEGG enrichment revealed that the pentose phosphate pathway, glutathione metabolism, and lipoic acid metabolism were significantly implicated in CINV pathogenesis. Multi‐omics integration revealed Bacteroides sp. A1C1 strongly correlated with hesperetin, arbutin, orciprenaline, and myristolic acid. In rats, cisplatin‐induced CINV models showed higher kaolin consumption versus controls ( p  < 0.05). FMT from non‐CINV donors reduced kaolin consumption in cisplatin‐treated rats ( p  < 0.05). The expression of 5‐HT3R, NK1R, and NK2R in the medulla oblongata and colon was significantly increased in the cisplatin model group ( p  < 0.05) and partially reversed by non‐CINV FMT ( p  < 0.05). Conclusions Gut microbiota dysbiosis directly contributes to CINV pathogenesis. Bacteroides sp. A1C1 and its putatively identified metabolites (hesperetin, arbutin, orciprenaline, and myristolic acid) represent potential diagnostic biomarkers for CINV.

Hyperspectral Imaging of Whole‐Cell Region for Differentiating Cervical Squamous Intraepithelial Lesion Cytology

ABSTRACT Background Cervical cytology offers a relatively safe and reliable method for cancer screening, but the tests contain vague grading criteria, such as atypical squamous cells, and cannot exclude high‐grade squamous intraepithelial lesions (ASC‐H) and atypical squamous cells of undetermined significance (ASC‐US). Methods To explore distinct differentiation points among ASC‐H, high‐grade squamous intraepithelial lesions (HSIL), and non‐keratinizing squamous cell carcinoma (SCC), and among ASC‐US, low‐grade squamous intraepithelial lesions (LSIL), and negative for intraepithelial lesion or malignancy, hyperspectral imaging analyses were performed in cells mounted on 150 Papanicolaou‐stained specimens containing nine cervical cell types. Hyperspectral data were obtained from nuclei, cytoplasm, and whole‐cell regions in 4841 cells without overlap at 15‐nm increments in wavelength within the visible light spectrum (450–750 nm). Results Significant differences in hyperspectral intensity were observed between ASC‐H and HSIL at 487 nm to 517 nm ( p  < 0.05), as well as among SCC at 457 nm ( p  < 0.01). Further, hyperspectral intensity differences between ASC‐US and LSIL were notable at multiple wavelengths with the lowest p ‐value ( p  = 0.006) at 532 nm. Interestingly, quantification of hyperspectral values revealed strong correlations between nucleus‐to‐cytoplasm ratio and hyperspectral intensity value of whole cell ( R 2  = 0.8339, p  < 0.001), indicating that intensity from the whole cell provided the most informative indicator of cervical cells. Conclusion These results suggest that hyperspectral analysis of whole cells offers a valuable tool for differentiating atypical squamous cells from other cell types.

Quality of life in endometrial cancer survivors by grade of disease

AbstractBackgroundEndometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with overall incidence increasing, particularly high‐grade disease. There is sparse information regarding quality of life (QOL) in EC survivors with a focus on grade of disease.MethodsA total of 259 women with EC diagnosed between 2016 and 2020 were identified via the Metropolitan Detroit Cancer Surveillance System and consented to enroll in the Detroit Research on Cancer Survivors cohort study (if African American, n = 138) or completed the baseline interview (if non‐Hispanic white, n = 121). Each respondent provided information about their health history, educational attainment, health behaviors, and demographics. The Functional Assessment of Cancer Therapy‐General (FACT‐G) and Endometrial‐specific (FACT‐En) were used to assess QOL.ResultsWomen diagnosed with high‐grade (n = 112) and low‐grade (n = 147) EC participated in this study. EC survivors with high‐grade disease reported significantly lower QOL compared to survivors with low‐grade disease (85 vs. 91, respectively, p value = 0.025) as assessed by the FACT‐G. This difference was driven by lower physical and functional subscales among women with high‐grade disease compared to those with low‐grade disease (p value = 0.016 and p = 0.028, respectively). Interestingly, EC‐specific QOL measures, as assessed by the FACT‐En, did not differ by grade.ConclusionGrade of disease impacts QOL in EC survivors, as well as socioeconomic, psychological, and physical factors. Most of these factors are amenable to interventions and should be assessed in patients after an EC diagnosis.

Predicting Risk of Lymph Node Metastasis in Neuroendocrine Carcinoma of Cervix: A Validated Nomogram Incorporating Neuroendocrine Markers and Clinical Parameters

ABSTRACT Objective Lymph node metastasis (LNM) is an important factor leading to poor prognosis of tumors. This study aims to predict the risk probability of LNM in neuroendocrine carcinoma of cervix (NECC). Methods 202 and 92 patients were included as the training cohort and the validation cohort respectively. Logistics regression analysis was conducted to determine the risk factors related to LNM in the training cohort. The validity of the model was evaluated by the calibration curve and the consistency index. The receiver operating characteristic curve was used to determine the optimal threshold for predicting the risk of LNM. Then, it compared the predictive ability of the different models and their ability to identify low‐risk patients. Results Multivariate logistic regression analysis confirmed that the depth of stromal invasion ( p  = 0.029), parametrium invasion ( p  = 0.046), lymphovascular space invasion ( p  = 0.011), cervical‐uterine junction invasion ( p  = 0.046), and positive CD56 ( p  = 0.008) were the independent risk factors for LNM, which were included in the construction of the nomogram model. Both the internal and external calibration curves showed that the model fits well. The C‐index of the training cohort and the validation cohort in this developed model (0.894 and 0.92, respectively) was superior to other models. The optimal threshold of risk probability of LNM predicted by the model was 0.20. Based on this threshold, this model showed a good recognition ability to identify low‐risk patients. Conclusion The nomogram model constructed by combining clinical parameters with neuroendocrine markers could effectively predict the risk probability of LNM in NECC and identify the low‐risk population.

Increased Risk of Second Squamous Cell Carcinomas Following Cervical Cancer: A Nationwide Danish Case–Control Study

ABSTRACT Introduction This nationwide case–control study investigated the risk of second primary cancers among cervical cancer (CC) survivors compared to cancer‐free women. Methods Women aged ≥ 18 diagnosed with CC from 1987 to 2012 were identified via the Danish Cancer Registry (DCR) and matched 1:5 by age and residence to cancer‐free controls. A subpopulation with histologically confirmed squamous cell carcinoma of the cervix (SCC‐C) was defined using the Danish Pathology Register. Adjusted sub‐hazard ratios (aSHR) for subsequent primary cancers were estimated. Results The study included 10,728 CC cases and 53,597 matched controls, including 7910 SCC‐C cases and 39,358 controls. Over a median follow‐up of 14.2 years, CC survivors had a modest but statistically significant reduction in the overall risk of second primary cancers (aSHR: 0.87; 95% CI, 0.81–0.93), including lower risks of colorectal cancer (aSHR: 0.77; 95% CI, 0.63–0.93), breast cancer (aSHR: 0.76; 95% CI, 0.67–0.87), and malignant melanoma (aSHR: 0.59; 95% CI, 0.42–0.84). In contrast, the risk of lung cancer was increased (aSHR: 1.33; 95% CI, 1.15–1.54). Among SCC‐C survivors, the risk of second SCC was increased at both HPV‐related sites (aSHR: 1.78; 95% CI, 1.18–2.68) and non‐HPV sites (aSHR: 2.59; 95% CI, 1.92–3.47), primarily due to a marked increased risk of lung SCC (aSHR: 2.88; 95% CI, 1.97–4.20). Discussion Although the overall risk of second primary cancers was lower among CC survivors compared to controls, the increased incidence of second SCCs, particularly lung SCC, highlights the need for targeted long‐term surveillance strategies.

A Clinical Prediction Model for Pathologic Upgrade to Invasive Carcinoma Following Conization of Cervical High‐Grade Squamous Intraepithelial Lesions

ABSTRACT Objective To explore the risk factors associated with the pathological progression to invasive carcinoma following the conization of cervical high‐grade squamous intraepithelial lesions (HSIL) and to construct a risk prediction model to guide preoperative risk assessment and optimize the selection of surgical approaches. Methods A retrospective analysis was conducted on the clinical data of 3337 patients who underwent cervical conization for HSIL at Hunan Provincial Maternal and Child Health Care Hospital from December 2016 to March 2022. The patients were categorized into the pathological progression group (398 cases) and the nonprogression group (2939 cases) based on postconization pathology results. Statistical significance factors were selected by least absolute shrinkage and selection operator regression and then multivariate logistic regression was utilized to build predictive models, which were presented as a nomogram and evaluated for discriminability, calibration, and decision curves. The Bootstrap method was utilized for internal validation. A total of 277 patients were enrolled from April 2022 to October 2022 for external validation. Results The percentage of pathologic upgrades to invasive carcinoma following cervical conization was 11.9%. The predictive model included age, contact bleeding symptoms, HPV16/18 infection, HSIL cytology, cervical biopsy pathology diagnosis level, suspicious stromal infiltration in the biopsy pathology diagnosis, and endocervical curettage HSIL. The model demonstrated good overall discrimination in predicting the risk of HSIL progression to early invasive cancer, and internal validation confirmed its reliability (C‐index = 0.787). Area under the curve analysis indicated good model discriminability across external datasets. The decision curve analysis also suggested that this model is clinically useful. Conclusion We developed and validated a nomogram incorporating multiple clinically relevant variables to better identify cases of HSIL progressing to early cervical cancer, providing a basis for individualized treatment and surgical approach selection.

Adipose tissue area is a predictive biomarker for the efficacy of pegylated liposomal doxorubicin in platinum‐refractory/resistant ovarian cancer

AbstractBackgroundPegylated liposomal doxorubicin (PLD), an anthracycline agent, is widely used as a treatment option for platinum‐refractory/resistant epithelial ovarian cancer (EOC). Although only a subset of patients with platinum‐refractory/resistant EOC derive benefit from PLD, predictive biomarkers for patients who will respond to the drug have not yet been established. Here, we evaluated the relationship between adipose tissue status and PLD efficacy in patients with platinum‐refractory/resistant EOC.MethodsPatients with platinum‐refractory/resistant EOC who were treated with single‐agent PLD were included in this retrospective cohort study. Adipose tissue areas including visceral adipose tissue area (VATA), subcutaneous adipose tissue area (SATA), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated prior to the initiation of PLD using computed tomography images. The associations of adipose tissue areas with objective response rate (ORR) and patient survival were evaluated.ResultsForty‐four patients with platinum‐refractory/resistant EOC who received single‐agent PLD were included. Subjects were categorized into high and low groups according to the median VATA, SATA, and VSR values, and body mass index (BMI). The ORR of PLD was significantly lower in the VSR‐high group than in the VSR‐low group (p = 0.0089). Patients in the high VSR group showed significantly shorter progression‐free survival (PFS) compared with patients in the low VSR group (median, 4.0 vs. 8.5 months; p = 0.020). In the multivariable analysis, high VSR was a significant prognostic factor for shorter PFS (hazard ratio, 2.07; 95% confidence interval, 1.05–4.19; p = 0.035). VATA, SATA, and BMI showed no significant association with ORR and survival of patients who received PLD.ConclusionsHigh VSR is associated with lower ORR and shorter PFS in patients with platinum‐refractory/resistant EOC who received single‐agent PLD. VSR is a robust predictive biomarker for the efficacy of PLD.

Pan‐cancer analysis of oncogenic role of insulin‐like growth factor‐binding proteins and validation in ovarian cancer

AbstractBackgroundNumerous studies have shown that the insulin‐like growth factor (IGF) pathway is highly associated with tumor initial and progression in several tumors. However, compared with IGF1/1R and IGF2/2R, insufficient studies have focused on IGF‐binding proteins (IGFBPs).MethodsThe GDC TCGA and GTEx data of 33 cancers, TCGA pan‐cancer immune phenotypes, tumor mutation burdens, and the copy number alterations of IGFBPs were extracted. Next, the prognostic value of IGFBPs was analyzed based on a univariate Cox analysis. Additionally, the ESTIMATE algorithm was used to calculate stromal and immune scores and tumor purity, and the CIBERSORT algorithm was used to estimate tumor‐infiltrating immunocyte levels. Ultimately, the correlation between IGFBP expression and cancer hallmark pathways was estimated with a Spearman analysis.ResultsThe expression of IGFBPs was differentially expressed and correlated with prognosis in specific cancers. IGFBPs may operate as biological markers for carcinogenesis and progression and as prognostic biomarkers. Additionally, IGFBP5 has been proved that promotes the invasion and migration of ovarian cancer.ConclusionsIn general, IGFBPs can serve as predictable biomarkers and potential therapeutic targets for specific tumors. Our results could provide underlying targets for the design of laboratory experiments to elucidate the mechanism of IGFBPs in cancers and identify IGFBP5 as a prognostic factor in ovarian cancers.

Molecular and phenotypic characteristics influencing the degree of cytoreduction in high‐grade serous ovarian carcinomas

AbstractBackgroundHigh‐grade serous ovarian carcinoma (HGSOC) is the deadliest ovarian cancer subtype, and survival relates to initial cytoreductive surgical treatment. The existing tools for surgical outcome prediction remain inadequate for anticipating the outcomes of the complex relationship between tumour biology, clinical phenotypes, co‐morbidity and surgical skills. In this genotype–phenotype association study, we combine phenotypic markers with targeted DNA sequencing to discover novel biomarkers to guide the surgical management of primary HGSOC.MethodsPrimary tumour tissue samples (n = 97) and matched blood from a phenotypically well‐characterised treatment‐naïve HGSOC patient cohort were analysed by targeted massive parallel DNA sequencing (next generation sequencing [NGS]) of a panel of 360 cancer‐related genes. Association analyses were performed on phenotypic traits related to complete cytoreductive surgery, while logistic regression analysis was applied for the predictive model.ResultsThe positive influence of complete cytoreductive surgery (R0) on overall survival was confirmed (p = 0.003). Before surgery, low volumes of ascitic fluid, lower CA125 levels, higher platelet counts and relatively lower clinical stage at diagnosis were all indicators, alone and combined, for complete cytoreduction (R0). Mutations in either the chromatin remodelling SWI_SNF (p = 0.036) pathway or the histone H3K4 methylation pathway (p = 0.034) correlated with R0. The R0 group also demonstrated higher tumour mutational burden levels (p = 0.028). A predictive model was developed by combining two phenotypes and the mutational status of five genes and one genetic pathway, enabling the prediction of surgical outcomes in 87.6% of the cases in this cohort.ConclusionInclusion of molecular biomarkers adds value to the pre‐operative stratification of HGSOC patients. A potential preoperative risk stratification model combining phenotypic traits and single‐gene mutational status is suggested, but the set‐up needs to be validated in larger cohorts.

Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study

AbstractBackgroundAnti‐angiogenic therapy with bevacizumab (BEV), an anti‐VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed.MethodsTo overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient‐derived xenografts (PDXs) of immunodeficient mice.ResultsBEV/CCR2i demonstrated a significant effect of growth suppression in the BEV‐resistant serous PDX and BEV‐sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti‐α‐SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV‐resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased‐dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B‐MAPK pathway.ConclusionsBEV/CCR2i showed a sustained anticancer immunity‐independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma.

Awareness of ovarian cancer symptoms and risk factors in a young ethnically diverse British population

AbstractBackgroundOvarian cancer does not cause many symptoms in the early stages, which is why the majority of cases are of advanced disease. Increasing awareness of ovarian cancer symptoms may lead to earlier diagnosis and improved outcomes.MethodsParticipants in Britain completed the Ovarian Cancer Awareness Measure by online survey (n = 459).ResultsOur participants were 75% female, 25% male and a young (27.89 ± 11.44 years) ethnically diverse population (40.3% White, 29.3% Asian and 18.0% Black). Individuals recalled 1.24 ± 1.30 symptoms, and recognised 5.96 ± 2.4 symptoms. We found higher levels of recall and recognition compared to previous research possibly due to using an online survey. Recognition was lowest for difficulty eating (39.4%) and persistently feeling full (38.7%). Males had slightly lower symptom recall and recognition than females. Participants incorrectly recalled an irregular menstrual cycle (22.4%) as an ovarian cancer symptom and 67% answered the age of incidence question incorrectly. Suggesting that participants incorrectly associate ovarian cancer as a disease of pre‐menopausal women.Individuals recalled 1.47 ± 1.20 risk factors, and recognised 6.1 ± 2.4 risk factors. Family history of ovarian cancer was recalled by 59% of participants. Recognition was lowest for in vitro fertilisation treatment (23.0%) and talcum powder in the genital area (23.0%). The generic cancer risk factors of alcohol (9.3%) and poor diet (8.8%) were recalled as specific ovarian cancer risk factors. 57.9% of participants incorrectly answered that there is an ovarian cancer screening programme. Suggesting confusion between ovarian and cervical cancer as participants also recalled cervical cancer risk factors of sexually transmitted diseases (6.3%) and human papillomavirus (1.5%). 29.7% of female participants would seek help for an ovarian cancer symptom within 1–2 days. Help seeking was higher in the Black and Asian ethnicities (44.4% and 45.0%; p = 0.018).ConclusionAwareness of ovarian cancer symptoms is low. Ovarian cancer awareness campaigns should include common misconceptions identified in this research.

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

AbstractBackgroundCornichon homolog 4 (CNIH4) belongs to the CNIH family. It functions as an oncogene in many tumors. However, CNIH4's significance in the immune landscape and its predictive potential in cervical cancer (CESC) is unexplored.MethodsCNIH4 levels and its effect on the survival of patients with CESC were evaluated using data retrieved from The Cancer Genome Atlas (TCGA). The oncogenic effect of CNIH4 in CESC was determined using small interfering RNA‐mediated transfected cell lines and tumorigenesis experiments in animal models.ResultsHigher expression of CNIH4 was found in advanced tumor and pathological stages, as well as lymph node metastasis. CNIH4 expression correlated positively with the infiltration of macrophages M2 and resting dendritic cells into the affected tissue. Additionally, functional enrichment of RNA‐sequencing of CNIH4‐knocked down CESC cell lines showed the association of CNIH4 to the PI3K‐Akt signaling pathway. Single‐sample gene set enrichment analysis highlighted several immune pathways that were elevated in the CESC samples with enhanced levels of CNIH4, including Type‐I and Type‐II IFN‐response pathways. The impact of CNIH4 on drug sensitivity was further assessed using the GDSC database. As CNIH4 is linked to the immune landscape in CESC, this study determined a four‐gene risk prediction signature utilizing CNIH4‐related immunomodulators. The risk score quantified from the prediction signature was an independent predictive indicator in CESC. Receiver operating characteristic curve analysis verified the good predictive ability of the four‐gene signature in TCGA‐CESC cohort. Thus, the CNIH4‐related model showed potential as an auxiliary TNM staging system tool.ConclusionCNIH4 may be an effective predictive biomarker for patients with cervical cancer, thus providing new ideas and research directions for CESC.

A survey of carboplatin desensitization therapy in Japan: A multicenter retrospective study

AbstractIntroductionHypersensitivity reactions (HSRs) to chemotherapy are serious adverse events associated with cancer drug therapy and can occur with any antitumor drug. This study investigated the safety and efficacy of carboplatin desensitization therapy in Japan and established a method for treating carboplatin HSRs.MethodsPatients diagnosed with gynecological (ovarian, endometrial, or cervical) cancers who underwent carboplatin desensitization therapy between 2016 and 2020 at the Gynecologic Cancer Study Group of Japan Clinical Oncology Group were included. The carboplatin desensitization therapy at each institution and the implementation cases were registered in an online case report form.ResultsThis retrospective study enrolled 136 patients (ovarian, 108; endometrial, 17; and cervical cancer, 11). Pre‐existing allergies were present in 37 (27.2%) patients, and 32 (23.5%) patients exhibited prodromal symptoms during treatment before HSR onset. Erythema was the most common symptom at HSR onset, affecting 93 (68.4%) patients, followed by itching in 72 (52.9%) patients and decreased oxygen saturation in 43 (31.6%) patients. Loss of consciousness occurred in three (2.2%) patients. The most common timing of HSR onset was during the first recurrence treatment (47%). The mean total carboplatin dose until HSR onset was 7331 (2620–18,282) mg, and the mean number of doses was 14 (4–63). Desensitization treatment was completed in 75% of cases, and breakthrough HSRs occurred in 25% (34/136). No deaths occurred in the study cohort. The risk factors for HSRs were not identified.ConclusionAlthough carboplatin desensitization therapy has high success rates in Japan, erythema and pruritus are important HSRs to consider.

Clinical factor‐based risk stratification for precision therapy in locally advanced squamous cell carcinoma of the uterine cervix

AbstractBackgroundConcurrent chemoradiotherapy (CCRT) is the standard of care for locally advanced cervical cancer. In this study, we analyzed the pretreatment clinical and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) characteristics of patients with locally advanced cervical squamous cell carcinoma (SCC) to develop a scoring prototype for risk stratification.MethodsTwo cohorts were constructed in this study. Cohort 1 comprised patients with cervical SCC with 2009 FIGO stage III‐IVA or stage I–II with positive pelvic or para‐aortic lymph node (PALN) on PET/CT from AGOG09‐001 trial. Cohort 2 comprised patients with similar characteristics who had received adequate therapy in our hospital between 2016 and 2021. Pretreatment patient characteristics and PET/CT parameters including maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of primary tumor and nodal SUVmax were assessed for cancer‐specific survival (CSS) using multivariate Cox regression.ResultsAnalysis of combined data from cohorts 1 (n = 55) and 2 (n = 128) indicated age ≥ 66 years, primary tumor MTV ≥87 mL, and positive PALN on PET/CT to be independently significant adverse predictors for CSS (p < 0.001, p = 0.014, and p = 0.026, respectively) with a median follow‐up duration of 51 months. Assigning a score of 1 to each adverse predictor, patients with cumulative risk scores of 0, 1, 2, and 3 were discovered to have a 5‐year CSS of 86.9%, 71.0%, 32.2%, and 0%, respectively (p < 0.001).ConclusionAge, primary tumor MTV, and positive PALN on PET/CT may serve as independent predictors of poor survival in patients with locally advanced cervical SCC. Our findings indicate that patients without any adverse factors can receive standard CCRT, whereas those with at least one adverse factor can consider novel combination therapies or clinical trials.

Reasons for truly negative cytology reports preceding the diagnoses of invasive cervical cancer—Results of a false‐negative cytology audit in Polish Cervical Cancer Screening Programme

AbstractBackgroundFalse‐negative (FN) results in cervical cancer (CC) screening pose significant risk for participants and should be audited. The aim of the study was to analyse the results of audit of FN slides collected in 2010–2013 in Polish Cervical Cancer Screening Program (CCSP) and to seek for risk factors of obtaining true‐negative result (TN; not containing abnormal cells as confirmed in audit) before CC diagnosis.MethodsScreening database was merged with National Cancer Registry to identify negative slides preceding histologically confirmed CC diagnosis up to 42 months. Two blinding slides were randomly assigned per each FN. The whole set was reassessed independently by three pathologists with 30 years of experience in cytology evaluation. Final audit result was established in the case of ≥2 coherent reports. Agreement rates and kappa (κ) coefficients were calculated. Logistic analysis of risk factors for obtaining TN result was performed.ResultsOf 374 included FNs, 204 were considered abnormal (54.6%) and 91 were confirmed negative for intraepithelial neoplasia (24.3%). Agreement between experts was moderate for FNs (κ = 0.266) and fair for blinding slides (κ = 0.142) when grouping abnormal slides. Adenocarcinoma diagnosis elevated the risk of TN result (OR = 3.83); detection of macroscopic changes on the cervix and smoking lowered the risk (OR = 0.39, OR = 0.40 respectively).ConclusionsMisinterpretation was the main reason for FN cytology in the CCSP which indicated the need of further personnel training to increase screening quality. Rather low agreement between auditors requires further insight. A standardised process of auditors' selection should be planned to increase audit quality.

A population‐based study of age‐related associations between vaginal pH and the development of cervical intraepithelial neoplasia

AbstractThe association between vaginal pH and the risk of cervical intraepithelial neoplasia (CIN) is unclear. We evaluated the dose‐response relationship between vaginal pH and CIN risk, as well as the combined influence of vaginal pH and high‐risk human papillomavirus (hrHPV) on the risk of CIN and the mediation effects of hrHPV infection on vaginal pH level and the development of CIN. We investigated 2304 women in Shanxi, China. The dose‐response relationship between vaginal pH and CIN risk was assessed using categoric and spline analyses. We established interaction and mediation models to determine the correlation between pH and hrHPV in the development of CIN. After adjusting covariates, a positive association was observed between hrHPV infection and the development of CIN [OR (95% CI) = 4.75 (3.52‐6.40) for CIN2+; OR (95% CI) = 7.30 (4.10‐13.00) for CIN3+], while a negative correlation was showed between vaginal pH level and CIN3+ [OR (95% CI) = 1.04 (0.59‐1.84); high vs low: OR (95% CI) = 0.32 (0.15‐0.69), P = .002]. The highest risk of CIN (5.24 of CIN2+ and 5.80 of CIN3+) were observed when hrHPV infection was combined with middle vaginal pH (4.6‐5.0). A significant mediation effect of hrHPV infection was observed in the association between vaginal pH level with CIN2+ (P = .002) and CIN3+ (P = .004). In conclusion, abnormal vaginal pH significantly induced the risk of high‐stage CIN in Chinese women infected with hrHPV. Therefore, maintaining normal vaginal pH levels may reduce the risk of CIN.

Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer

AbstractBackgroundHigh‐grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS‐4718, against multiple primary EAC cell lines and xenografts.MethodsWhole‐exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS‐4718, or their combination through oral gavage.ResultsWES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p‐FAK) as well as decreased p‐MEK and p‐ERK. In vivo the combination of avutometinib/VS‐4718 demonstrated superior tumor growth inhibition compared to single‐agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts.ConclusionsAvutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high‐grade EAC patients.

Should we abandon hormonal therapy in endometrial cancer? Outcomes of recurrent and metastatic endometrial cancer treated with systemic progestins

AbstractPurposeThe objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins.MethodsA retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method.ResultsOf 2342 cases reviewed, 74 met inclusion criteria. Sixty‐six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2–17.9) and 23.3 months (14.8–36.8), respectively. The PFS for patients with Grade 1–2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1–2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty‐four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy‐naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy‐naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.ConclusionsThis real‐world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy‐naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy‐OS was 29.1 months (17.9, 61.1) for chemotherapy‐naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.

Exploring the Clinical Signatures of Cervical Dysplasia Patients and Their Association With Vaginal Microbiota

ABSTRACTAimsThe vaginal microbiota plays a crucial role in women's health, and an imbalanced vaginal microbiota is linked to various diseases, including human papillomavirus (HPV) infection. However, most available data comes from Western countries and primarily focuses on HPV infection, with only a few studies considering detailed clinical factors to explore the relationship between vaginal microbiota and the development of cervical cancer, especially in China.Materials and MethodsOur study involved 266 women, including individuals at all stages of cervical dysplasia, and healthy controls with and without HPV infection. We assessed several aspects of the vaginal environment, including vaginal microbiota composition using 16S rRNA gene sequencing, HPV infection status using the standard Roche Cobas method, pH value, age, and H2O2 levels from clinical records, and partner numbers and contraceptive methods obtained through questionnaires. The association of these clinical signatures with cervical dysplasia stages and vaginal microbiota was analyzed.Key FindingsOur findings demonstrate a significant association between vaginal microbiota and cervical dysplasia stages. Patients with cervical dysplasia and cancer showed a substantial increase in HPV 16 infection, a higher prevalence of pH > 5, a lower H2O2 level, and older ages compared to healthy individuals. Additionally, these factors influence the beta diversity of the vaginal microbiota.SignificanceThese results underscore the importance of considering the vaginal microbiota within the cancer microenvironment and highlight the need to integrate all available data to aid in the current diagnosis and understanding of cervical dysplasia and the cervical cancer microenvironment.

A novel nomogram and risk stratification for early metastasis in cervical cancer after radical radiotherapy

AbstractObjectThis study aimed to establish an effective risk nomogram to predict the early distant metastasis (EDM) probability of cervical cancer (CC) patients treated with radical radiotherapy to aid individualized clinical decision‐making.MethodsA total of 489 patients with biopsy‐confirmed CC between December 2018 and January 2021 were enrolled. Logistic regression with the stepwise backward method was used to identify independent risk factors. The nomogram efficacy was evaluated by using the area under the receiver operating characteristic curve (AUC), C‐index by 1000 bootstrap replications, etc. Finally, patients were divided into high‐ and low‐risk groups of EDM based on the cut‐off value of nomogram points.Results36 (7.36%) CC patients had EDM, and 20 (55.6%) EDM had more than one metastatic site involved. Age below 51 (OR = 2.298, p < 0.001), tumor size larger than 4.5 cm (OR = 3.817, p < 0.001) and radiotherapy (OR = 3.319, p < 0.001) were independent risk factors of EDM. For the nomogram model, C‐index was 0.701 (95% CI = 0.604–0.798), and 0.675 (95% CI = 0.578–0.760) after 1000 bootstrap resampling validations. The Hosmer–Lemeshow test demonstrated no overfitting (p = 0.924). According to the Kaplan–Meier curve of risk score, patients with high risk were more prone to get EDM (p < 0.001).ConclusionThis is the first research to focus on EDM in CC patients. We have developed a robust scoring system to predict the risk of EDM in CC patients to screen out appropriate cases for consolidation therapy and more intensive follow‐up.

Region of origin and cervical cancer stage in multiethnic Hispanic/Latinx patients living in the United States

AbstractBackgroundHispanic/Latinx people have the second highest cervical cancer incidence rates in the U.S. However, there is a lack of disaggregated data on clinical outcomes for this diverse and populous group, which is critical to direct resources and funding where they are most needed. This study assessed differences in stage at diagnosis of cervical cancer among Hispanic/Latinx subpopulations and associated factors.MethodsWe analyzed patients with primary cervical cancer from 2004 to 2019 in the National Cancer Database. Hispanic/Latinx patients were further categorized into Mexican, Puerto Rican (PR), Cuban, Dominican, and Central/South American, as per standard NCDB categories, and evaluated based on stage at diagnosis and sociodemographic characteristics. Multinomial logistic regression quantified the odds of advanced stage at presentation. Regression models were adjusted for age, education, neighborhood income, insurance status, and additional factors.ResultsHispanic/Latinx cervical cancer patients were more likely to be uninsured (18.9% vs. 6.0%, p < 0.001) and more likely to live in low‐income neighborhoods (28.6% vs. 16.9%, p < 0.001) when compared to non‐Hispanic White populations. Uninsured Hispanic/Latinx patients had 37.0% higher odds of presenting with regional versus localized disease (OR 1.37; 95% CI, 1.19–1.58) and 47.0% higher odds of presenting with distant versus. Localized disease than insured patients (OR 1.47; 95% CI, 1.33–1.62). When adjusting for age, education, neighborhood income, and insurance status, PR patients were 48% more likely than Mexican patients to present with stage IV versus stage I disease (OR 1.48; 95% CI, 1.34–1.64).ConclusionDisaggregating health data revealed differences in stage at cervical cancer presentation among Hispanic/Latinx subpopulations, with insurance status as a major predictor. Further work targeting structural factors, such as insurance status, within specific Hispanic/Latinx subpopulations is needed.

TPX2 promotes ovarian tumorigenesis by interacting with Lamin A/C and affecting its stability

AbstractObjectiveOvarian cancer (OC) is one of the fatal gynecologic malignancies. However, there are no effective prognostic or therapeutic indicators for OC. Herein, we aim to reveal the potential function of targeting protein for Xklp2 (TPX2) in OC progression.MethodsImmunohistochemical and bioinformatic analyses were used to evaluate the level of TPX2 in OC samples. Effects of TPX2 on cell proliferation, cell apoptosis and ROS production were evaluated in vivo and in vitro. Mass spectrometry, Co‐IP and immunofluorescence assays were performed to identify and verify protein‐protein interactions.ResultsOur data showed that pathological overexpression (OE) of the TPX2 in OC could manifest a poor prognosis. Functional studies demonstrated that TPX2 silencing led to the suppression of cell proliferation in vitro and in vivo through an increase in reactive oxygen species (ROS) level and apoptosis, while TPX2 OE exhibited the opposite effect. Furthermore, by mass spectrometric analysis, we identified a novel interacting partner, Lamin A/C, for TPX2. Mechanistically, TPX2 regulated Lamin A/C's stability by modulating the level of phospho‐Lamin A/C (Ser 22).ConclusionOur findings thus suggest that TPX2 may be a promising therapeutic target for OC.

MRI‐based radiomic signatures for pretreatment prognostication in cervical cancer

AbstractBackgroundAccurate pretherapeutic prognostication is important for tailoring treatment in cervical cancer (CC).PurposeTo investigate whether pretreatment MRI‐based radiomic signatures predict disease‐specific survival (DSS) in CC.Study TypeRetrospective.PopulationCC patients (n = 133) allocated into training(T) (nT = 89)/validation(V) (nV = 44) cohorts.Field Strength/SequenceT2‐weighted imaging (T2WI) and diffusion‐weighted imaging (DWI) at 1.5T or 3.0T.AssessmentRadiomic features from segmented tumors were extracted from T2WI and DWI (high b‐value DWI and apparent diffusion coefficient (ADC) maps).Statistical TestsRadiomic signatures for prediction of DSS from T2WI (T2rad) and T2WI with DWI (T2 + DWIrad) were constructed by least absolute shrinkage and selection operator (LASSO) Cox regression. Area under time‐dependent receiver operating characteristics curves (AUC) were used to evaluate and compare the prognostic performance of the radiomic signatures, MRI‐derived maximum tumor size ≤/> 4 cm (MAXsize), and 2018 International Federation of Gynecology and Obstetrics (FIGO) stage (I–II/III–IV). Survival was analyzed using Cox model estimating hazard ratios (HR) and Kaplan–Meier method with log‐rank tests.ResultsThe radiomic signatures T2rad and T2 + DWIrad yielded AUCT/AUCV of 0.80/0.62 and 0.81/0.75, respectively, for predicting 5‐year DSS. Both signatures yielded better or equal prognostic performance to that of MAXsize (AUCT/AUCV: 0.69/0.65) and FIGO (AUCT/AUCV: 0.77/0.64) and were significant predictors of DSS after adjusting for FIGO (HRT/HRV for T2rad: 4.0/2.5 and T2 + DWIrad: 4.8/2.1). Adding T2rad and T2 + DWIrad to FIGO significantly improved DSS prediction compared to FIGO alone in cohort(T) (AUCT 0.86 and 0.88 vs. 0.77), and FIGO with T2 + DWIrad tended to the same in cohort(V) (AUCV 0.75 vs. 0.64, p = 0.07). High radiomic score for T2 + DWIrad was significantly associated with reduced DSS in both cohorts.Data ConclusionRadiomic signatures from T2WI and T2WI with DWI may provide added value for pretreatment risk assessment and for guiding tailored treatment strategies in CC.

Lidocaine inhibits the metastatic potential of ovarian cancer by blocking NaV1.5‐mediated EMT and FAK/Paxillin signaling pathway

AbstractLidocaine, one of the most commonly used local anesthetics during surgery, has been reported to suppress cancer cell growth via blocking voltage‐gated sodium channels (VGSCs). VGSC 1.5 (NaV1.5) is highly expressed in invasive cancers including ovarian cancer. This study aims to investigate whether lidocaine inhibits the malignancy of ovarian cancer through NaV1.5 blockage. Human ovarian cancer, its metastatic cancer and normal ovarian tissues were probed with anti‐NaV1.5 antibody in situ. Human ovarian cancer A2780 and SKOV3 cells were cultured and their growth, epithelial‐mesenchymal transition (EMT), migration, and invasion in the presence or absence of lidocaine together with underlying molecular mechanisms were assessed. Murine syngeneic ovarian cancer (ID8) model was also used to determine the chemotherapeutic efficiency of cisplatin in combination with lidocaine. The high level of NaV1.5 expression was found in human ovarian cancer and even higher in its metastatic cancer but not in normal ovarian tissues. Lidocaine decreased the growth, EMT, migration, and invasion of human ovarian cancer A2780 and SKOV3 cells. Lidocaine enhanced the chemotherapeutic efficiency of cisplatin in both ovarian cancer cell cultures and a murine ovarian metastatic model. Furthermore, a downregulation of NaV1.5 by siRNA transfection, or FAK inhibitor application, inhibited the malignant properties of SKOV3 cells through inactivating FAK/Paxillin signaling pathway. Our data may indicate that lidocaine suppresses the metastasis of ovarian cancer and sensitizes cisplatin through blocking NaV1.5‐mediated EMT and FAK/paxillin signaling pathway. The translational value of lidocaine local application as an ovarian cancer adjuvant treatment warrants further study.

Initial treatment for FIGO 2018 stage IIIC cervical cancer based on histological type: A 14‐year multicenter study

AbstractBackgroundTo compare the oncological outcomes of radical chemotherapy (R‐CT), abdominal radical hysterectomy (ARH), and neoadjuvant chemotherapy and radical surgery (NACT) for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIIC cervical cancer, according to histological types: squamous cell carcinoma (SCC) and adenocarcinoma (AC)/adenosquamous cell carcinoma (ASC).MethodsA comparison of 5‐year overall survival (OS) and disease‐free survival (DFS) was performed for the SCC and AC/ASC subgroups for the three initial treatments, assessed using Kaplan–Meier and Cox proportional hazards regression analysis and validated using propensity score matching (PSM).ResultsThe study included 4086 patients: R‐CT, n = 1913; ARH, n = 1529; and NACT, n = 644. AC/ASC had a lower survival rate (63.7%) than SCC (73.6%) and a higher recurrence and mortality rate (36.3% and 26.4%, respectively). The 5‐year OS and DFS rates were different in the SCC group for R‐CT, ARH, and NACT (OS: 69.8% vs. 80.8% vs. 73.0%, p < 0.001; DFS: 66.7% vs. 70.7% vs. 56.4%, p < 0.001), also in the AC/ASC group (OS: 46.1% vs. 70.6% vs. 55.6%, p < 0.001; DFS: 42.7% vs. 64.6% vs. 40.8%, p < 0.001). As for initial treatment, survival outcomes were worse for AC/ASC treated with R‐CT and ARH than for SCC (both p < 0.05), with no group differences between the two treated with NACT.ConclusionInitial treatment influences oncological prognosis for patients with FIGO 2018 stage IIIC cervical cancer. ARH is an alternative treatment for stage IIIC cervical SCC and AC/ASC, and NACT needs to be chosen with caution, moreover, R‐CT for AC/ASC requires careful selection.

Identification of lymph node metastasis in pre‐operation cervical cancer patients by weakly supervised deep learning from histopathological whole‐slide biopsy images

AbstractBackgroundLymph node metastasis (LNM) significantly impacts the prognosis of individuals diagnosed with cervical cancer, as it is closely linked to disease recurrence and mortality, thereby impacting therapeutic schedule choices for patients. However, accurately predicting LNM prior to treatment remains challenging. Consequently, this study seeks to utilize digital pathological features extracted from histopathological slides of primary cervical cancer patients to preoperatively predict the presence of LNM.MethodsA deep learning (DL) model was trained using the Vision transformer (ViT) and recurrent neural network (RNN) frameworks to predict LNM. This prediction was based on the analysis of 554 histopathological whole‐slide images (WSIs) obtained from Qilu Hospital of Shandong University. To validate the model's performance, an external test was conducted using 336 WSIs from four other hospitals. Additionally, the efficiency of the DL model was evaluated using 190 cervical biopsies WSIs in a prospective set.ResultsIn the internal test set, our DL model achieved an area under the curve (AUC) of 0.919, with sensitivity and specificity values of 0.923 and 0.905, respectively, and an accuracy (ACC) of 0.909. The performance of the DL model remained strong in the external test set. In the prospective cohort, the AUC was 0.91, and the ACC was 0.895. Additionally, the DL model exhibited higher accuracy compared to imaging examination in the evaluation of LNM. By utilizing the transformer visualization method, we generated a heatmap that illustrates the local pathological features in primary lesions relevant to LNM.ConclusionDL‐based image analysis has demonstrated efficiency in predicting LNM in early operable cervical cancer through the utilization of biopsies WSI. This approach has the potential to enhance therapeutic decision‐making for patients diagnosed with cervical cancer.

Epidemiology of cervical cancer in elderly women: Analysis of incidence, treatment, and survival using German registry data

AbstractBackgroundCervical cancer (CC) screening is generally recommended until age 65. The incidence of CC could be underestimated, particularly in older women, due to a lack of hysterectomy correction. Furthermore, elderly women (≥65 years) are more often diagnosed with late‐stage disease and have worse outcomes than younger patients. This study aims to provide an in‐depth overview of CC in Germany.MethodsIncidence rates of CC (ICD‐10 C53) were determined using data from the German Centre of Cancer Registry data (ZfKD) of six federal state registries. Incidence was corrected by using hysterectomy prevalence values from a real‐world study. The distribution of treatment modalities (surgery, chemotherapy, radiation therapy) was assessed. Relative survival was calculated using the period approach (2011–2015). Survival was stratified by tumor (T) stage and histological type.ResultsIn total, 14,528 CC cases were included, 27.6% of which occurred in elderly women. Cumulative (2001–2015) age‐standardized incidence rates were 12.5 per 100,000 women without hysterectomy correction and 15.5 per 100,000 women after hysterectomy correction (+24% relative change). A lower proportion of elderly women were treated, especially in advanced tumor stages. Younger women (20–64 years) had a higher 5‐year relative survival compared to elderly women: 76.7% versus 46.9%, respectively. Survival was worse with increasing stage and for glandular histological subgroups, particularly among elderly women.ConclusionsCC incidence in elderly women is underestimated and survival is lower compared to younger women in Germany. Due to the high disease burden in elderly women, screening and treatment strategies need to be improved.

Cancer inequalities in incidence and mortality in the State of São Paulo, Brazil 2001–17

AbstractBackgroundCancer disparities exist between and within countries; we sought to compare cancer‐specific incidence and mortality according to area‐level socioeconomic status (SES) in the State of São Paulo, Brazil.MethodsCancer cases diagnosed 2003–2017 in the Barretos region and 2001–2015 in the municipality of São Paulo were obtained from the respective cancer registries. Corresponding cancer deaths were obtained from a Brazilian public government database. Age‐standardized rates for all cancer combined and the six most common cancers were calculated by SES quartiles.ResultsThere were 14,628 cancer cases and 7513 cancer deaths in Barretos, and 472,712 corresponding cases and 194,705 deaths in São Paulo. A clear SES‐cancer gradient was seen in São Paulo, with rates varying from 188.4 to 333.1 in low to high SES areas, respectively. There was a lesser social gradient for mortality, with rates in low to high SES areas ranging from 86.4 to 98.0 in Barretos, and from 99.2 to 100.1 in São Paulo. The magnitude of the incidence rates rose markedly with increasing SES in São Paulo city for colorectal, lung, female breast, and prostate cancer. Conversely, both cervical cancer incidence and mortality rose with lower levels of SES in both regions.ConclusionsA clear SES association was seen for cancers of the prostate, female breast, colorectum, and lung for São Paulo. This study offers a better understanding of the cancer incidence and mortality profile according to SES within a highly populated Brazilian state.

Innovations in healthcare delivery: Human papilloma virus self sampling diagnostics and participatory innovations for CCS

AbstractBackgroundHuman papillomavirus (HPV) infection is a major contributor to the development of cervical cancer, resulting in over 500,000 cases and 266,000 deaths annually worldwide. Previous cervical cancer screening programs have been successful in reducing cervical cancer rates, but have faced challenges such as low acceptance and adherence rates. Innovations in screening technology, such as the HerSwab self‐sampling test, have the potential to increase awareness, acceptance, and participation in cervical cancer screening programs.AimThis literature review examines the effectiveness of HerSwab and participatory innovations in increasing adherence to cervical cancer screening.MethodThis manuscript comprised a comprehensive narrative literature review encompassing the years 2006–2022. The review process adhered to the PRISMA diagram as a guiding framework. Among the search terms utilized, a total of 200 articles were initially retrieved. However, after applying the predefined inclusion criteria, only 57 articles were included.ResultsThe HerSwab self‐sampling test is described, including how it is performed, challenges, and facilitators, and evaluation and assessment of its effectiveness. While the HerSwab diagnostic test is not currently widely available, studies should assess its feasibility in less developed countries where cervical cancer mortality rates are high.ConclusionBy increasing awareness and availability of innovative screening techniques, such as HerSwab, we can work toward reducing the incidence of cervical cancer and improving outcomes for women worldwide.

Predictive significance of lymphocyte level and neutrophil‐to‐lymphocyte ratio values during radiotherapy in cervical cancer treatment

AbstractObjectiveThe objective of this research was to analyze the prognostic significance of the minimum count of lymphocytes (LY) and the corresponding ratio of neutrophil‐to‐lymphocyte (NLR) in cervical cancer (CC) patients receiving radiotherapy.MethodsWe retrospectively collected data from 202 CC patients who received concurrent chemoradiotherapy or radiotherapy alone at our hospital. Statistical methods including the Kaplan–Meier method, log‐rank test and the Cox proportional hazards model were included to examine survival differences and identify independent factors that may affect overall survival (OS) and progression‐free survival (PFS).ResultsThe research enrolled a total of 202 patients. Patients with higher LY levels and lower NLR values during radiotherapy had significantly better survival prognosis than those with lower LY levels and higher NLR values. Multivariate COX regression analysis revealed that FIGO stage I, pathological types of SqCC, absence of lymph node metastasis, concurrent chemoradiotherapy, higher LY levels during radiotherapy, and lower NLR values before radiotherapy were independently associated with poorer PFS. Similarly, FIGO stage I, absence of lymph node metastasis and lower NLR values during and before radiotherapy were independently linked with poorer OS.ConclusionMinimum LY value and its corresponding NLR during radiotherapy serve as prognostic factors for CC.

Construction of refined staging classification systems integrating FIGO/T‐categories and corpus uterine invasion for non‐metastatic cervical cancer

AbstractBackgroundTo investigate the prognostic value of corpus uterine invasion (CUI) in cervical cancer (CC), and determine the necessity to incorporate it for staging.MethodsA total of 809 cases of biopsy‐proven, non‐metastatic CC were identified from an academic cancer center. Recursive partitioning analysis (RPA) method was used to develop the refined staging systems with respect to overall survival (OS). Internal validation was performed by using calibration curve with 1000 bootstrap resampling. Performances of the RPA‐refined stages were compared against the conventional FIGO 2018 and 9th edition TNM‐stage classifications by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA).ResultsWe identified that CUI was independently prognostic for death and relapse in our cohort. RPA modeling using a two‐tiered stratification by CUI (positive and negative) and FIGO/T‐categories divided CC into three risk groupings (FIGO I′‐III'/T1′‐3′), with 5‐year OS of 90.8%, 82.1%, and 68.5% for proposed FIGO stage I′–III', respectively (p ≤ 0.003 for all pairwise comparisons), and 89.7%, 78.8%, and 68.0% for proposed T1′‐3′, respectively (p < 0.001 for all pairwise comparisons). The RPA‐refined staging systems were well validated with RPA‐predicted OS rates showed optimal agreement with actual observed survivals. Additionally, the RPA‐refined stages outperformed the conventional FIGO/TNM‐stage with significantly higher accuracy of survival prediction (AUC: RPA‐FIGO vs. FIGO, 0.663 [95% CI 0.629–0.695] vs. 0.638 [0.604–0.671], p = 0.047; RPA‐T vs. T, 0.661 [0.627–0.694] vs. 0.627 [0.592–0.660], p = 0.036).ConclusionCUI affects the survival outcomes in patients with CC. Disease extended to corpus uterine should be classified as stage III/T3.

Diagnostic value of high‐risk HPV other than type 16/18 in high‐grade cervical neoplasia among cytology‐negative women: A multicenter retrospective study

AbstractBackgroundHuman papillomavirus (HPV) is a necessary cause of cervical cancer, and a tool more sensitive than cytology for the early screening of cervical precancers. The two most carcinogenic genotypes HPV 16/18 have been reported in the majority of studies. High‐risk HPVs other than HPV 16/18 (non‐16/18‐hrHPVs) cause approximately a quarter of cervical cancers, and we aimed to analyze the genotype‐specific prevalence, risk and diagnostic efficiency of non‐16/18‐hrHPVs in cervical carcinogenesis among Chinese cytology‐negative women.MethodsA total of 7043 females who had abnormal cervical testing results from January 2018 to October 2021 were enrolled, among them 3091 were cytology‐negative. Descriptive statistics was used to estimate the HPV genotype‐specific prevalence, and multivariable logistic regression was used to estimate the genotype‐specific non‐16/18 hrHPVs risk of cervical carcinogenesis. The evaluation of diagnostic value among HPV genotypes included the possibility of predicting cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/CIN3+) and the diagnostic efficiency measured by increased referral rate and referral numbers of colposcopies per additional CIN2+/CIN3+ detected.ResultsAmong HPV‐positive cytology‐negative women, the five dominant genotypes for CIN2+/CIN3+ were HPV 31/33/35/52/58. HPV 52/58/33 had comparatively high sensitivity and specificity in predicting CIN2+/CIN3+, while the referral strategy of multiple HPV58 required 26 colposcopies to detect 1 CIN3+, compared with 14, 12, and 8 required by multiple HPV52, 31, and 33, respectively.ConclusionsHPV31/33/35/52/58 infections are significant risk factors for cervical lesions, and multiple HPV 31/33/52 infections should be included in the previously recommended HPV16/18 genotyping triage for colposcopy in China, as the benefits of disease prevention may outweigh the disadvantages of increasing requirements for colposcopy services.

Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3Tyr705 phosphorylation

AbstractAberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES‐mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial‐mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway.

Identification of EMP1 as a critical gene for cisplatin resistance in ovarian cancer by using integrated bioinformatics analysis

AbstractBackgroundCisplatin resistance is among the main reasons for the poor prognosis of ovarian cancer (OC) patients. Until now, effective biomarkers for predicting cisplatin resistance in OC and specific drugs for reversing this resistance are lacking. This study identified the critical gene associated with cisplatin resistance in OC and provided a potential target for overcoming this resistance.MethodsDifferentially expressed genes between cisplatin‐resistant and ‐sensitive OCs were identified by screening public datasets. Survival analysis was conducted to screen prognosis‐related DEGs. CIBERSORT, ESTIMATE, and immune checkpoint genes were used to assess the association between EMP1 expression and tumor microenvironment features. CTRP and GDSC databases were employed to analyze the correlation between EMP1 expression and cisplatin resistance. Furthermore, immunohistochemistry, qPCR, Western blotting, siRNA interference, and the CCK8 assay were performed to verify the role of EMP1 in cisplatin resistance in vitro. Finally, xenograft mouse models were generated to further confirm the role of EMP1 in cisplatin resistance in vivo.ResultsEMP1 was identified as a critical gene associated with cisplatin resistance in OC. According to bioinformatics analyses, increased EMP1 expression was linked to higher stromal/ESTIMATE scores as well as greater ICG expression levels. The in vitro experiments showed that EMP1 was highly expressed in cisplatin‐resistant OC tissues and cells, and silencing this EMP1 expression enhanced OC cell sensitivity to cisplatin. Finally, in vivo experiments confirmed that EMP1 promotes tumor growth and cisplatin resistance.ConclusionsEMP1 can act as a predictive biomarker for cisplatin resistance in OC and as a potential therapeutic target.

Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer

AbstractObjectivePatients with epithelial ovarian cancer (EOC) typically present with late‐stage disease, posing a significant challenge to treatment. Although taxane and platinum‐based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti‐tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC.MethodsWe used the spontaneous Tg‐MISIIR‐Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry.ResultsWe found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8‐Treg ratio.ConclusionsOur findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced‐stage EOC susceptible to immunotherapeutic treatment modalities.

New small‐molecule compound Hu‐17 inhibits estrogen biosynthesis by aromatase in human ovarian granulosa cancer cells

AbstractEstrogen‐dependent cancers (breast, endometrial, and ovarian) are among the leading causes of morbidity and mortality in women worldwide. Aromatase is the main enzyme that catalyzes the biosynthesis of estrogen, which drives proliferation, and antiestrogens can inhibit the growth of these estrogen‐dependent cancers. Hu‐17, an aromatase inhibitor, is a novel small‐molecule compound that suppresses viability of and promotes apoptosis in ovarian cancer cells. Therefore, this study aimed to predict targets of Hu‐17 and assess its intracellular signaling in ovarian cancer cells. Using the Similarity Ensemble Approach software to predict the potential mechanism of Hu‐17 and combining phospho‐proteome arrays with western blot analysis, we observed that Hu‐17 could inhibit the ERK pathway, resulting in reduced estrogen synthesis in KGN cells, a cell line derived from a patient with invasive ovarian granulosa cell carcinoma. Hu‐17 reduced the expression of CYP19A1 mRNA, responsible for producing aromatase, by suppressing the phosphorylation of cAMP response element binding‐1. Hu‐17 also accelerated aromatase protein degradation but had no effect on aromatase activity. Therefore, Hu‐17 could serve as a potential treatment for estrogen‐dependent cancers albeit further investigation is warranted.

The Combined Prognostic Value of 18F‐FDG PET/CT Metabolic Parameters of Immune Organs and Hematological Immune‐Related Markers in Patients With Locally Advanced Cervical Cancer

ABSTRACTBackgroundThis study aimed to explore the prognostic value of fluorine‐18 fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) metabolic parameters of immune organs and hematological immune‐related markers for patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT), and to establish prognostic nomograms based on these potential biomarkers.MethodsA total of 180 patients with LACC undergoing CCRT were retrospectively reviewed and randomly divided into training and validation groups at a 7:3 ratio. Cox regression analysis was performed to identify independent prognostic factors for progression‐free survival (PFS) and overall survival (OS) from hematological immune‐related markers and 18F‐FDG PET/CT metabolic parameters of the primary tumor, spleen, and bone marrow (BM). Nomograms were developed and evaluated using receiver operating characteristic curves, concordance index (C‐index), calibration curves, and decision curve analysis (DCA). Spearman correlation analysis was used to assess the relationships among metabolic parameters.ResultsMultivariable analysis identified International Federation of Gynecology and Obstetrics (FIGO) stage, neutrophil‐to‐lymphocyte ratio (NLR), and spleen maximum standardized uptake value (SUVspleen) as independent prognostic factors for PFS. For OS, the independent prognostic factors were FIGO stage, NLR, metabolic tumor volume, and SUVspleen. The nomograms demonstrated better prognostic performance for PFS (area under curve [AUC]: 0.875 and 0.862; C‐index: 0.809 and 0.775) and OS (AUC: 0.858 and 0.814; C‐index: 0.828 and 0.792) in the training and validation groups. Calibration curves and DCA indicated that the nomograms have good predictive accuracy and clinical utility. Spearman correlation analysis revealed significant positive correlations among total lesion glycolysis, SUVspleen, SUVBM, and platelet‐to‐lymphocyte ratio.ConclusionThe nomograms based on metabolic parameters of immune organs and hematological immune‐related markers demonstrated high predictive value for patients with LACC undergoing CCRT. The observed correlations between the metabolic parameters of the primary tumor and immune organs suggest a widespread disturbance of systemic immunity caused by the tumor.

Survival and recurrence after intraperitoneal chemotherapy use: Retrospective review of ovarian cancer hospital registry data

AbstractBackgroundIntraperitoneal/intravenous chemotherapy (IP/IV) was associated with improved survival for ovarian cancer (OC) patients in several randomized clinical trials. However, the uptake of IP/IV in clinical practice is varied due to conflicting evidence about its impact on survival and recurrence. The aim of this study was to explore the uptake of IP/IV treatment and to evaluate its impact on survival and recurrence in OC patients.MethodsDemographic and clinical information on OC patients (N = 2916) who underwent treatment for OC between 2000 and 2017 was obtained from the large healthcare system cancer registry. Duplicate records, grade 1, rare (eg, gelatinous carcinoma), and non‐epithelial (eg, granulosa cell carcinoma) tumors were excluded. Kaplan‐Meier survival curves were constructed to compare 5‐ and 10‐year survival based on the chemotherapy type, surgery type, and stage. Multivariable Gray's piecewise constant time‐varying coefficient models were fitted to evaluate the effect of IP/IV on adjusted hazard ratio (AHR) of OC survival and recurrence adjusting for potential confounders.ResultsThe final sample consisted of 1846 OC patients, 14% (250/1846) of which received IP/IV chemotherapy. IP/IV was significantly associated with improved 10‐year survival (P < .001). Multivariable Gray's model demonstrated that IP/IV therapy significantly reduced the AHR of death (AHR = 0.39‐1.07, P < .001) with the beneficial effect gradually declining over time. Use of IP/IV chemotherapy had no impact on OC recurrence.ConclusionsThese findings demonstrated that only a small fraction of eligible patients underwent IP/IV chemotherapy. We report a significant 10‐year survival, but not necessarily recurrence benefit is associated with IP/IV chemotherapy compared to IV only, suggesting the need for novel ways of identifying patients who may benefit from IP/IV chemotherapy.

MAGI2‐AS3 suppresses MYC signaling to inhibit cell proliferation and migration in ovarian cancer through targeting miR‐525‐5p/MXD1 axis

AbstractOvarian cancer (OV) is one of the most lethal gynecological malignance in females, and usually diagnosed at advanced stages. Long noncoding RNAs (lncRNAs) exhibit their crucial functions in modulatory mechanisms of cancers. Substantive studies have proven the anti‐tumor role of MAGI2‐AS3 in multiple cancers, but the physiological functions of MAGI2‐AS3 in OV need more detailed explanations. The current study corroborated that overexpression of MAGI2‐AS3 executed inhibitory activity in OV via hindering cell proliferation, cell cycle, migration as well as invasion while promoted apoptosis. Moreover MAGI2‐AS3 bound with miR‐525‐5p and negatively regulated the expression of miR‐525‐5p. Further studies testified that MXD1 was a downstream target of miR‐525‐5p and the competing relationship between MAGI2‐AS3 and MXD1 were confirmed by RNA pull down. Based on the combination between MAX and MYC, we analyzed the effects of MAGI2‐AS3 on MXD1 and MYC, unveiling the competing relationship between MXD1 and MYC for binding to MAX. Finally, we constructed rescue assays to certify that MAGI2‐AS3 suppressed the course of OV via enhancing MXD1 expression. In summary, MAGI2‐AS3 repressed the progression of OV by targeting miR‐525‐5p/MXD1 axis, offering a novel insight into understanding OV at the molecular level.

Maintenance treatment with rucaparib for recurrent ovarian carcinoma in ARIEL3, a randomized phase 3 trial: The effects of best response to last platinum‐based regimen and disease at baseline on efficacy and safety

AbstractBackgroundThe efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum‐based chemotherapy and baseline disease.MethodsPatients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator‐assessed PFS was assessed in prespecified, nested cohorts: BRCA‐mutated, homologous recombination deficient (HRD; BRCA mutated or wild‐type BRCA/high loss of heterozygosity), and the intent‐to‐treat (ITT) population.ResultsMedian PFS for patients in the ITT population with a complete response to most recent platinum‐based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA‐mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups.ConclusionRucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum‐based chemotherapy or baseline disease.

Exosomes released from M2 macrophages transfer miR‐221‐3p contributed to EOC progression through targeting CDKN1B

AbstractIn contrast to other solid tumors within the abdominal cavity, epithelial ovarian cancers (EOCs) tend to undergo peritoneal metastasis. Thus, the peritoneal immune microenvironment is crucial for EOC progression. Previous reports indicate that the main immune cells within the peritoneum are M2 macrophages, specifically tumor‐associated macrophages (TAMs). The communication between TAMs and tumor cells plays an important role in EOC development, and exosomes, acting as micro–message carriers, occupy an essential position in this process. Microarray analyses of exosomes revealed that miR‐221‐3p was enriched in M2 exosomes. Furthermore, miR‐221‐3p suppressed cyclin‐dependent kinase inhibitor 1B (CDKN1B) directly. Thus, miR‐221‐3p contributed to the proliferation and G1/S transition of EOC cells. Additionally, low levels of CDKN1B were associated with EOC progression and poor prognosis. These observations suggest that TAMs‐derived exosomal miR‐221‐3p acts as a regulator of EOC progression by targeting CDKN1B. The results of this study confirm that certain exosomal microRNAs may provide novel diagnostic biomarkers and therapeutic targets for EOC.

Improved targeting of an anti‐TAG‐72 antibody drug conjugate for the treatment of ovarian cancer

AbstractIntroductionOvarian cancer has only a 17% 5‐year survival rate in patients diagnosed with late stage disease. Tumor‐associated glycoprotein‐72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody‐targeted therapy, as it is not expressed in normal human adult tissues, except in the secretory endometrium.MethodsUsing the clinically relevant anti‐TAG72 murine monoclonal antibody CC49, we evaluated antibody drug conjugates (ADCs) incorporating the highly potent, synthetic antimitotic agent monomethylauristatin E (MMAE). MMAE was conjugated to CC49 via reduced disulfides in the hinge region, using three different types of linker chemistry, vinylsulfone (VS‐MMAE), bromoacetamido (Br‐MMAE), and maleimido (mal‐MMAE).ResultsThe drug antibody ratios (DARs) of the three ADCs were 2.3 for VS‐MMAE, 10 for Br‐MMAE, and 9.5 for mal‐MMAE. All three ADCs exhibited excellent tumor to blood ratios on PET imaging, but the absolute uptake of CC49‐mal‐MMAE (3.3%ID/g) was low compared to CC49‐Br‐MMAE (6.43%ID/g), at 142 hours. Blood clearance at 43 hours was 38% for intact CC49, about 24% for both CC49‐VS‐MMAE and CC49‐Br‐MMAE, and 7% for CC49‐mal‐MMAE. CC49‐VS‐MMAE was not further studied due to its low DAR, while CC49‐mal‐MMAE was ineffective in the OVCAR3 xenograft likely due to its rapid blood clearance. In contrast, CC49‐Br‐MMAE treated mice exhibited an average of a 15.6 day tumor growth delay and a 40% increase in survival vs controls with four doses of 7.5 or 15 mg/kg of CC49‐Br‐MMAE.ConclusionWe conclude that CC49‐Br‐MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model.

TIGIT enhances CD4+ regulatory T‐cell response and mediates immune suppression in a murine ovarian cancer model

AbstractOvarian cancer (OC) is the fifth‐leading cause of cancer‐related death in women with a pathogenesis involving activation of regulatory T cells (Tregs). The T‐cell immunoglobulin and ITIM domain (TIGIT) is a well‐known immune checkpoint molecule that inhibits T‐cell responses. However, the role of TIGIT in OC is not comprehensively understood. In this study, we revealed crucial functions of TIGIT in the development and progression of OC. ID8 cells were used to establish a murine OC model. TIGIT expression was increased in immune cells of OC mice, particularly in CD4+ Tregs. Anti‐TIGIT monoclonal antibodies (mAb) were used to block the function of TIGIT in OC mice, and we found that the anti‐TIGIT treatment reduced the proportion of CD4+ Tregs, but did not affect CD4+ and CD8+ T cells or natural killer cells. Splenic CD4+ Tregs from OC mice were isolated after the anti‐TIGIT treatment, and their functioning was examined. Inhibition of TIGIT lowered the degree of immunosuppression induced by CD4+ Tregs. A survival curve suggested that anti‐TIGIT treatment can improve the survival rate of OC in mice. We conclude that TIGIT enhanced CD4+ Tregs response and mediated immunosuppression in the OC model. Our data suggest that inhibition of TIGIT is a potential therapeutic target in OC patients.

Circ‐PGAM1 promotes malignant progression of epithelial ovarian cancer through regulation of the miR‐542‐3p/CDC5L/PEAK1 pathway

AbstractBackgroundEpithelial ovarian cancer (EOC) is the most common ovarian malignant cancer. Circular RNA is a type of endogenous noncoding RNA and is considered as a novel regulatory molecule in the development and progression of tumors. This study investigated the expression and functions of a circular RNA, circular‐phosphoglycerate mutase 1 (circ‐PGAM1), in EOC tissues and cells.MethodsThe expression of circ‐PGAM1 and miR‐542‐3p in EOC was analyzed using quantitative RT‐PCR. Immunohistochemistry and western blot were performed to confirm the localization and expression of cell division cycle 5‐like (CDC5L) and pseudopodium enriched atypical kinase 1 (PEAK1) in EOC tissues. Cell lines (CAOV3 and OVCAR3) overexpressing or silencingcirc‐PGAM1 and miR‐542‐3p were established to explore the functions of circ‐PGAM1 and miR‐542‐3p in ovarian cancer cells. Furthermore, dual‐luciferase reporter assay was performed to study the interactions between circ‐PGAM1 and miR‐542‐3p and between miR‐542‐3p and CDC5L. CCK‐8, transwell, and flow cytometry were used to study the effect of circ‐PGAM1 and miR‐542‐3p on cell biological behaviors including proliferation, migration, invasion, and apoptosis. The interaction between CDC5L and the PEAK1 gene promoter was confirmed using chromatin immunoprecipitation (ChIP).ResultsCirc‐PGAM1 was upregulated in EOC tissues, whereas linear PGAM1 was not deregulated in EOC tissues. Silencing of circ‐PAGM1 inhibited proliferation, migration, and invasion of ovarian cancer cells and promoted cell apoptosis. MiR‐542‐3p was downregulated in EOC tissues, and miR‐542‐3p overexpression inhibited malignant progression of ovarian cancer cells. Circ‐PGAM1 directly interacted with miR‐542‐3p, with mutual negative feedback between them. CDC5L was a direct target of miR‐542‐3p and played an oncogenic role in ovarian cancer cells. Furthermore, the CDC5L protein binds directly to the PEAK1 promoter to promote its transcription. PEAK1 overexpression activated ERK1/2 and JAK2 signaling pathways and promoted malignant biological behaviors of ovarian cancer cells. Circ‐PAGM1 silencing combined with miR‐542‐3p overexpression played the greatest anticancer role in vivo.ConclusionThe circ‐PGAM1/miR‐542‐3p/CDC5L/PEAK1 pathway played an important role in the progression of ovarian cancer and might be a novel therapeutic target for ovarian cancer.

Association between DNA damage repair gene somatic mutations and immune‐related gene expression in ovarian cancer

AbstractBackgroundDefects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased immunogenicity. DDR deficiency is prevalent in ovarian cancer (OvCa); however, the association of DDR mutation with immune profiles in OvCa remains largely unknown. This knowledge will provide an essential basis to the rational design of biomarker‐guided immune combination therapy of OvCa in the future.MethodsWhole‐exome sequencing data of 587 OvCa from The Cancer Genome Atlas (TCGA) were used to determine the expression profiles of 47 immune‐related genes and the abundance of tumor‐infiltrating immune cells. A Chinese OvCa cohort (n = 220) tested by next‐generation sequencing (NGS) was used to validate the association between DDR status and tumor mutation burden (TMB).ResultsA total of 19.3% in TCGA cohort and 25.9% in Chinese cohort harbored at least one DDR somatic mutation. DDR deficiency exhibited a distinct immune profile with significant higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1 in OvCa in the TCGA cohort. Different DDR pathway deficiency displayed various immune profiles. Increased levels of Th1 cells, TMB, and neoantigen were also observed in DDR‐deficient tumors.ConclusionsDDR deficiency was associated with specific immune signatures in OvCa. Our findings emphasize the urgent need for biomarker‐guided rational immune combination therapy to maximize the OvCa patients who could benefit from immunotherapy.

Upregulation of hsa_circ_0007874 suppresses the progression of ovarian cancer by regulating the miR‐760/SOCS3 pathway

AbstractOvarian cancer (OVA) is a fatal and common malignancy in women worldwide. Circular RNAs (circRNAs) consist of a family of circular endogenous RNAs generated by selective splicing, and they are involved in many diseases. Previous studies reported that hsa_circ_0007874 is aberrantly expressed in cancer and functions in tumorigenesis. While the hsa_circ_0007874 role in OVA is unclear. Here, we detected the hsa_circ_0007874 expression in OVA cell lines using Rt‐qPCR. Hsa_circ_0007874 subcellular localization was confirmed by fluorescence in situ hybridization. The relationship between hsa_circ_0007874, microRNAs (miRNAs), and relative protein levels was assessed using the luciferase reporter assays. Results verified that hsa_circ_0007874 is downregulated in OVA cell lines. hsa_circ_0007874 overexpression decreased the OVA cell migration and proliferation in vitro and in vivo. Bioinformatics and luciferase reporter assays confirmed that miR‐760 and SOCS3 are the downstream targets of hsa_circ_0007874. Downregulation of SOCS3 or miR‐760 overexpression restored the migration and proliferation ability of SKOV3 or A2780 cells overexpressing hsa_circ_0007874. Downregulation of SOCS3 restored the proliferation and migration in miR‐760 knockdown SKOV3 and A2780 cells. In summary, the data suggest that hsa_circ_0007874 acts as a tumor suppressor by regulating the miR‐760/SOCS3 axis, highlighting its potential as an effective therapeutic target for OVA.

Biguanides in combination with olaparib limits tumorigenesis of drug‐resistant ovarian cancer cells through inhibition of Snail

AbstractOvarian cancer is the most lethal gynecological malignancy. Currently, new chemotherapeutic strategies are required to improve patient outcome and survival. Biguanides, classic anti‐diabetic drugs, have gained importance for theiri antitumor potency demonstrated by various studies. Olaparib is a PARP inhibitor approved for maintenance therapy following platinum‐based chemotherapy. Furthermore, Snai1, a transcription factor that works as a master regulator of the epithelial/mesenchymal transition process (EMT) is involved in ovarian cancer resistance and progression. Here we aimed to demonstrate the possible cross talk between biguanides and Snail in response to olaparib combination therapy. In this study, we have shown that while in A2780CR cells biguanides reduced cell survival (single treatments ~20%; combined treatment ~44%) and cell migration (single treatments ~45%; biguanide‐olaparib ~80%) significantly, A2780PAR exhibited superior efficacy with single (~60%) and combined treatments (~80%). Moreover, our results indicate that knock‐down of Snail further enhances the attenuation of migration, inhibits EMT related‐proteins (~90%) and induces a synergistic effect in biguanide‐olaparib treatment. Altogether, this work suggests a novel treatment strategy against drug‐resistant or recurrent ovarian cancer.

Bioinformatic profiling identifies a platinum‐resistant–related risk signature for ovarian cancer

AbstractMost high‐grade serous ovarian cancer (HGSOC) patients develop resistance to platinum‐based chemotherapy and recur. Many biomarkers related to the survival and prognosis of drug‐resistant patients have been delved by mining databases; however, the prediction effect of single‐gene biomarker is not specific and sensitive enough. The present study aimed to develop a novel prognostic gene signature of platinum‐based resistance for patients with HGSOC. The gene expression profiles were obtained from Gene Expression Omnibus and The Cancer Genome Atlas database. A total of 269 differentially expressed genes (DEGs) associated with platinum resistance were identified (P < .05, fold change >1.5). Functional analysis revealed that these DEGs were mainly involved in apoptosis process, PI3K‐Akt pathway. Furthermore, we established a set of seven‐gene signature that was significantly associated with overall survival (OS) in the test series. Compared with the low‐risk score group, patients with a high‐risk score suffered poorer OS (P < .001). The area under the curve (AUC) was found to be 0.710, which means the risk score had a certain accuracy on predicting OS in HGSOC (AUC > 0.7). Surprisingly, the risk score was identified as an independent prognostic indicator for HGSOC (P < .001). Subgroup analyses suggested that the risk score had a greater prognostic value for patients with grade 3‐4, stage III‐IV, venous invasion and objective response. In conclusion, we developed a seven‐gene signature relating to platinum resistance, which can predict survival for HGSOC and provide novel insights into understanding of platinum resistance mechanisms and identification of HGSOC patients with poor prognosis.

Neoadjuvant Chemotherapy Versus Primary Cytoreductive Surgery for Metastatic Endometrial Cancer

ABSTRACT Objective To evaluate the pattern of use and clinical outcomes associated with neoadjuvant chemotherapy (NACT) compared with primary debulking surgery (PDS) in patients with stage IV endometrial cancer. Methods We utilized the National Cancer Database to identify individuals diagnosed with stage IV endometrial cancer, and categorized them according to receipt of NACT or PDS. Propensity score weighting using inverse probability of treatment weighting was applied. Survival outcomes were evaluated using both an intention‐to‐treat (ITT) analysis, which included all eligible patients, and a per‐protocol (PP) analysis restricted to those who underwent chemotherapy and surgery. Results Among 18,205 patients, NACT utilization rose from 30.3% in 2010 to 73.8% in 2021 ( p  < 0.0001). In the multivariable analysis, patients diagnosed in more recent years, Black and Hispanic race and ethnicity, Medicaid insurance, serous histology, and greater comorbidities were associated with NACT ( p  < 0.05). In the ITT analysis, there was no mortality difference within 4 months after diagnosis between NACT patients and PDS patients (aHR = 1.03; 95% CI: 0.96–1.11); however, after 4 months, patients treated with NACT experienced higher mortality than those undergoing PDS (aHR = 1.58; 95% CI: 1.51–1.64). In the PP analysis, NACT patients had lower mortality compared to PDS patients within 24 months after diagnosis (aHR = 0.93; 95% CI, 0.88–0.99) but a 34% higher mortality after 24 months (aHR = 1.34; 95% CI, 1.23–1.47). Conclusion Utilization of NACT has expanded among patients with metastatic endometrial cancer. Primary debulking surgery with postoperative chemotherapy is linked to higher early mortality but improved long‐term outcomes relative to treatment strategies beginning with NACT followed by surgery.

Follow‐Up After Receiving Abnormal Results From Self‐Sampled Colorectal and Cervical Cancer Screening Tests Among Underserved Patients

ABSTRACT Introduction Increasing cancer screening through at‐home self‐sampling test modalities is a public health priority. Patients with abnormal screening results should receive diagnostic follow‐up care; optimizing this process is a challenge. We conducted a mixed methods study to examine the cancer screening process among underserved patients who received abnormal results on a self‐sampled cancer screening test. Methods Participants were drawn from a parent study examining the impact of self‐sampled colorectal and cervical cancer screening tests among patients at federally qualified health centers in Pennsylvania. Those who had received abnormal results on their screening were completed a survey and semi‐structured interview about their experience ( n  = 5). We conducted mixed methods analysis to examine participants' (1) understanding and follow‐up care for abnormal results and (2) satisfaction with the self‐sampling cancer screening process. Results Quantitatively, participants indicated very high satisfaction with each self‐sampled cancer screening, and 60% preferred a self‐sampled test for their next cancer screening. Qualitatively, participants differed in the extent to which they seemed to understand their screening results, but they were generally satisfied with the self‐sampling process. In mixed methods analysis, participants' baseline knowledge about cancer screening supported better understanding of abnormal screening results, and participants' preference for their next cancer screening was related to their experiences with self‐sampling. Conclusions Among this sample of patients who received abnormal results on their self‐sampled colorectal or cervical cancer screening test, knowledge and understanding were not prerequisites for accessing follow‐up care. Satisfaction with the self‐sampling screening process was very high. These findings provide additional support for public health priorities to expand access to self‐sampling cancer screening tests.

Subjective and Objective Cancer‐Related Cognitive Impairments Among Systemic and Radiation Therapy‐Naïve Female Cancer Patients

ABSTRACTBackgroundCancer‐related cognitive impairment (CRCI) is a frequent and burdensome problem that is still insufficiently understood and managed. We investigated subjective and objective measures of CRCI, as recommended by the International Cancer and Cognition Task Force (ICCTF) in cancer patients prior to systemic or radiation therapy with respect to potential influencing or associated psychosocial, demographic, or lifestyle factors.MethodsFemale patients with breast or gynecological tumors (n = 239, mean age = 55.5, SD = 11.6) prior to any systemic or radiation therapy completed validated subjective (FACT‐Cog: perceived cognitive impairment [PCI], perceived cognitive ability [PCA], impact on quality of life [IQoL]) and objective measures of CRCI (Trail Making Test [TMT‐A and ‐B], Controlled Oral Word Association Test [COWA], and Hopkins Verbal Learning Test‐Revised [HVLT‐R]). Association with cross‐sectionally assessed age, body mass index, education, smoking, alcohol intake, sleep problems, social support, anxiety, and pain was investigated using multiple linear regression models.ResultsA quarter (25.1%) of patients showed indication for CRCI based on the PCI score. Subjective and objective CRCI measures showed no or only weak correlations, also when adjusting for age and education (partial Spearman correlations with each other, all |r| ≤ 0.21). Anxiety, sleep problems, and pain were significantly associated with low subjective cognitive function (PCI, PCA, and IQoL). Poor objective cognitive values (TMT, COWA, and HVLT‐R) were mainly determined by higher age and lower education.ConclusionsCancer‐related cognitive impairment is not solely (chemo‐)therapy‐induced but may be triggered or influenced by anxiety, sleep problems, and pain. Addressing these issues early in the treatment phase could potentially alleviate perceived CRCI. The ICCTF‐recommended neuropsychological tests do not adequately capture this CRCI prior to systemic or radiation therapy, but could serve as complementary tools to monitor cognitive changes over time, independent of psychosocial influences.

Effect of the surgical approach on survival outcomes in patients undergoing radical hysterectomy for cervical cancer: A real‐world multicenter study of a large Chinese cohort from 2006 to 2017

AbstractObjectiveTo compare survival outcomes of minimally invasive surgery (MIS) and laparotomy in early‐stage cervical cancer (CC) patients.MethodsA multicenter retrospective cohort study was conducted with International Federation of Gynecology and Obstetrics (FIGO, 2009) stage IA1 (lymphovascular invasion)‐IIA1 CC patients undergoing MIS or laparotomy at four tertiary hospitals from 2006 to 2017. Propensity score matching and weighting and multivariate Cox regression analyses were performed. Survival was compared in various matched cohorts and subgroups.ResultsThree thousand two hundred and fifty‐two patients (2439 MIS and 813 laparotomy) were included after matching. (1) The 2‐ and 5‐year recurrence‐free survival (RFS) (2‐year, hazard ratio [HR], 1.81;95% confidence interval [CI], 1.09‐3.0; 5‐year, HR, 2.17; 95% CI, 1.21‐3.89) or overall survival (OS) (2‐year, HR, 1.87; 95% CI, 1.03‐3.40; 5‐year, HR, 2.57; 95% CI, 1.29‐5.10) were significantly worse for MIS in patients with stage I B1, but not the cohort overall (2‐year RFS, HR, 1.04; 95% CI, 0.76‐1.42; 2‐year OS, HR, 0.99; 95% CI, 0.70‐1.41; 5‐year RFS, HR, 1.12; 95% CI, 0.76‐1.65; 5‐year OS, HR, 1.20; 95% CI, 0.79‐1.83) or other stages (2) In a subgroup analysis, MIS exhibited poorer survival in many population subsets, even in patients with less risk factors, such as patients with squamous cell carcinoma, negative for parametrial involvement, with negative surgical margins, negative for lymph node metastasis, and deep stromal invasion < 2/3. (3) In the cohort treated with (2172, 54%) or without adjuvant treatment (1814, 46%), MIS showed worse RFS than laparotomy in patients treated without adjuvant treatment, whereas no differences in RFS and OS were observed in adjuvant‐treatment cohort. (4) Inadequate surgeon proficiency strongly correlated with poor RFS and OS in patients receiving MIS compared with laparotomy.ConclusionsMIS exhibited poorer survival outcomes than laparotomy group in many population subsets, even in low‐risk subgroups. Therefore, laparotomy should be the recommended approach for CC patients.

Pamiparib dose escalation in Chinese patients with non‐mucinous high‐grade ovarian cancer or advanced triple‐negative breast cancer

AbstractBackgroundThe recommended phase 2 dose (RP2D) of pamiparib, an investigational PARP1/2 inhibitor, was established as 60 mg twice daily (BID) in a first‐in‐human (FIH) study (NCT02361723).MethodsChinese patients with advanced non‐mucinous high‐grade ovarian cancer (HGOC) or triple‐negative breast cancer (TNBC) whose disease either progressed despite standard therapy, or for which there is no standard therapy were enrolled in the dose‐escalation (DE) portion of a phase 1/2 study (NCT03333915). The primary endpoint was safety/tolerability; secondary objectives were pharmacokinetics and antitumor activity. BRCA1/2 mutation status was retrospectively evaluated.ResultsNine HGOC and six TNBC patients (N = 15; n = 4, 20 mg; n = 4, 40 mg; n = 7, 60 mg) were enrolled; as of 30 September 2019, one HGOC patient remained on treatment. Seven patients (n = 5, HGOC; n = 2, TNBC) had germline BRCA1/2 mutation (gBRCAmut); all HGOC patients were resistant/refractory to platinum. Asthenia and nausea (n = 12 each) were the most common treatment‐related adverse events (TRAEs). Decreased hemoglobin was the most common grade 3 TRAE (n = 3); no grade ≥4 AEs were observed. No dose‐limiting toxicities (DLTs) were reported. Pamiparib plasma exposure was similar to exposure observed in the FIH study after a single‐dose administration, albeit slightly higher at steady state. Among 13 RECIST‐evaluable patients, two with HGOC (gBRCAmut, n = 1) achieved a confirmed partial response and six with HGOC (gBRCAmut, n = 4) achieved stable disease; all TNBC RECIST‐evaluable patients (n = 5) reported progressive disease.ConclusionsPamiparib was generally well tolerated in Chinese patients, with durable responses observed in patients with HGOC. Based on these results, pamiparib 60 mg BID was confirmed as the RP2D.

Advances in exosome biomarkers for cervical cancer

AbstractCervical cancer (CC) ranks as the fourth most frequently diagnosed malignancy in females worldwide. Exosomes are a subclass of extracellular vesicles released by nearly all types of cells that act as cargo transport vehicles, carrying proteins, and genetic material (such as miRNAs, long noncoding RNAs, and mRNAs) derived from their parent cells may affect receiving cells and thus have emerged as key players in several biological processes, including inflammatory pathways. In this review, we concentrated on the findings of exosome investigations in CC, particularly their components. They direct the actions of CC cells by inducing surface molecules associated with various biological pathways. We summarized the current knowledge of exosomal RNAs and proteins from CC cells and discussed the feasibility of exosomes as potential biomarkers for CC. We suggest that cancer‐derived exosomes promote metastasis in CC by supporting EMT, controlling the proliferation, invasion, or migration of cancer cells, as well as influencing immune escape and aiding angiogenesis. Overall, cancer‐derived exosomes are critical in the progression of CC, and further studies are necessary to advance our understanding of the clinical value of exosomes in CC.

A nomogram to predict the cancer‐specific survival of stage II–IV Epithelial ovarian cancer after bulking surgery and chemotherapy

AbstractObjectiveIn order to predict the survival rate of ovarian cancer patients, multiple independent risk factors are integrated to establish a prognostic nomogram.MethodsCox analysis was used to construct the nomogram. All of the mainly independent factors, which can be used to predict 3‐year and 5‐year survival rates for cancer in the training cohort, were incorporated to establish nomograms. The C‐index, operating characteristic, ROC curves, and calibration plots can show evaluation results of performance.ResultsModel derivation was based on 3277 patients who belong to different races. The best threshold for age was 51, 59, and 67 year old and the older the people, the worse their survival. Meanwhile, many lymph node examinations indicated a favorable survival and the survival of the positive set was worse than of that. In addition, the optional threshold was 64 mm for tumor size and the set larger than 64 mm had a better survival than that less than 64 mm. Univariate Cox proportional hazards regression model showed that the similar worse outcomes were showed in black race, advanced grade, stage T3, stage M1, lymph nodes positive, and CA125 positive compared with the first group. We found that the number of lymph nodes examined and tumor size had an inverse relationship with its corresponding score of CSS in training cases with bulking surgery and chemotherapy.ConclusionsWe developed a model which relatively accurately predicted the prognosis of ovarian cancer by multiple univariate analysis, at the same time, the proposed nomograms exhibit superior prognostic discrimination and survival prediction.

Performance of cervical cancer screening and triage strategies among women living with HIV in China

AbstractObjectivesTo evaluate the clinical performance of liquid‐based cytology (LBC), HPV tests and visual inspections with acetic acid or Lugol's iodine (VIA/VILI) as primary screening and triage strategies among Chinese women living with HIV (WLHIV).MethodsWLHIV aged 18 years and older were recruited from HIV/AIDS treatment clinic in Yunnan, China from 2019 to 2020. Women were screened with self‐ and physician‐sampling for HPV tests, LBC, and VIA/VILI. Women positive for any HPV or with cytological abnormalities were recalled for colposcopy examination and biopsy when necessary. Clinical performance of primary and triage strategies for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was evaluated.ResultsFor primary screening, sensitivity of physician‐HPV tests was 100%, 89.5%, and 100% for hybrid capture 2 (HC2), cobas, and Sansure HPV, and specificity was 80.4%, 85.1%, and 72.0%, respectively. Self‐HPV test achieved considerable performance with physician‐HPV. Sensitivity and specificity were 61.1% and 96.3% for LBC (atypical squamous cells of undetermined significance or worse [ASCUS+]), 40.0% and 77.3% for VIA/VILI. For triaging HPV‐positive women, LBC (ASCUS+), HPV‐16/18 genotyping, and VIA/VILI‐elevated specificity with sensitivity declined 30%–50% compared with HPV screening alone. Restricted HPV genotyping triage (HPV‐16/18/31/33/45/52/58) demonstrated the optimal accuracy (89.5% sensitivity, 81.9% specificity), and was similar to HPV‐16/18 with reflex LBC (ASCUS+). Combination antiretroviral therapies (cARTs) <2 years were associated with decreased specificity of HC2 (aOR: 1.87, 95% CI: 1.22–3.91) and Sansure HPV (2.48, 1.43–4.29).ConclusionsSelf‐HPV with restricted genotyping triage is highly recommended for cervical cancer screening for WLHIV in China. Feasible triage to increase HPV specificity among women with short duration of cART is needed.

Emerging Radiopharmaceuticals Beyond FDG for Ovarian Cancer: A Review of Advances in Nuclear Medicine

ABSTRACT Aims This review summarizes the role and future prospects of nuclear medicine in ovarian cancer, focusing on novel radiopharmaceuticals beyond FDG for diagnostic, predictive, and therapeutic applications within a theranostic framework. Materials and Methods A narrative literature review was conducted using major databases. Peer‐reviewed articles addressing non‐FDG radiopharmaceuticals in ovarian cancer were identified and assessed; FDG‐based studies were excluded due to the availability of prior comprehensive reviews. Results Novel radiopharmaceuticals show potential to enhance diagnostic accuracy, allow early evaluation of treatment response, predict chemotherapy resistance, and support stratification for targeted therapies. Several tracers are under investigation for theranostic use, offering combined diagnostic and therapeutic benefits. Discussion Incorporating novel radiopharmaceuticals into ovarian cancer management may help overcome limitations of conventional imaging and systemic therapy. Theranostic strategies, uniting molecular imaging with radionuclide therapy, represent a promising step toward personalized medicine and could significantly influence clinical outcomes. Conclusion Nuclear medicine, through innovative radiopharmaceuticals and theranostic approaches beyond FDG, is expected to expand its role in ovarian cancer care. Further research is needed to validate these applications and facilitate their integration into clinical practice.

Nomogram Prediction Model and Prognostic Comparison of Cervical Clear Cell Carcinoma and Cervical Endometrioid Adenocarcinoma: A SEER Database Study

ABSTRACT Background Cervical clear cell adenocarcinoma (CCAC) and cervical endometrioid adenocarcinoma (CEAC) are rare and aggressive non‐HPV‐associated malignancies. Despite their histological similarities, these subtypes demonstrate distinct biological behaviors, presenting challenges in treatment and prognosis. Objective To develop and validate a multivariable prognostic model for CCAC and CEAC, utilizing the SEER database to enhance clinical decision‐making. Methods A total of 775 CEAC and 421 CCAC cases were analyzed using a multivariable nomogram. Patients were randomly allocated to model‐development ( n  = 838) and validation ( n  = 358) cohorts in a 7:3 ratio. The model's performance was evaluated through AUC, Brier score, and Calibration. Decision Curve Analysis (DCA) and Clinical Impact Curve (CIC) were assessed in both development and internal validation cohorts. Results The model exhibited excellent calibration and discrimination in predicting overall survival (OS). In the development cohort, the 12‐ and 24‐month prediction models had AUCs of 0.894 (95% CI: 0.860–0.928) and 0.857 (95% CI: 0.821–0.892), respectively. In the internal validation cohort, the 12‐ and 24‐month models achieved AUCs of 0.814 (95% CI: 0.788–0.840) and 0.798 (95% CI: 0.775–0.822), respectively. The model effectively stratified patients into low‐, intermediate‐, and high‐risk groups, with significantly different median survival times ( p  < 0.0001). DCA and CIC further validated the model's clinical utility. Conclusion We developed a robust nomogram for quantifying OS risk in CCAC and CEAC patients. This model provides clinicians with a tool for identifying high‐risk patients and implementing timely interventions.

Development and Validation of Prognostic Characteristics Associated With Chromatin Remodeling‐Related Genes in Ovarian Cancer

ABSTRACTBackgroundOvarian cancer (OC) is a prevalent malignant tumor in the field of gynecology, exhibiting the third highest incidence rate and the highest mortality rate among gynecological tumors. Chromatin remodeling accomplishes specific chromatin condensation at distinct genomic loci and plays an essential role in epigenetic regulation associated with various processes related to cancer development.MethodsDifferentially expressed genes (DEGs) between OC and control samples were screened from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) databases, combined with chromatin remodeling‐related genes (CRRGs) obtained from the GeneCards database to identify differentially expressed CRRGs (DECRRGs). Enrichment analysis and protein–protein interaction (PPI) network were performed on the DECRRGs. Prognostic genes of OC were screened using univariate Cox and least absolute shrinkage and selection operator (Lasso) analyses. A risk model based on prognostic genes was developed, and the survival probability of OC patients in different risk groups was analyzed by Kaplan–Meier (KM) curve. Finally, the expression levels of prognostic genes were validated by quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blotting.ResultsIn total, 7 potential prognostic genes associated with the progression of OC patients were obtained, including ARID1B, ATRX, CHRAC1, HDAC1, INO80, MBD2, and SS18. Based on the expression level of prognostic genes, OC patients were divided into high‐risk group and low‐risk group. Survival analysis indicated that patients classified into the high‐risk group had higher mortality rates, which enables this prediction model to be utilized as an independent predictor of OC. Immunocorrelation analysis showed that low‐risk patients were more likely to benefit from immunotherapy.ConclusionIn this study, we have identified 7 prognostic genes, including ARID1B, ATRX, CHRAC1, HDAC1, INO80, MBD2, and SS18. Overall, our findings provided a foundation for further comprehension of the potential molecular mechanisms underlying OC pathogenesis and progression.

Recurrent patterns after postoperative radiotherapy for early stage endometrial cancer: A competing risk analysis model

AbstractObjectiveThe study aimed to evaluate site‐specific recurrent patterns via competing risks analysis and hazard function to provide evidence for adjuvant treatment and follow‐up for early staged endometrial cancer (EC).MethodsA total of 858 patients with International Federation of Gynecology and Obstetrics stage I–II EC who received adjuvant radiotherapy at our institution (2000–2017) were included. The radiotherapy modality comprised external beam radiotherapy (EBRT) with or without vaginal brachytherapy (VBT) or VBT alone. Competing risks analysis and hazard rate function were employed to evaluate the recurrence rate according to the ESMO–ESGO–ESTRO risk classification.ResultsThe 5‐year overall survival rates of the low‐risk (LR), intermediate‐risk (IR), high–intermediate risk (HIR), and high‐risk (HR) groups were 96.1%, 95%, 93%, and 89.7%, respectively (p = 0.018). Sixty‐eight patients developed recurrence. The 5‐year incidence of distant recurrence was the highest in the HR group (14.87%), followed by the HIR (7.71%), IR (5.27%), and LR (1.26%) groups (Gray's test, p < 0.001). The LR and IR groups showed late metastasis behaviors for distant metastasis. The HR group presented a large magnitude of distant metastasis with an early peak that increased beyond 3 years. Subgroup analysis revealed that EBRT±VBT tended to reduce the locoregional relapse rate compared with VBT in the HIR–HR group (2.36% vs. 7.73%, Gray's test, p = 0.08).ConclusionThe established competing risk modeling demonstrated different recurrence patterns across the risk groups and radiotherapy modes. A better understanding of the change in site‐specific recurrence behavior allows more targeted adjuvant treatment and surveillance regimens.

Acceptability of Home‐Based Urine Self‐Collection for Cervical Cancer Screening Among Women Receiving Care at the Arab Community Center for Economic and Social Services in Michigan

ABSTRACTBackgroundMichigan's Middle Eastern‐North African (MENA) community is an essential and growing part of the state's population. However, MENA individuals are underrepresented in the research literature due to a lack of recognized demographic categorization. Prior work shows that MENA women face barriers to traditional clinician‐directed cervical cancer screening. This study aims to capture the perspectives of MENA women about home‐based urine cervical cancer screening using HPV kits and to assess whether such methods could positively impact future screening intent.MethodsThrough collaboration with a community partner in southeast Michigan, we recruited MENA women ages 30–65, with 44 completing the study. Participants used urine HPV self‐sampling kits at home and then shared their perspectives through a phone interview. We used an inductive, thematic approach to analyze the interviews, which captured experiences with home‐based self‐sampling, screening preferences, and impact on future screening intent.ResultsParticipants found that urine home‐based self‐sampling was acceptable as a convenient and comfortable way to screen for cervical cancer. Most (80%) preferred self‐sampling over traditional clinician‐directed screening and preferred collecting urine samples at home (73%) rather than in the clinic. Overall, 80% reported that access to urine self‐sampling would positively impact their future screening intent.ConclusionsMENA participants in this study positively received home‐based cervical cancer screening using urine HPV self‐sampling kits. These findings support the clinical implementation of self‐sampling and home‐based cervical cancer screening to increase participation, particularly among those in under‐screened communities.

Patient‐derived organoid culture in epithelial ovarian cancers—Techniques, applications, and future perspectives

AbstractEpithelial ovarian cancer (EOC) is a heterogeneous disease composed of different cell types with different molecular aberrations. Traditional cell lines and mice models cannot recapitulate the human tumor biology and tumor microenvironment (TME). Patient‐derived organoids (PDOs) are freshly derived from patients' tissues and are then cultured with extracellular matrix and conditioned medium. The high concordance of epigenetic, genomic, and proteomic landscapes between the parental tumors and PDOs suggests that PDOs can provide more reliable results in studying cancer biology, allowing high throughput drug screening, and identifying their associated signaling pathways and resistance mechanisms. However, despite having a heterogeneity of cells in PDOs, some cells in TME will be lost during the culture process. Next‐generation organoids have been developed to circumvent some of the limitations. Genetically engineered organoids involving targeted gene editing can facilitate the understanding of tumorigenesis and drug response. Co‐culture systems where PDOs are cultured with different cell components like immune cells can allow research using immunotherapy which is otherwise impossible in conventional cell lines. In this review, the limitations of the traditional in vitro and in vivo assays, the use of PDOs, the challenges including some tips and tricks of PDO generation in EOC, and the future perspectives, will be discussed.

Risk factors for the failure of first‐line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA‐3004)

AbstractObjectiveTo identify the risk factors for failure of first‐line poly (ADP‐ribose) polymerase inhibitor (PARPi) maintenance therapy in patients with advanced ovarian cancer.MethodPatients with stage III‐IV epithelial ovarian cancer who received first‐line PARPi maintenance therapy were retrospectively reviewed. Clinicopathologic factors were compared between two groups—recur/progression of disease (PD) and non‐recur/PD.ResultsIn total, 191 patients were included. Median follow‐up was 9.9 months, and recurrence rate was 20.9%. BRCA mutations were found in 63.4% patients. Postoperative residual tumor (60.5% vs. 37.8%), non‐high grade serous carcinoma (HGSC) (15.0% vs. 6.0%), neoadjuvant chemotherapy (NAC) (55.0% vs. 35.8%), and pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (35.9% vs. 15.2%) were more frequently observed in the recur/PD group. Multivariate Cox‐regression analysis revealed pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (HR, 2.17; 95%CI, 1.03–4.57; p = 0.042), non‐HGSC (3.28; 1.20–8.97; p = 0.021), NAC (2.11; 1.04–4.26; p = 0.037), and no BRCA mutation (2.23; 1.12–4.44; p = 0.023) as independent risk factors associated with poor progression‐free survival (PFS). A subgroup analysis according to BRCA mutation status showed that pre‐PARPi serum CA‐125 levels ≥26.4 U/mL were the only independent risk factor for poor PFS in women with BRCA mutations (2.75; 1.03–7.39; p = 0.044). Non‐HGSC (5.05; 1.80–14.18; p = 0.002) and NAC (3.36; 1.25–9.04; p = 0.016) were independent risk factors in women without BRCA mutations.ConclusionHigh pre‐PARPi serum CA‐125 levels, non‐HGSC histology, NAC, and no BRCA mutation might be risk factors for early failure of first‐line PARPi maintenance therapy. In women with BRCA mutations, high pre‐PARPi serum CA‐125 levels, which represent a large tumor burden before PARPi, were the only independent risk factor for poor PFS.

Pathogenic germline variants in SMARCA4 and further cancer predisposition genes in early onset ovarian cancer

To assess the role of germline pathogenic variants (PVs) in SMARCA4 and further established ovarian cancer (OC) predisposition genes in early onset OC, we investigated a clinical cohort of 206 unrelated OC index patients with an age at diagnosis of OC ≤40 years using an extended panel of 24 (candidate) cancer predisposition genes. PVs in established OC predisposition genes were most frequent in patients with high grade serous OC (21/62, 33.9%), comparatively rare in patients with epithelial OC other than high grade serous (5/74, 6.8%) or borderline ovarian tumours (2/39, 5.1%) and absent in mucinous OC (0/27). We demonstrate that germline PVs in SMARCA4 unlikely predispose for early onset OC other than SCCOHT.

Multiple types of distress are prospectively associated with increased risk of ovarian cancer

AbstractBackgroundFew modifiable risk factors for epithelial ovarian cancer have been identified. We and other investigators have found that individual psychosocial factors related to distress are associated with higher risk of ovarian cancer. The present study examined whether co‐occurring distress‐related factors are associated with ovarian cancer risk.MethodsFive distress‐related factors were measured repeatedly over 21 years of follow‐up: depression, anxiety, social isolation, widowhood, and, in a subset or women, posttraumatic stress disorder (PTSD). Cox proportional hazards models estimate relative risks (RR) and 95% confidence intervals (CI) of ovarian cancer for a time‐updated count of distress‐related factors, in age‐adjusted models, then further adjusted for ovarian cancer risk factors and behavior‐related health risk factors.ResultsAcross 1,193,927 person‐years of follow‐up, 526 incident ovarian cancers occurred. Women with ≥3 versus no distress‐related psychosocial factors demonstrated increased ovarian cancer risk (HRage‐adjusted = 1.71; 95% CI = 1.16, 2.52). No significant difference in ovarian cancer risk was observed in women with one or two versus no distress‐related psychosocial factors. In the subsample with PTSD assessed, ≥3 versus no distress‐related psychosocial factors was associated with twofold greater ovarian cancer risk (HRage‐adjusted = 2.08, 95% CI = 1.01, 4.29). Further analysis suggested that women at highest ovarian cancer risk had PTSD co‐occurring with any other distress‐related factor (HR = 2.19, 95% CI = 1.20, 4.01). Adjusting for cancer risk factors and health behaviors minimally impacted risk estimates.ConclusionsPresence of multiple indicators of distress was associated with risk of ovarian cancer. When including PTSD as an indicator of distress, the association was strengthened.

Discovery and validation of novel biomarkers for detection of cervical cancer

AbstractAimsTo investigate novel biomarker for diagnosis of cervical cancer, we analyzed the datasets in Gene Expression Omnibus (GEO) and confirmed the candidate biomarker in patient sample.Materials and methodsWe collected major datasets of cervical cancer in GEO, and analyzed the differential expression of normal and cancer samples online with GEO2R and tested the differences, then focus on the GSE63514 to screen the target genes in different histological grades by using the R‐Bioconductor package and R‐heatmap. Then human specimens from the cervix in different histological grades were used to confirm the top 8 genes expression by immunohistochemical staining using Ki67 as a standard control.ResultsWe identified genes differentially expressed in normal and cervical cancer, 274 upregulated genes and 206 downregulated genes. After intersection with GSE63514, we found the obvious tendency in different histological grades. Then we screened the top 24 genes, and confirmed the top 8 genes in human cervix tissues. Immunohistochemical (IHC) results confirmed that keratin 17 (KRT17) was not expressed in normal cervical tissues and was over‐expressed in cervical cancer. Cysteine‐rich secretory protein‐2 (CRISP2) was less expressed in high‐grade squamous intraepithelial lesions (HSILs) than in other histological grades.ConclusionFor the good repeatability and consistency of KRT17 and CRISP2, they may be good candidate biomarkers. Combined analysis of KRT17, CRISP2 expression at both genetic and protein levels can determine different histological grades of cervical squamous cell carcinoma. Such combined analysis is capable of improving diagnostic accuracy of cervical cancer.

Circulating serum miRNAs predict response to platinum chemotherapy in high‐grade serous ovarian cancer

Abstract Background Platinum chemotherapy is the cornerstone of treatment for high‐grade serous ovarian cancer (HGSOC); however, validated biomarkers that can accurately predict platinum response are lacking. Based on their roles in the underlying pathophysiology, circulating microRNAs are potential, noninvasive biomarkers in cancer. In the present study, we aimed to evaluate the circulating miRNA profiles of patients with HGSOC and to assess their potential utility as biomarkers to predict platinum response. Methods Pretreatment serum samples collected from patients who received platinum chemotherapy for Stage III–IV HGSOC between 2008 and 2016 were analyzed using miRNA microarray. LASSO logistic regression analysis was used to construct predictive models for treatment‐free interval of platinum (TFIp). Results The median follow‐up was 54.6 (range, 3.5–144.1) months. The comprehensive analysis of 2588 miRNAs was performed in serum samples of 153 eligible patients, and predictive models were constructed using a combination of circulating miRNAs with an area under the receiver operating characteristic curve of 0.944 for TFIp >1 month, 0.637 for TFIp ≥6 months, 0.705 for TFIp ≥12 months, and 0.938 for TFIp ≥36 months. Each predictive model provided a significant TFIp classification ( p  = 0.001 in TFIp >1 month, p  = 0.013 in TFIp ≥6 months, p  < 0.001 in TFIp ≥12 months, and p  < 0.001 in TFIp ≥36 months). Conclusion Circulating miRNA profiles has potential utility in predicting platinum response in patients with HGSOC and can aid clinicians in choosing appropriate treatment strategies.

A Multicenter Cohort Study on DNA Methylation for Endometrial Cancer Detection in Cervical Scrapings

ABSTRACT Background The increasing incidence of endometrial cancer (EC) has highlighted the need for improved early detection methods. This study aimed to develop and validate a novel DNA methylation classifier, EMPap, for EC detection using cervical scrapings. Methods EMPap incorporated the methylation status of BHLHE22 and CDO1 , along with age and body mass index (BMI), into a logistic regression model to calculate the endometrial cancer methylation (EM) score for identifying EC in cervical scrapings. We enrolled 1297 patients with highly suspected EC, including 196 confirmed EC cases, and assessed the EMPap performance in detecting EC. Results EMPap demonstrated robust diagnostic accuracy, with an area under the curve of 0.93, sensitivity of 90.3%, and specificity of 89.3%. It effectively detected EC across various disease stages, grades, and histological subtypes, and consistently performed well across patient demographics and symptoms. EMPap correctly identified 87.5% of the type II ECs and 53.8% of premalignant lesions. Notably, compared with transvaginal ultrasonography (TVS) in patients with postmenopausal bleeding, EMPap exhibited superior sensitivity (100% vs. 82.0%) and specificity (85.2% vs. 38.5%). In asymptomatic postmenopausal women, EMPap maintained high sensitivity (89.5%) and negative predictive value (NPV) (98.3%). Conclusions This study demonstrated the potential of EMPap as an effective tool for EC detection. Despite the limited sample size, EMPap showed promise for identifying type II EC and detecting over 50% of premalignant lesions. As a DNA methylation classifier, EMPap can reduce unnecessary uterine interventions and improve diagnosis and outcomes.

Cervical cancer‐specific long non‐coding RNA landscape reveals the favorable prognosis predictive performance of an ion‐channel‐related signature model

AbstractBackgroundIon channels play an important role in tumorigenesis and progression of cervical cancer. Multiple long non‐coding RNA genes are widely involved in ion channel‐related signaling regulation. However, the association and potential clinical application of lncRNAs in the prognosis of cervical cancer are still poorly explored.MethodsThirteen patients with cervical cancer were enrolled in current study. Whole transcriptome (involving both mRNAs and lncRNAs) sequencing was performed on fresh tumor and adjacent normal tissues that were surgically resected from patients. A comprehensive cervical cancer‐specific lncRNA landscape was obtained by our custom pipeline. Then, a prognostic scoring model of ion‐channel‐related lncRNAs was established by regression algorithms. The performance of the predictive model as well as its association with the clinical characteristics and tumor microenvironment (TME) status were further evaluated.ResultsTo comprehensively identify cervical cancer‐specific lncRNAs, we sequenced 26 samples of cervical cancer patients and integrated the transcriptomic results. We built a custom analysis pipeline to improve the accuracy of lncRNA identification and functional annotation and obtained 18,482 novel lncRNAs in cervical cancer. Then, 159 ion channel‐ and tumorigenesis‐related (ICTR‐) lncRNAs were identified. Based on nine ICTR‐lncRNAs, we also established a prognostic scoring model and validated its accuracy and robustness in assessing the prognosis of patients with cervical cancer. Besides, the TME was characterized, and we found that B cells, activated CD8+ T, and tertiary lymphoid structures were significantly associated with ICTR‐lncRNAs signature scores.ConclusionWe provided a thorough landscape of cervical cancer‐specific lncRNAs. Through integrative analyses, we identified ion‐channel‐related lncRNAs and established a predictive model for assessing the prognosis of patients with cervical cancer. Meanwhile, we characterized its association with TME status. This study improved our knowledge of the prominent roles of lncRNAs in regulating ion channel in cervical cancer.

Evaluating human papillomavirus (HPV) self‐sampling among Latinas in the United States: A systematic review

AbstractBackgroundLatinas experience the greatest cervical cancer incidence compared with other ethnic/racial groups in the United States (US) due in part to significant disparities in screening uptake. Social and structural conditions that impede access to and participation in screening include language barriers, concerns about documentation status, logistical issues (e.g., transportation, limited clinic hours), and cultural beliefs regarding modesty and promiscuity. To overcome these challenges, self‐sampling for human papillomavirus (HPV) DNA testing has emerged as a potentially promising method for promoting cervical cancer screening among this population. Thus, this systematic review aimed to assess the acceptability of HPV self‐sampling among US Latinas.MethodsUsing EBSCOhost and PubMed databases, we searched for studies published in the past two decades (2003–2023) that described participation in HPV self‐sampling among Latinas. Eleven articles met inclusion criteria.ResultsThe majority of studies were conducted in Florida, California, and Puerto Rico, were single‐arm designs, and involved the use of community health workers and Spanish‐language materials (e.g., brochures). Across studies, the majority of participants reported that self‐sampling was acceptable with respect to ease of use, comfort (lack of pain), privacy, and convenience; however, some women were concerned about the accuracy of self‐sampling or whether they had performed sample collection correctly.ConclusionGiven the high acceptability, self‐collection of cervicovaginal samples for HPV testing may offer a feasible option for enhancing participation in cervical cancer screening in this population that encounters significant barriers to screening.

Evaluation of colposcopy after the addition of human papillomavirus testing to the Turkish cervical cancer screening program

AbstractObjectiveTo evaluate colposcopy performance following the human papillomavirus (HPV) DNA screening program in Turkey.MethodsWomen aged 30–65 years are screened for cervical cancer every 5 years, with individuals positive for HPV 16 and/or 18 or other high‐risk HPV types with abnormal cytology referred for colposcopy. Both HPV test and cytology are obtained at the same visit. If HPV is negative, cytology will not be assessed. However, if HPV is positive, both cytology and HPV genotyping will be performed. Colposcopy‐require was defined as HPV 16/18 positivity or abnormal smear results with any hrHPV positivity, and the remaining patients (normal smear with hrHPV positivity other than HPV 16/18) were grouped as colposcopy non‐required. National data on colposcopy outcomes and unnecessary performance rates in February 2018–2019 were evaluated via a questionnaire.ResultsA total of 9808 patients were included, divided based on colposcopy requirement: 5751 (58.6%) patients required colposcopy and 4057 (41.4%) did not. Unnecessary colposcopy was performed on 90.1% of the non‐required group (3657 of 4057 patients). In the colposcopy‐required group, 4455 patients (79.9%) underwent punch biopsy; 3194 (57.1%), endocervical curettage (ECC); and 421 (7.5%), “see and treat” in the non‐required group, the results were 2790 (76.3%), 1957 (53.2%), and 211 (5.7%), respectively. A total of 746 cervical intraepithelial neoplasia (CIN)‐3 isolates were detected, including 702 using existing screening and triage with 94.1% sensitivity (702/746). Multiple biopsies were taken in 69.8% (n = 3110) of patients from the colposcopy‐required group and 63.7% (n = 1777) from the non‐required group. The ECC samples included 19 cervical cancers and 212 ≥CIN‐3 lesions in the colposcopy‐required group, and four cancers and 41 ≥CIN‐3 lesions in the non‐required group. The proportion of ≥CIN‐3 lesions detected by ECC only was 4.7% (35 of 746 ≥CIN‐3 lesions).ConclusionOur results showed high rates of unnecessary colposcopies, and a high percentage of multiple and random punch biopsies and ECC.

An MRI‐based machine learning radiomics can predict short‐term response to neoadjuvant chemotherapy in patients with cervical squamous cell carcinoma: A multicenter study

AbstractBackground and PurposeNeoadjuvant chemotherapy (NACT) has become an essential component of the comprehensive treatment of cervical squamous cell carcinoma (CSCC). However, not all patients respond to chemotherapy due to individual differences in sensitivity and tolerance to chemotherapy drugs. Therefore, accurately predicting the sensitivity of CSCC patients to NACT was vital for individual chemotherapy. This study aims to construct a machine learning radiomics model based on magnetic resonance imaging (MRI) to assess its efficacy in predicting NACT susceptibility among CSCC patients.MethodsThis study included 234 patients with CSCC from two hospitals, who were divided into a training set (n = 180), a testing set (n = 20), and an external validation set (n = 34). Manual radiomic features were extracted from transverse section MRI images, and feature selection was performed using the recursive feature elimination (RFE) method. A prediction model was then generated using three machine learning algorithms, namely logistic regression, random forest, and support vector machines (SVM), for predicting NACT susceptibility. The model's performance was assessed based on the area under the receiver operating characteristic curve (AUC), accuracy, and sensitivity.ResultsThe SVM approach achieves the highest scores on both the testing set and the external validation set. In the testing set and external validation set, the AUC of the model was 0.88 and 0.764, and the accuracy was 0.90 and 0.853, the sensitivity was 0.93 and 0.962, respectively.ConclusionsMachine learning radiomics models based on MRI images have achieved satisfactory performance in predicting the sensitivity of NACT in CSCC patients with high accuracy and robustness, which has great significance for the treatment and personalized medicine of CSCC patients.

Patterns of Care and Outcomes Among Women With Locally Advanced Cervical Cancer Treated With Curative Intent at a Tertiary Center in South Africa

ABSTRACTObjectiveCervical cancer is the leading cause of cancer‐related deaths for women in South Africa. The standard of care treatment for locally advanced cervical cancer (LACC) is external beam radiation followed by brachytherapy with concurrent platinum‐based chemotherapy. There exists a paucity of data regarding the treatment regimens received by women with LACC in South Africa. The aim of this study is to assess the patterns of care and survival for patients with LACC treated with curative intent at a tertiary care center in South Africa.Materials and MethodsThis is a retrospective review of cervical cancer patients with histologically confirmed LACC (stage IB2—IVA) who underwent radiation with curative intent at Groote Schuur Hospital in Cape Town, South Africa between July 2013 and July 2018. Overall survival (OS) and disease‐free survival (DFS) were evaluated using the Kaplan–Meier method. Cox proportional hazards modeling analyzed patient and treatment factor associations with survival. Logistic regression modeling was performed to assess factors associated with the receipt of chemotherapy and baseline hemoglobin.ResultsAmong 278 patients, 28.4% (n = 79) of women had co‐infection with HIV, and 64.8% (n = 180) received chemoradiation. Regardless of HIV status, patients who received chemoradiation had improved 2‐year OS (87.4% vs. 52.8%, p < 0.001) and DFS (80.2% vs. 58.3%, p < 0.001) compared to those receiving radiation alone. Factors associated with improved OS were receipt of chemotherapy (HR 0.32, p = 0.005) and higher baseline hemoglobin (HR 0.86, p = 0.018). Upon multivariate logistic regression, adjusting for age, stage, and HIV status, patients with stage III/IV disease were less likely to receive chemotherapy (HR 48.17, p < 0.001) and were less likely to have hemoglobin ≥ 10 g/dL (HR 0.20, p < 0.001).ConclusionsAddition of chemotherapy to standard radiation improved OS in women with LACC, regardless of HIV status. Our findings add to a body of literature highlighting the importance of providing concurrent chemoradiotherapy to all patients with LACC, including persons living with HIV and those with stage III/IV disease.

Disability‐Adjusted Life Years ( DALYs ) due to Breast, Cervical, Colorectal and Oral Cancers in Taiwan Regions

ABSTRACT Background Cancer is a leading cause of death globally, with significant variations in incidence and mortality rates among different cancer types and regions. In Taiwan, breast cancer (BC), cervical cancer (CxCa), colorectal cancer (CRC), and oral cancer (OC) are prevalent and have prompted government‐led screening programs to mitigate their impact. This study aims to assess the burden of these cancers at the county scale using disability‐adjusted life years (DALYs) as a metric, focusing on the years 2010, 2015, 2018, 2019, and 2020. Methods Data on cancer incidence, mortality, disability weights, and treatment outcomes were sourced from the Taiwan HPA, Ministry of Health and Welfare, and Taiwan Cancer Registry. Years of life lost (YLLs) and years lived with disability (YLDs) were calculated for each cancer, considering age, stage, and treatment. The correlation between cancer screening rates and disease burden also conducted. Results The analysis highlights significant trends in cancer mortality, incidence, and disease burden in Taiwan from 2010 to 2020. BC and CRC showed rising ASMR and DALYs rates, while CxCa experienced consistent declines. OC had a fluctuating pattern, particularly in eastern regions. YLLs contributed significantly to DALYs for all cancers, emphasizing premature mortality's role in the disease burden. Screening rates, particularly for BC and CxCa, correlated with changes in burden, with BC rates increasing and CxCa decreasing, reflecting the impact of preventive measures on cancer outcomes. Conclusions The findings underscore the importance of targeted interventions and evidence‐informed resource allocation to address regional differences in cancer burden in Taiwan.

A comprehensive narrative review of challenges and facilitators in the implementation of various HPV vaccination program worldwide

AbstractIntroductionCervical cancer has been considered as one of the most common cancers in women (15–44 years) globally, but the advent of the human papilloma virus (HPV) vaccine has raised the anticipation that eradication of cervical carcinoma might be achieved in the near future as several prophylactic cervical carcinoma vaccines have already been currently licensed in various countries. Countries should devise strategies, practices and policies to attain and sustain higher levels of HPV immunization coverage as still 68% countries have introduced HPV vaccine in their national immunization programs even after 17 years following the licensure of the first prophylactic HPV vaccine.MethodologyA comprehensive literature analysis was conducted using various databases and search engines, to include the most relevant research articles and data available and critically discussed the operational gaps that need to be answered to achieve adequate coverage of HPV vaccination.ResultsThe present review highlights the existing HPV vaccination strategies, unmet needs and challenges needed to be addressed for proper implementation framework as well as the collaborations required to achieve decent vaccination coverage. Well‐coordinated vaccination strategy with focus on adolescent girls and if possible, boys can lead to dramatic impact on disease reduction around the world.

Heterogeneous treatment effects of adjuvant therapy for patients with cervical cancer in the intermediate‐risk group

AbstractBackgroundThe efficacy of adjuvant therapy for patients with cervical cancer with intermediate risk (CC‐IR) remains controversial. We examined the impact of adjuvant therapy on survival outcomes in patients with CC‐IR and evaluated the heterogeneous treatment effects (HTEs) of adjuvant therapies based on clinicopathologic characteristics.MethodsWe retrospectively analyzed a previous Japanese nationwide cohort of 6192 patients with stage IB–IIB cervical cancer who underwent radical hysterectomy. We created two pairs of propensity score‐matched treatment/control groups to investigate the treatment effects of adjuvant therapies: (1) adjuvant therapy versus non‐adjuvant therapy; (2) chemotherapy versus radiotherapy conditional on adjuvant therapy. Multivariate analyses with treatment interactions were performed to evaluate the HTEs.ResultsAmong the 1613 patients with CC‐IR, 619 and 994 were in the non‐treatment and treatment groups, respectively. Survival outcomes did not differ between the two groups: 3‐year progression‐free survival (PFS) rates were 88.1% and 90.3% in the non‐treatment and treatment groups, respectively (p = 0.199). Of the patients in the treatment group, 654 and 340 received radiotherapy and chemotherapy, respectively. Patients who received chemotherapy had better PFS than those who received radiotherapy (3‐year PFS, 90.9% vs. 82.9%, p = 0.010). Tumor size was a significant factor that affected the treatment effects of chemotherapy; patients with large tumors gained better therapeutic effects from chemotherapy than those with small tumors.ConclusionAdjuvant therapy is optional for some patients with CC‐IR; however, chemotherapy can be recommended as adjuvant therapy, particularly for patients with large tumors.

Construction and validation of a novel aging‐related gene signature and prognostic nomogram for predicting the overall survival in ovarian cancer

AbstractBackgroundOvarian cancer (OC) is the most lethal gynecological malignancy. The objective of this study was to establish and validate an individual aging‐related gene signature and a clinical nomogram that can powerfully predict independently the overall survival rate of patients with ovarian cancer.MethodsData on transcriptomic profile and relevant clinical information were retrieved from The Cancer Genome Atlas (TCGA) database as a training group, and the same data from three public Gene Expression Omnibus (GEO) databases as validation groups. Univariate Cox regression analysis, lasso regression analysis, and multiple multivariate Cox analysis were analyzed sequentially to select the genes to be included in the aging‐associated signature. A risk scoring model was established and verified, the predictive value of the model was evaluated, and a clinical nomogram was established.ResultsWe found eight genes that were most relevant to prognosis and constructed an eight‐mRNA signature. Based on the model, each OC patient's risk score was able to be calculated and patients were split into groups of low and high risks with a distinct outcome. Survival analysis confirmed that the outcome of patients in the high‐risk group was dramatically shorter than that of those in the low‐risk group, and the eight‐mRNA signature can be considered as a powerful and independent predictor that could predict the outcome of OC patient. Additionally, the risk score and age can be used to construct a clinical nomogram as a simpler tool for predicting prognosis. We also explored the association between the risk score and immunity and drug sensitivity.ConclusionThis study suggested that the aging‐related gene signature could be used as an intervention point and latent prognostic predictor in OC, which may provide new perceptions for postoperative treatment strategies.

Primary neuroendocrine tumors of the ovary: Management and outcomes

AbstractBackgroundThere is currently no recognized first‐line treatment strategy for ovarian neuroendocrine tumors (NETs). Furthermore, because of the low incidence of ovarian NETs, no studies have reported prognostic statistics derived from large samples. This retrospective study aimed to investigate the clinical behavior of ovarian NETs.MethodsThe Surveillance, Epidemiology, and End Results database was used to identify women diagnosed with ovarian NETs from 2004 to 2015. Overall survival (OS), cancer‐specific survival (CSS), and independent prognostic factors for ovarian NETs were evaluated. The effects of different treatments on prognosis were also compared, as were OS and CSS rates for histological subtypes.ResultsThe 5‐year OS rates were 83.3%, 30.0%, 20.3%, and 9.8% for patients in stages I (n = 159), II (n = 23), III (n = 101), and IV (n = 148), respectively. The 5‐year CSS rates were 85.6%, 41.7%, 21.2%, and 9.8% for patients in stages I–IV, respectively. Age, American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, treatment, and histological type were related to poor OS and CSS. In the early stage, the 5‐year OS and CSS rates were 97.03% and 96.90%, respectively. For patients in the advanced stage receiving comprehensive treatment (surgery + chemotherapy + radiotherapy), the 5‐year OS and CSS rates were 72.9% and 70.00%, respectively. When comparing low‐ and high‐grade neuroendocrine carcinoma, 5‐year OS rates were 93.96% and 7.01%, 5‐year CSS rates were 97.44% and 7.31%, 10‐year OS rates were 93.56% and 2.34%, and 10‐year CSS rates were 97.44% and 4.88%, respectively.ConclusionAge, AJCC stage, treatment, and histological type are independent prognostic factors of ovarian NETs. OS and CSS are relatively good for early‐stage cases treated with surgery alone, whereas more comprehensive treatment is required to improve OS and CSS in the advanced stage.

ONC201 induces the unfolded protein response (UPR) in high‐ and low‐grade ovarian carcinoma cell lines and leads to cell death regardless of platinum sensitivity

AbstractObjectivesTreatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA.MethodsCisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy.ResultsONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433).ConclusionsOur findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA.

Body composition and risk of major gynecologic malignancies: Results from the UK Biobank prospective cohort

AbstractObjectiveTo evaluate the association between body composition and subsequent risk of the major gynecologic malignancies.MethodsThis is a prospective analysis of participants from the UK Biobank. We measured baseline body composition and confirmed cancer diagnosis through linkage to cancer and death registries. We evaluated hazard ratios (HRs) and confidence interval (CIs) with COX models adjusting for potential confounders.ResultsWe document 1430 cases of the top three gynecologic malignancies (uterine corpus cancer 847 cases, ovarian cancer 514 cases, and cervical cancer 69 cases) from 245,084 female participants (75,307 were premenopausal and 169,777 were postmenopausal). For premenopausal women, whole body fat‐free mass (WBFFM) was associated with an increased risk of uterine corpus cancer (Adjusted HR per unit increase 1.04, 95% CI 1.02–1.06). For postmenopausal women, compared with the first quartile, the fourth quartile of WBFFM and whole body fat mass(WBFM) was associated with 2.16 (95% CI 1.49–3.13) times and 1.89 (95% CI 1.31–2.72) times of increased uterine corpus cancer risk, respectively. Regarding the distribution of body fat mass (FM)/fat‐free mass (FFM), FFM distributed in the trunk was associate with increased uterine corpus cancer risk in premenopausal (HR 1.18,95% CI 1.07–1.31) and postmenopausal women (HR 1.13,95% CI 1.09–1.18). Meanwhile, FM/FFM distributed in the limbs present an U‐shaped associations with uterine corpus cancer risk. We did not observe any association between aforementioned body composition indices with ovarian or cervical cancer.ConclusionFM is associated with an increased risk of uterine corpus cancer in postmenopausal women. Meanwhile, FFM is found to be a risk factor for uterine corpus cancer in both premenopausal and postmenopausal women. No association of body composition with ovarian or cervical cancer was observed.

Peripheral and tumor‐infiltrating immune cells are correlated with patient outcomes in ovarian cancer

AbstractObjectiveAt present, there is still a lack of reliable biomarkers for ovarian cancer (OC) to guide prognosis prediction and accurately evaluate the dominant population of immunotherapy. In recent years, the relationship between peripheral blood markers and tumor‐infiltrating immune cells (TICs) with cancer has attracted much attention. However, the relationship between the survival of OC patients and intratumoral‐ or extratumoral‐associated immune cells remains controversial.MethodsIn this study, four machine‐learning algorithms were used to predict overall survival in OC patients based on peripheral blood indicators. To further screen out immune‐related gene and molecular targets, we systematically explored the correlation between TICs and OC patient survival based on The Cancer Genome Atlas database. Using the TICs score method, patients were divided into a low immune infiltrating cell group and a high immune infiltrating cell group.ResultsThe results showed that there was a significant statistical significance between the peripheral blood indicators and the survival prognosis of OC patients. Survival analysis showed that TICs play a crucial role in the survival of OC patients. Four core genes, CXCL9, CD79A, MS4A1, and MZB1, were identified by cross‐PPI and COX regression analysis. Further analysis found that these genes were significantly associated with both TICs and survival in OC patients.ConclusionsThese results suggest that both peripheral blood markers and TICs can be used as prognostic predictors in patients with OC, and CXCL9, CD79A, MS4A1, and MZB1 may be potential therapeutic targets for OC immunotherapy.

Spatial cytotoxic and memory T cells in tumor predict superior survival outcomes in patients with high‐grade serous ovarian cancer

AbstractAlthough the association between tumor‐infiltrating CD3+ T and CD8+ T cells and superior survival in high‐grade serous ovarian cancer (HGSOC) has been observed, the different spatial localization of tumor‐infiltrating lymphocytes (TILs) possesses heterogeneous effects. We performed localized measurements in 260 HGSOC from 2 independent cohorts represented in tissue microarray format to determine the localized expression pattern and clinical significance of CD3+ T, CD8+ T, and CD45RO+ cells in HGSOC. Different density of spatial localization of CD3+ T, CD8+ T, and CD45RO+ cells exhibited heterogeneous association with OS. The combination of the center of the tumor and invasive margin localized CD8+T cells (CD8CT&IM) with the same margin localized CD45RO (CD45ROCT&IM) was the most robust prognostic predictor. Immune score (IS) was constructed by integrating FIGO stage with CD8CT&IM and CD45ROIM&CT and had the best prognostic value in HGSOC. The low‐, intermediate‐, and high‐IS groups were observed in 44.7%, 41.6%, and 13.7% of patients, respectively. Low‐IS identified patients were at higher risk of death compared to high‐IS identified patients (HR = 12.426; 95% CI 5.317–29.039, p < 0.001); meanwhile, we evaluate the RMSTs over 10 years of follow‐up and obtained RMST values of 104.09 months (95% CI 96.31–111.87 months) in the high‐IS group, 75.26 months (95% CI 59.92–90.60 months) in the intermediate‐IS group, and 48.68 months (95%CI 38.82–58.54 months) in the low‐IS group. In general, spatial localization can modulate the clinical effects of TILs in HGSOC. Thus, the spatial expression of CD8 and CD45RO could aid clinicians to determine the follow‐up plan of patients with HGSOC.

MRPL15 is a novel prognostic biomarker and therapeutic target for epithelial ovarian cancer

AbstractPurposeTo analyze the role of six human epididymis protein 4 (HE4)‐related mitochondrial ribosomal proteins (MRPs) in ovarian cancer and selected MRPL15, which is most closely related to the tumorigenesis and prognosis of ovarian cancer, for further analyses.MethodsUsing STRING database and MCODE plugin in Cytoscape, six MRPs were identified among genes that are upregulated in response to HE4 overexpression in epithelial ovarian cancer cells. The Cancer Genome Atlas (TCGA) ovarian cancer, GTEX, Oncomine, and TISIDB were used to analyze the expression of the six MRPs. The prognostic impact and genetic variation of these six MRPs in ovarian cancer were evaluated using Kaplan‐Meier Plotter and cBioPortal, respectively. MRPL15 was selected for immunohistochemistry and GEO verification. TCGA ovarian cancer data, gene set enrichment analysis, and Enrichr were used to explore the mechanism of MRPL15 in ovarian cancer. Finally, the relationship between MRPL15 expression and immune subtype, tumor‐infiltrating lymphocytes, and immune regulatory factors was analyzed using TCGA ovarian cancer data and TISIDB.ResultsSix MRPs (MRPL10, MRPL15, MRPL36, MRPL39, MRPS16, and MRPS31) related to HE4 in ovarian cancer were selected. MRPL15 was highly expressed and amplified in ovarian cancer and was related to the poor prognosis of patients. Mechanism analysis indicated that MRPL15 plays a role in ovarian cancer through pathways such as the cell cycle, DNA repair, and mTOR 1 signaling. High expression of MRPL15 in ovarian cancer may be associated with its amplification and hypomethylation. Additionally, MRPL15 showed the lowest expression in C3 ovarian cancer and was correlated with proliferation of CD8+ T cells and dendritic cells as well as TGFβR1 and IDO1 expression.ConclusionMRPL15 may be a prognostic indicator and therapeutic target for ovarian cancer. Because of its close correlation with HE4, this study provides insights into the mechanism of HE4 in ovarian cancer.

Identification of a glycolysis‐related gene signature for survival prediction of ovarian cancer patients

Abstract Background Ovarian cancer (OV) is deemed the most lethal gynecological cancer in women. The aim of this study was to construct an effective gene prognostic model for predicting overall survival (OS) in patients with OV. Methods The expression profiles of glycolysis‐related genes (GRGs) and clinical data of patients with OV were extracted from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analyses were conducted, and a prognostic signature based on GRGs was constructed. The predictive ability of the signature was analyzed using training and test sets. Results A gene risk signature based on nine GRGs ( ISG20 , CITED2 , PYGB , IRS2 , ANGPTL4 , TGFBI , LHX9 , PC , and DDIT4 ) was identified to predict the survival outcome of patients with OV. The signature showed a good prognostic ability for OV, particularly high‐grade OV, in the TCGA dataset, with areas under the curve (AUC) of 0.709 and 0.762 for 3‐ and 5‐year survival, respectively. Similar results were found in the test sets, and the AUCs of 3‐, 5‐year OS were 0.714 and 0.772 in the combined test set. And our signature was an independent prognostic factor. Moreover, a nomogram combining the prediction model and clinical factors was developed. Conclusion Our study established a nine‐GRG risk model and nomogram to better predict OS in patients with OV. The risk model represents a promising and independent prognostic predictor for patients with OV. Moreover, our study on GRGs could offer guidance for the elucidation of underlying mechanisms in future studies.

Sentinel lymph node biopsy in early stage cervical cancer: A meta‐analysis

AbstractBackgroundThe aim of this study was to determine the specific side detection rate of the sentinel lymph node biopsy and the accuracy in predicting lymph node metastasis in early stage cervical cancer.MethodsA systematic search of databases was performed from the inception of the databases to 27 June 2020. Studies of cervical cancer patients with FIGO stage FIGO ⅠA~ⅡB, evaluating the sentinel lymph node biopsy with blue dye, technetium 99, combined technique (blue dye with technetium 99) or indocyanine green with a reference standard of systematic pelvis lymph node dissection or clinical follow‐up were included. Stata12.0 and Meta‐Disc 1.4 were used for the meta‐analysis.ResultsOf 2825 articles found, 21 studies (2234 women) were eventually included. Out of 21 studies, 20 met the detection rate evaluation criteria and six were included for sensitivity meta‐analysis. Due to heterogeneity, it was inappropriate to pool all studies. The pooled specific side detection rates were 85% in tumors up to 2 cm, 67% in tumors over 2 cm, 75.2% for blue dye, 74.7% for technetium 99, 84% for combined technique, and 85.5% for indocyanine green. The sentinel lymph node biopsy had a pooled specific side sensitivity of 88%. Adverse effects of sentinel lymph node biopsy appear minimal for most patients and are mainly related to the injection of blue dye.ConclusionsSentinel lymph node biopsy using a tracer with a high detection rate and ultrastaging is highly accurate and reliable when limited to seriously selected patients, with satisfactory bilateral lymph node mapping and where enough cases for learning curve optimization exist. Indocyanine green sentinel lymph node mapping seems to be a superior sentinel lymph node mapping technique compared to other methods at present.

Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first‐line platinum chemotherapy in high grade serous ovarian cancer

AbstractBackgroundIn high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum‐based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor).MethodsFollowing primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III–IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression‐free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA‐sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD‐L1 expression was scored by immunohistochemistry (IHC).ResultsA total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss‐of‐function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD‐L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD‐L1 protein expression in the GR group.ConclusionsOur research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer

ABSTRACTBackgroundPaclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients.MethodsEarly breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18–24.9 kg/m2 and overweight/obese, ≥25 kg/m2, respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software.ResultsEighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2, mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two‐sample t‐test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2‐sample t‐test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, −0.009; p > 0.05).ConclusionWhen dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under‐dosing of this drug.Trial registrationThis study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

The association of resistance training with risk of ovarian cancer

ABSTRACTBackgroundIncreasing evidence, including multiple putative inflammatory risk factors (e.g., c‐reactive protein, and adiposity), supports that inflammation plays an important role in ovarian carcinogenesis. Resistance training (RT) is associated with lower levels of circulating inflammatory markers, independent of physical activity.MethodsWe evaluated the relationship between RT and risk of ovarian cancer accounting for other physical activity (e.g., walking) in two large prospective cohorts, the Nurses’ Health Study (NHS) and NHSII.Key ResultsIn total, analyses included 42,005 NHS participants (2000–2016) and 67,289 NHSII participants (2001–2017) with RT assessed every 4 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RT with ovarian cancer risk overall and by tumor subtype, adjusting for known and putative ovarian cancer risk factors. We identified a total of 609 cases over 1,748,884 person‐years. No association was observed with overall ovarian cancer risk (RT ≥60 vs 0 min/wk, HR = 0.95, 95%CI: 0.74–1.22) or by histotype (comparable HR = 0.86 and 0.98 for type I and II tumors, respectively). Results did not differ by body mass index (Pinteraction = 0.97), or other physical activity (Pinteraction = 0.31).Conclusions & InferencesWe observed no evidence that moderate levels of RT were associated with risk of ovarian cancer. Further investigations are required to confirm these findings.

Bladder cancer cell‐intrinsic PD‐L1 signals promote mTOR and autophagy activation that can be inhibited to improve cytotoxic chemotherapy

AbstractTumor cell‐intrinsic programmed death‐ligand 1 (PD‐L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell‐intrinsic PD‐L1 signals in mouse MB49 and human RT4, UM‐UC3, and UM‐UC‐14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α‐PD‐L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell‐intrinsic PD‐L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune‐independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell‐intrinsic PD‐L1 signals also promoted basal and stress‐induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell‐intrinsic PD‐L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis‐platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell‐intrinsic PD‐L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof‐of‐concept, we showed that the autophagy inhibitor chloroquine improved cis‐platinum treatment efficacy in vivo, with greater efficacy in PD‐L1 null versus PD‐L1‐replete BC.

Identification of MEG8/miR‐378d/SOBP axis as a novel regulatory network and associated with immune infiltrates in ovarian carcinoma by integrated bioinformatics analysis

AbstractBackgroundTo investigate the potential molecular mechanism of ovarian cancer (OC) evolution and immunological correlation using the integrated bioinformatics analysis.MethodsData from the Gene Expression Omnibus was used to gain differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway analysis were completed by utilizing the Database for Annotation, Visualization, and Integrated Discovery. After multiple validations via The Cancer Genome Atlas (TCGA), Genotype‐Tissue Expression (GTEx) projects, the Human Protein Atlas, Kaplan–Meier (KM) plotter, and immune logical relationships of the key gene SOBP were evaluated based on Tumor Immune Estimation Resource, and Gene Set Enrichment Analysis (GSEA) software. Finally, the lncRNAs‐miRNAs‐mRNAs subnetwork was predicted by starBase, TargetScan, miRBD, and LncBase, individually. Correlation of expression and prognosis for mRNAs, miRNAs, and lncRNAs were confirmed by TCGA, Gene Expression Profiling Interactive Analysis 2 (GEPIA 2), starBase, and KM.ResultsA total of 192 shared DEGs were discovered from the four data sets, including 125 upregulated and 67 downregulated genes. Functional enrichment analysis presented that they were mainly enriched in cartilage development, pathway in PI3 K‐Akt signaling pathway. Lower expression of SOBP was the independent prognostic factor for inferior prognosis in OC patients. The downregulation of SOBP enhanced the infiltration levels of B cells, CD8+ T cells, Macrophage, Neutrophil, and Dendritic cells. GSEA also disclosed low SOBP showed a significantly associated with the activation of various immune‐related pathways. Finally, we first reported that the MEG8/miR‐378d/SOBP axis was linked to the development and prognosis of OC through regulating the cytokines pathway.ConclusionsOur study establishes a novel MEG8/miR‐378d/SOBP axis in the development and prognosis of OC, and the triple subnetwork probably affects the progression of the OC by regulating the cytokines pathway.

Knockout of vasohibin‐2 reduces tubulin carboxypeptidase activity and increases paclitaxel sensitivity in ovarian cancer

AbstractVasohibin‐1 (VASH1) is a VEGF‐inducible endothelium‐derived angiogenesis inhibitor, and vasohibin‐2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere‐forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.

Incidence of venous thromboembolism after standard treatment in patients with epithelial ovarian cancer in Korea

AbstractBackgroundVenous thromboembolism (VTE) is a hospital‐associated severe complication that may adversely affect patient prognosis. In this study, we evaluated the incidence of VTE and its risk factors in patients with epithelial ovarian cancer (EOC).MethodsWe retrospectively analyzed the electronic health record data of 1268 patients with EOC who received primary treatment at the National Cancer Center, Korea between January 2007 and December 2017 to identify patients who developed VTE. Demographic, clinical, and surgical characteristics of these patients were ascertained. Competing risks analyses were performed to estimate the cumulative incidence of VTE according to the treatment type. The associations between putative risk factors and the incidence of VTE were evaluated using the Fine–Gray regression models accounting for competing risks of death.ResultsVTE was the most prevalent cardiovascular event, found in 9.6% (n = 122) of all patients. Of these VTE events, 115 (94.3%) occurred within 2 years of EOC diagnosis. Advanced cancer stage at diagnosis (distant vs. localized, hazards ratio [HR])= 14.49, p = 0.015) and extended hospital stay (≥15 days, HR =3.87, p = 0.004) were associated with the incidence of VTE. There was no significant difference in the cumulative incidence of VTE between primary cytoreductive surgery followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval cytoreductive surgery (HR =0.81, p = 0.390).ConclusionsApproximately 10% of patients with EOC were diagnosed with VTE, which was the most common cardiovascular disease found in this study. The assessment of VTE risks in patients with advanced‐stage EOC with an extended hospital stay is needed to facilitate adequate prophylactic treatment.

Opioid use by cancer status and time since diagnosis among older adults enrolled in the Prostate, Lung, Colorectal, and Ovarian screening trial in the United States

AbstractBackgroundDosing limits in opioid clinical practice guidelines in the United States are likely misapplied to cancer patients, however, opioid use may be difficult to ascertain as they are largely excluded from opioid use studies.MethodsThe primary objective was to determine whether cancer patients were more likely to be chronic opioid users after diagnosis. We described prescription opioid use among U.S. older adult cancer patients during two time periods, within 2 years of diagnosis (short‐term) and at least 2 years beyond diagnosis (long‐term), compared to those without cancer (controls). Among participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial with linkages to Medicare Part D data during 2011–2015, we used multivariable logistic regression to estimate the association between cancer diagnosis and opioid use outcomes controlling for demographics. The primary outcome of opioid use was measured with the following metrics: Any opioid use, chronic use (90 consecutive days supply of opioid use while allowing for a 7‐day gap between refills), high use (average daily morphine equivalent (MME) ≥120 mg for any 90‐day period), and total MME dose above 2,000 mg (MME2000).ResultsThe short‐term cohort included 1,491 cancer patients and 24,930 controls. Any use in the 2‐year post‐diagnosis period was higher among cancer patients OR 3.3 (95% CI: 3.0–3.7). Chronic use rates were similar by cancer status (4.6% vs. 3.8% for cases and controls, respectively). The long‐term cohort included 4,377 cancer patients and 27,545 controls. Rates of any use were similar among cancer patients and controls (63% vs. 59%).ConclusionsAny opioid use was similar among long‐term cancer survivors compared to controls, but differed among short‐term survivors for any opioid use and marginally for chronic opioid use.

An immature inhibin‐α‐expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis

AbstractInhibin‐α, a member of transforming growth factor‐β, is elevated in multiple tumors, but its specific roles are poorly understood. Here, we examined the feature of inhibin‐α‐expressing cells in ovarian tumors. Immunohistochemically, inhibin‐α‐expressing tumor cells were detected only in ovarian clear cell carcinoma (OCCC) among various types of ovarian tumors. By comparing the expression of inhibin‐α and Ki‐67, inhibin‐α‐expressing tumor cells were revealed to be less proliferative. When spheroids and chemoresistant cells were derived from OCCC cell lines, the expression level of inhibin‐α was elevated, and that of an immature marker, aldehyde dehydrogenase, was also elevated. In consistent with this, inhibin‐α expression was correlated with other immature markers, such as OCT3/4 and SOX2, and inversely correlated with proliferative marker MKI67 in public database on OCCC. Knockdown of inhibin‐α in OCCC cell decreased chemoresistance. Moreover, prognostic analysis with 69 surgically resected OCCC cases revealed that the increased inhibin‐α expression was an independent unfavorable prognostic factor. These findings suggested that inhibin‐α‐expressing subpopulation of OCCC tumor cells appeared to be less proliferative, immature, and angiogenic and to be related to acceleration of malignant progression.

Characterization of rare histological subtypes of ovarian cancer based on molecular profiling

AbstractObjectivePan‐cancer analysis across The Cancer Genome Atlas has revealed the molecular profiles of major types of carcinomas. High‐grade serous carcinomas (HGSCs) have been characterized; however, in ovarian cancer, the profile of carcinoma with minor histopathological changes remains unclear. This study aimed to perform the molecular profiling of rare malignant ovarian tumors, including non‐epithelial tumors (NETs; germ cell tumors and sex cord tumors) and clear cell carcinoma (CCC), to determine how they differ from the major HGSCs.MethodsSixty‐nine malignant ovarian tumors surgically resected at the Shizuoka Cancer Center between January 2014 and March 2019 were classified based on their histopathological types. The germline and somatic mutations in these carcinomas, including NETs, were determined using next‐generation sequencing. Gene expression analysis was performed to investigate the major pathways of drug resistance, which is a characteristic of CCC.ResultsNETs harbored copy‐neutral loss of heterozygosity, accompanied by a high homologous recombination deficiency score; germline mutations of PALB2 and BARD1 were identified in two patients with NET. In chemoresistant CCC, the epithelial‐mesenchymal transition pathway was activated regardless of ABC transporter expression.ConclusionThis study revealed some genomic characteristics of rare malignant ovarian tumors, including NETs and CCC.

Patients with stage IA ovarian clear cell carcinoma do not require chemotherapy following surgery

AbstractBackgroundOvarian clear cell carcinoma (OCCC) is an infrequent histological subtype of epithelial ovarian cancer (EOC). The present study aimed to investigate whether chemotherapy is indispensable for patients with stage IA OCCC.MethodsData were collected from the Surveillance, Epidemiology and End Results database between 2004 and 2015. All subjects were diagnosed with stage IA OCCC, according to their postoperative pathological reports. In the present study, 1038 patients were retrospectively investigated, among whom 692 patients received chemotherapy. Propensity score matching (PSM) was performed to prevent selection bias. The multivariate Cox proportional hazards model was used to analyze the correlation between variables and 5‐year overall survival.ResultsAn equal number of patients (n = 346) who did or did not undergo chemotherapy after PSM were further enrolled in the study. The results showed that the mortality of OCCC increased for the patients aged ≥50 years. In addition, older age was associated with lower 5‐year overall survival (p < 0.05). However, chemotherapy did not extend the 5‐year overall survival (p = 0.524) of patients with stage IA OCCC, according to the multivariate Cox regression analysis.ConclusionsChemotherapy did not affect the overall survival of patients with stage IA OCCC following surgery.

Outcome and prognostic factors of unexpected ovarian carcinomas

AbstractBackgroundWe investigated risk factors influencing the outcome of unexpected ovarian carcinomas.MethodsWe reviewed the ovarian carcinoma patients treated at atertiary medical institution between 2000 and 2017 and analyze the clinico‐pathological characteristics, treatment strategies, recurrence status, and outcome.ResultsA total of 112 women (65 primary laparoscopic surgery [LSC] and 47 laparotomic surgery [LAPA]) were included in the analysis. The LSC group had smaller ovarian tumors (10.5 ± 7.3 cm vs. 16.6 ± 8.7 cm, p = 0.031) and higher incidence of subsequent staging surgery (56.9% vs. 25.5%, p = 0.0001) compared to the LAPA group. There were 98/112 (86.6%) of early stages (I/II) diseases. The difference between the recurrent rate (27.7% vs. 31.9%), disease‐free survival (DFS), and overall survival (OS) were not significant among surgical groups. In the multivariate analysis, FIGO stage (stage II hazard ratio [HR] 6.61, p = 0.007; stage III HR 8.40, p = 0.002) was the only prognostic factor for DFS. FIGO stage (stage II HR 20.78, p = 0.0001; stage III HR 7.99, p = 0.017), histological type (mucinous HR 12.49, p = 0.036), and tumor grade (grade 3 HR 35.01, p = 0.003) were independent prognostic factors for OS, while women with latency >28 days from primary to staging surgery had significantly poorer OS (p = 0.008). Women with latency >28 days between primary surgery and adjuvant chemotherapy had similar DFS (p = 0.31) and a trend of poorer OS (p = 0.064).ConclusionsThe prognosis of unexpected ovarian cancer is independent from the primary surgical procedure and comprehensive staging surgery should be performed at close proximity after the diagnosis of unexpected ovarian malignancy.

BDP1 as a biomarker in serous ovarian cancer

AbstractBackgroundTFIIIB, an RNA polymerase III specific transcription factor has been found to be deregulated in human cancers with much of the research focused on the TBP, BRF1, and BRF2 subunits. To date, the TFIIIB specific subunit BDP1 has not been investigated in ovarian cancer but has previously been shown to be deregulated in neuroblastoma, breast cancer, and Non‐Hodgkins lymphoma.ResultsUsing in silico analysis of clinically derived platforms, we report a decreased BDP1 expression as a result of deletion in serous ovarian cancer and a correlation with higher and advanced ovarian stages. Further analysis in the context of TP53 mutations, a major contributor to ovarian tumorigenesis, suggests that high BDP1 expression is unfavorable for overall survival and high BDP1 expression occurs in stages 2, 3 and 4 serous ovarian cancer. Additionally, high BDP1 expression is disadvantageous and unfavorable for progression‐free survival. Lastly, BDP1 expression significantly decreased in patients treated with first‐line chemotherapy, platin and taxane, at twelve‐month relapse‐free survival.ConclusionsTaken together with a ROC analysis, the data suggest BDP1 could be of clinical relevance as a predictive biomarker in serous ovarian cancer. Lastly, this study further demonstrates that both the over‐ and under expression of BDP1 warrants further investigation and suggests BDP1 may exhibit dual function in the context of tumorigenesis.

Hsa_circ_0001445 works as a cancer suppressor via miR‐576‐5p/SFRP1 axis regulation in ovarian cancer

AbstractBackgroundOvarian cancer (OC) has high mortality and morbidity. Circular RNA (circRNA) can deeply impact the tumor occurrence and growth. The pathogenic activity of one particular circRNA, hsa_circ_0001445 (hcR1445), in OC remains unclear and was therefore analyzed in this study.MethodsHuman OC tissue specimens and cell lines (SKOV3, HO8910, and OVCAR8) were used to examine the levels of hcR1445 and the microRNA miR‐576‐5p using polymerase chain reaction. The 5‐ethynyl‐2′‐deoxyuridine, flow cytometry, cellular scratch test, CCK‐8, and Transwell migration assays were used to examine the biological activities of hcR1445 and miR‐576‐5p on cell apoptosis, invasion, migration, and proliferation in OC cells. Protein expression of WNT/β‐catenin and secreted frizzled‐related protein 1 (SFRP1) were tested using Western blot analysis. The potential interactions of miR‐576‐5p/SFRP1 and hcR1445/miR‐576‐5p were evaluated using a dual‐luciferase report assay. The effect of hcR1445 on OC growth and metastasis was further determined using an OC tumor xenograft model in vivo.ResultshcR1445 level was declined in OC cells and tissues. hcR1445 reduced cellular invasion, proliferation, and migration by blocking the ability of miR‐576‐5p to upregulate SFRP1 expression and consequently prohibit WNT/β‐catenin signal transduction. hcR1445 upregulation suppressed OC growth, development, and intraperitoneal metastasis in vivo.ConclusionhcR1445 acts an antioncogene by targeting the miR‐576‐5p/SFRP1 axis and blocking OC progression and development. Thus, hcR1445 may be employed as an indicator or a possible therapeutic target in OC patients.

Identification of miR‐30c‐5p as a tumor suppressor by targeting the m6A reader HNRNPA2B1 in ovarian cancer

AbstractBackgroundmicroRNAs (miRNAs) and N6‐methyladenosine (m6A) play important roles in ovarian cancer (OvCa). However, the mechanisms by which miRNAs regulate m6A in OvCa have not been elucidated so far.MethodsTo screen m6A‐related miRNAs, Pearson's correlation analysis of miRNAs and m6A regulators was implemented using The Cancer Genome Atlas database (TCGA). To determine the level of m6A, RNA m6A quantitative assays were used. Then, colony formation assays, EdU assays, wound healing assays, and Transwell assays were performed. The dual‐luciferase reporter assay was used to confirm the miRNA target genes. Protein–protein interaction (PPI) analysis of the target genes was performed, and hub genes were discovered using the cytoHubba/Cytoscape software. The underlying molecular mechanisms were explored by bioinformatics and RNA stability assays.ResultsA total of 126 miRNAs were identified as m6A‐related miRNAs by Pearson's correlation analysis. Among them, the high level of miR‐30c‐5p was associated with good prognosis in OvCa patients. In vitro, the miR‐30c‐5p agomir lowered the m6A level and inhibited OvCa cell proliferation, migration, and invasion. The hub target genes of miR‐30c‐5p were identified as (i) XPO1, (ii) AGO1, (iii) HNRNPA2B1, of which m6A reader HNRNPA2B1 was highly expressed in OvCa tissues and related with poor prognosis. In vitro, knockdown of HNRNPA2B1 significantly reduced m6A level and hampered the proliferation and migration of OvCa cells. The inhibition of m6A reader HNRNPA2B1 attenuated the suppression of proliferation and migration and the low m6A level induced by the miR‐30c‐5p downregulation. Mechanistically, m6A reader HNRNPA2B1 might regulate CDK19 mRNA stability to alter m6A level.ConclusionsmiR‐30c‐5p inhibits OvCa progression and reduces the m6A level by inhibiting m6A reader HNRNPA2B1, thus providing new insights into the m6A regulatory mechanism in OvCa.

Strong founder effect for BRCA1 c.3629_3630delAG pathogenic variant in Chechen patients with breast or ovarian cancer

AbstractCoding sequences of BRCA1, BRCA2, ATM, TP53, and PALB2 genes were analyzed in 68 consecutive Chechen patients with high‐grade serous ovarian cancer (HGSOC). Pathogenic BRCA1/2 variants were identified in 15 (22%) out of 68 HGSOC cases. Nine out of ten patients with BRCA1 pathogenic alleles carried the same deletion (c.3629_3630delAG), and three out of five BRCA2 heterozygotes had Q3299X allele. The analysis of 49 consecutive patients with triple‐negative breast cancer (TNBC) revealed 3 (6%) additional BRCA1 heterozygotes. All women with BRCA1 c.3629_3630delAG allele also carried linked c.1067G>A (Q356R) single nucleotide polymorphism, indicating that this is a genuine founder variant but not a mutational hotspot. An ATM truncating allele was detected in one HGSOC patient. There were no women with TP53 or PALB2 germline alterations. Genetic analysis of non‐selected HGSOC patients is an efficient tool for the identification of ethnicity‐specific BRCA1/2 pathogenic variants.

Construction of ovarian metastasis‐related immune signature predicting prognosis of gastric cancer patients

AbstractBackgroundOvarian metastasis (OM) results in poor survival of gastric cancer (GC) patients. While immunotherapy has emerged as a promising approach for late‐stage GC, validated immune‐related prognostic signatures still remain in need. In this study, we constructed an ovarian metastasis‐ and immune‐related prognostic signature (OMIRPS), characterized the molecular and immune features of OMIRPS‐categorized subgroups and predicted their potential response to immunotherapy.MethodsThree individual cohorts were used to construct and evaluate OMIRPS: RNA‐seq of matched primary GC and OM from Fudan University Shanghai Cancer Center (FUSCC) (discovery cohort, n = 4), The Cancer Genome Atlas (TCGA) (training cohort, n = 544) and GSE84437 (validation cohort, n = 433). Differentially expressed genes (DEGs) identified between primary GC and OM and immune‐related genes (IRGs) from the ImmPort and InnateDB databases were used to identify immune‐related prognostic hub genes, which were further used to construct OMIRPS by using LASSO regression analysis. Prognosis, molecular characteristics, immune features, and differential immunotherapy efficacy between different OMIRPS subgroups were analyzed.ResultsFunctional analyses of DEGs revealed the significance of immune‐related signatures and pathways in the OM. Immune‐related prognostic hub genes including TNFRSF18, CARD11, BCL11B, NRP1, BNIP3L, and ATF3 were utilized to construct OMIRPS, which was identified as an independent prognostic factor. Comprehensive analyses unveiled the distinctive molecular and immune characteristics of OMIRPS‐high and ‐low subgroup in regard to enriched pathways, mutation rate, tumor mutation burden, microsatellite instability status, infiltrated immune cell, immune exclusion score, and the prediction of immunotherapy efficacy. Additionally, OMIRPS was associated with Immune Subtypes with borderline significance.ConclusionsRNA‐seq of paired primary and ovarian metastatic tumors unveiled the significance of immune‐related pathways and tumor immune microenvironment in OM. OMIRPS served as a promising biomarker to predict the prognosis of GC patients and distinguish the molecular features, immune characteristics, and efficacy of immunotherapy between different subgroups.

Mental health disorders among ovarian cancer survivors in a population‐based cohort

AbstractBackgroundOvarian cancer is the fifth most common female cancer in the United States. There have been very few studies investigating mental health diagnoses among ovarian cancer survivors with long‐term follow up. The aim of this study is to examine the incidence of mental illness among ovarian cancer survivors compared to a general population cohort. A secondary aim is to investigate risk factors for mental illnesses among ovarian cancer survivors.Patients and methodsCohorts of 1689 ovarian cancer patients diagnosed between 1996 and 2012 and 7038 women without cancer matched by age and birth state from the general population were identified. Mental health diagnoses were identified from electronic medical records and statewide healthcare facilities data. Cox proportional hazard models were used to estimate hazard ratios (HRs).ResultsOvarian cancer survivors experienced increased risks of mental illnesses within the first 2 years after cancer diagnosis (HR = 3.55, 95% CI = 3.04–4.14). The risks of depression among ovarian cancer survivors were nearly 3‐fold within the first 2 years of cancer diagnosis (HR = 2.59, 95% CI = 1.94–3.47), and 1.69‐fold at 2–5 years after cancer diagnosis (HR = 1.69, 95% CI = 1.18–2.42). Ovarian cancer survivors experienced an 80% increased risk of death with a mental illness diagnosis (HR = 1.80, 95% CI = 1.48–2.18) and a 94% increased risk of death with a depression diagnosis (HR = 1.94, 95% CI = 1.56–2.40).ConclusionsHigher risks of mental illnesses were observed among ovarian cancer survivors throughout the follow‐up periods of 0–2 years and 2–5 years after cancer diagnosis. Multidisciplinary care is needed to monitor and treat mental illnesses among ovarian cancer survivors.

Minimally invasive surgery vs laparotomy for early stage cervical cancer: A propensity score‐matched cohort study

AbstractObjectiveTo compare the long‐term oncologic outcomes of minimally invasive surgery (MIS) vs laparotomy for patients with stage IB (2018 FIGO) cervical cancer.MethodsA matched retrospective study of cervical cancer patients who underwent MIS or laparotomy at Sun Yat‐sen University Cancer Center from January 2012 to December 2015 was carried out. Patients were restaged according to the 2018 FIGO staging system for cervical cancer, 700 cases with stage IB cervical cancer were enrolled. Propensity score matching (PSM) was performed by software SPSS version 22.0, and a total of 426 patients were enrolled and analyzed. Oncologic outcomes were compared between patients undergoing MIS vs laparotomy.ResultsAfter PSM, there were no statistical differences in other baseline characteristics between MIS and laparotomy, except for age (p = 0.008). In all stage IB patients, MIS group had significantly lower disease‐free survival (DFS) rate and overall survival (OS) rate compared with laparotomy group (5‐year DFS rate, 87.5% vs 94.1%, hazard ratio for disease recurrence, 2.403; 95% CI, 1.216‐4.744; 5‐year OS rate, 92.3% vs 98.1%, hazard ratio for death, 3.719; 95% CI, 1.370‐10.093). In stage IB1 patients population, MIS was still associated with worse DFS and OS compared to laparotomy (5‐year DFS rate: 89.5% vs 100%, p = 0.012; 5‐year OS rate: 93.4% vs 100%, p = 0.043). Even in stage IB1 patients without lymph vascular space invasion, worse oncologic outcome could be observed in MIS group (DFS: p = 0.021; OS: p = 0.076).ConclusionOur study suggested that laparotomy resulted in better OS and DFS compared with MIS among patients with stage IB cervical cancer. Even in stage IB1 patients without lymph vascular space invasion (2018 FIGO), laparotomy might be still an oncologically safer approach.

Serinc2 Drives the Progression of Cervical Cancer Through Regulating Myc Pathway

ABSTRACTBackgroundAs one of the most common malignancies, cervical cancer (CC) seriously affects women's health. This study aimed to investigate the biological function of Serinc2 in CC.MethodsSerinc2 expression was surveyed utilizing immunohistochemistry, western blot, and qRT‐PCR. CC cell viability, invasion, proliferation, migration, and apoptosis, were detected via CCK‐8, Transwell assay, colony formation, wound healing assay, and flow cytometry. Glucose consumption, lactate production, and ATP levels were determined by the corresponding kit. The protein expression of c‐Myc, PDK1, HK2, PFKP, LDHA, Snail, Vimentin, N‐cadherin, and E‐cadherin was detected via western blot. The interaction between the promoter of PFKP and Myc was confirmed through luciferase reporter assay and Chip assay. In vivo, to evaluate the function of Serinc2 on tumor growth, a xenograft mouse model was used.ResultsIn CC tissues and cells, Serinc2 was upregulated. In CC cells, knockdown of Serinc2 suppressed cell invasion, proliferation, migration, decreased the expression of Snail, Vimentin, N‐cadherin, HK2, PFKP, LDHA, and PDK1, increased E‐cadherin expression, reduced glucose consumption and the production of lactate and ATP, and induced cell apoptosis; Serinc2 overexpression led to the opposite results. Mechanically, Serinc2 promoted Myc expression, and Myc induced PFKP expression. Furthermore, overexpressed Myc abolished the inhibitive influences of Serinc2 knockdown on the malignant behaviors of CC cells. Additionally, knockdown of Serinc2 inhibited tumor growth and reduced the protein expression of c‐Myc, PFKP, LDHA, and PDK1 in vivo.ConclusionsKnockdown of Serinc2 inhibited the malignant progression of CC, which was achieved via Myc pathway. Our study provides novel insight into CC pathogenesis.

MiR‐362 suppresses cervical cancer progression via directly targeting BAP31 and activating TGFβ/Smad pathway

AbstractBAP31 (B‐cell receptor‐associated protein 31) is an important regulator of intracellular signal transduction and highly expressed in several cancer tissues or testicular tissues. Our previous study had revealed that elevated BAP31 plays a crucial role in the progress and metastasis of cervical cancer. Even so, the precise mechanism of abnormal BAP31 elevation in cervical cancer has not been fully elucidated. We revealed that the expression of BAP31 was mainly regulated by microRNA‐362 (miR‐362), which was markedly downregulated in cervical cancer tissues and negatively correlated with clinical tumor staging. Overexpression of miR‐362 inhibited cervical cancer cell proliferation and increased the proportion of apoptotic cells. Furthermore, miR‐362 reduced the tumor sizes and prolonged mice survival time in xenograft nude mice model. Finally, we demonstrated that the BAP31/SPTBN1 complex regulated tumor progression through the Smad 2/3 pathway under the control of miR‐362. Collectively, our findings demonstrated that miR‐362 could work as an anti‐oncomiR that inhibits proliferation and promotes apoptosis in cervical cancer cells via BAP31 and TGFβ/Smad pathway. Overexpression of miR‐362 might be a potential therapeutic strategy for cervical cancer.

The prognostic effect of residual tumor for advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy or primary debulking surgery

AbstractPurposeThe role of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) in advanced epithelial ovarian cancer (EOC) remains controversial. This study aimed to investigate the prognosis between NACT and PDS in advanced EOC. We also investigated the prognostic effect of the residual tumor (RT) after NACT and PDS.MethodsPatients with stage III‐IV EOC diagnosed between 2010 and 2017 were included from the Surveillance, Epidemiology, and End Results (SEER) database. Chi‐square test, multivariate logistic regression analysis, Kaplan–Meier curves, and Cox proportional hazards model were used for statistical analyses.ResultsA total of 5522 women patients were identified, 2017 (36.5%) and 3505 (63.5%) patients received NACT and PDS, respectively. There were 2971 (53.8%), 1637 (29.6%), and 914 (16.6%) patients who had no residual tumor, RT ≤1 cm, and RT >1 cm, respectively. There were 25.5% of patients receiving NACT in 2010 and 48.4% in 2017 (p < 0.001). Women treated with NACT were not related to a higher chance of complete resection than the PDS group (p = 0.098). Patients receiving PDS had significantly better cancer‐specific survival (CSS) than those receiving NACT (p < 0.001). The 5‐year CSS was 35.3% and 51.1% in those receiving NACT and PDS, respectively. In patients receiving NACT, those who had no residual tumor had significantly better CSS compared to those who had RT ≤1 cm (p < 0.001), while comparable CSS was found between those who had RT ≤1 cm and RT >1 cm (p = 0.442). In those receiving PDS, the CSS was decreased with a RT increase (p < 0.001).ConclusionsOur study suggests that PDS may be the optimal procedure for the majority of advanced EOC patients. Complete resection of all residual diseases should be the goal with the increased utilization of NACT.

Biomarkers expression among paired serous ovarian cancer primary lesions and their peritoneal cavity metastases in treatment‐naïve patients: A single‐center study

AbstractBackgroundHigh‐grade serous ovarian carcinoma (HGSOC), the most common histologic subtype of ovarian epithelial cancer, is associated with treatment resistance, enhanced recurrence rates, and poor prognosis. HGSOCs often metastasize to the peritoneal cavity, while fluid cytology examination could identify such metastases. This retrospective study aimed to identify potential biomarker discrepancies between paired HGSOC primary tissues and metastatic peritoneal fluid cytology samples, processed as cell blocks (CBs).MethodsTwenty‐four pairs of formalin‐fixed, paraffin‐embedded primary tissues and metastatic CBs from an equal number of treatment‐naïve patients were used, and immunohistochemistry (IHC) for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor, programmed cell death‐1 ligand 1 (PD‐L1), and CD147 was applied.Results13/24 pairs showed discordant EGFR IHC results; in all these 13 patients, EGFR was positive (≥1+ membranous staining intensity found in at least 10% of the cancer cells) in the peritoneal, yet negative in the primary tissue samples. Notably, EGFR IHC was positive in 15/24 of the metastatic, whereas in just 2/24 of the primary HGSOC samples (p < 0.001). Although most PD‐L1 results were concordant, 5/24 and 6/24 pairs exhibited discordant results when stained with the E1L3N and 22C3 clones, respectively. Lastly, CD147 overexpression was found more often in the metastatic rather than the matched primary HGSOCs stained with CD147, though the difference was not significant.ConclusionsCytology from effusions could be considered for biomarker testing when present, even when tissue from the primary cancer is also available and adequately cellular, as it could provide additional information of potential clinical significance.

Clinical significance of CD8‐positive lymphocytes on tumor cell clusters of ascites cell block in ovarian high‐grade serous carcinoma

AbstractBackgroundThe clinical significance of CD8‐positive (CD8+) lymphocytes on tumor cell clusters of ascites cell blocks in patients with ovarian high‐grade serous carcinoma (HGSC) was investigated.MethodsAmong HGSC patients who underwent surgery from January 2014 to December 2019, 38 patients with ascites cell block were selected. Using these cell blocks and primary ovarian tumor tissue, the presence of CD8+ lymphocytes and the expression of PD‐L1 were examined immunohistochemically. Tumor cell clusters were defined as cell clumps consisting of more than 10 malignant cells in cell block. Cases with at least one CD8+ lymphocyte in tumor cell cluster were defined as positive CD8+ lymphocytes (Group A); others were defined as negative CD8+ lymphocytes (Group B). The tumor tissue CD8+ lymphocytes were counted mechanically. Clinicopathological features were retrospectively compared between the two groups.ResultsIn total, 38 cases were identified: 25 (65.8%) in Group A and 13 (34.2%) in Group B. More cases in Group A were positive for CD4 (p < 0.01), PD‐L1 (p = 0.02), FoxP3 (p = 0.02) and had a higher number of CD8+ lymphocytes in the tissue (p = 0.03). Patients in Group A had better progression‐free survival (p < 0.01) and overall survival (p = 0.04). In multivariate analysis, Group A was an independent prognostic factor for both progression‐free survival (hazard ratio, 0.24; p < 0.01) and overall survival (hazard ratio, 0.21; p = 0.03).ConclusionThe presence of CD8+ lymphocytes in tumor cell clusters of ascites was associated with the status of immune reaction in the tissue and prognosis in patients with HGSC and might be useful information of the immune‐associated therapy.

Maternal survival of patients with pregnancy‐associated cancers in Taiwan – A national population‐based study

AbstractPregnancy‐associated cancer (PAC), defined as cancers diagnosed during pregnancy or the first year after delivery, affects one to two in every 1000 pregnancies. Although PAC is expected to be a growing issue, information about PAC in the Asian population is still scarce. Women with cancer diagnosed at the age of 16–49 years between 2001 and 2015 were selected from the Taiwan Cancer Registry and linked with the National Birth Reporting Database to identify PAC patients. We compared the overall survival of patients with PAC to patients without pregnancy. Among 126,646 female cancer patients of childbearing age, 512 were diagnosed during pregnancy, and 2151 during the first postpartum year. Breast cancer was the most common PAC (N = 755, 28%). Compared with patients without pregnancy in the control group, patients with cancers diagnosed during pregnancy and the first postpartum year generally had more advanced stages (odds ratio 1.35 and 1.36, 95% confidence interval [CI] 1.02–1.77 and 1.18–1.57, respectively). For all cancer types combined and controlled for the stage, age, and year of diagnosis, patients with PAC had similar overall survival with those in the control group, with a hazard ratio (HR) of 1.07 (95% CI 0.80–1.41) for the pregnancy group and HR 1.02 (95% CI 0.88–1.18) for the postpartum group. The diagnosis of breast cancer during the first postpartum year was linked with shorter survival (HR 1.34, 95% CI 1.05–1.72). In contrast, patients with postpartum lymphoma (HR 0.11, 95% CI 0.02–0.79) and cervical cancer (HR 0.40, 95% CI 0.20–0.82) had better prognosis. In general, the diagnosis of cancer during pregnancy or the first postpartum year does not affect the survival of patients with most cancer types. Exceptions include the worse prognosis of postpartum breast cancer and the better outcome of postpartum lymphoma and cervical cancer.

Genomic, transcriptomic, and viral integration profiles associated with recurrent/metastatic progression in high‐risk human papillomavirus cervical carcinomas

AbstractAcquisition of recurrent/metastatic potential by a tumor cell defines a critical step in malignant progression. However, understanding of metastatic progression at the molecular level is scarce for cervical carcinomas (CES). In this study, we performed genomic, transcriptomic, and viral profiling of five pairs of primary (CES‐P) and matched recurrent/metastatic tumors (CES‐R/M) with high risk human papillomavirus. Whole exome sequencing revealed mutation features of CES‐R/M including elevated mutation burdens and prevalent copy number alterations compared to their matched CES‐P. A relative deficit of APOBEC‐related mutation signatures accompanying the transcriptional downregulation ofAPOBEC3Awas observed for CES‐R/M. Mutations in genes encoding epigenetic regulators were commonly observed as CES‐R/M‐specific alterations. Immunoprofiling and gene set analysis revealed CES‐Ps were enriched with transcripts representing activated anticancer immunity such as interferon‐gamma pathway, while CES‐R/M exhibited upregulation of genes involved in epithelial‐mesenchymal transition and angiogenesis. Viral capture sequencing revealed that integration sites remained enriched in viral E1 protein domain during malignant progression. Moreover, we found transcriptional upregulation ofPOSTNand downregulation ofAPOBEC3Awere associated with unfavorable clinical outcomes in CES. Comprehensive genomic and transcriptomic profiling of a rare cohort including CES‐R/M identified metastases‐specific features to advance the molecular understanding into CES metastatic progression with potential clinical implications.

A public health approach to cervical cancer screening in Africa through community‐based self‐administered HPV testing and mobile treatment provision

Abstract The World Health Organization (WHO) refers to cervical cancer as a public health problem, and sub‐Saharan Africa bears the world's highest incidence. In the realm of screening, simplified WHO recommendations for low‐resource countries now present an opportunity for a public health approach to this public health problem. We evaluated the feasibility of such a public health approach to cervical cancer screening that features community‐based self‐administered HPV testing and mobile treatment provision. In two rural districts of western‐central Uganda, Village Health Team members led community mobilization for cervical cancer screening fairs in their communities, which offered self‐collection of vaginal samples for high‐risk human papillomavirus (hrHPV) testing. High‐risk human papillomavirus‐positive women were re‐contacted and referred for treatment with cryotherapy by a mobile treatment unit in their community. We also determined penetrance of the mobilization campaign message by interviewing a probability sample of adult women in study communities about the fair and their attendance. In 16 communities, 2142 women attended the health fairs; 1902 were eligible for cervical cancer screening of which 1892 (99.5%) provided a self‐collected vaginal sample. Among the 393 (21%) women with detectable hrHPV, 89% were successfully contacted about their results, of which 86% returned for treatment by a mobile treatment team. Most of the women in the community (93%) reported hearing about the fair, and among those who had heard of the fair, 68% attended. This public health approach to cervical cancer screening was feasible, effectively penetrated the communities, and was readily accepted by community women. The findings support further optimization and evaluation of this approach as a means of scaling up cervical cancer control in low‐resource settings.

Implementation of p16/Ki67 dual stain cytology in a Danish routine screening laboratory: Importance of adequate training and experience

AbstractBackgroundImmunocytochemical staining with p16/Ki67 has been suggested as a promising triage biomarker in cervical cancer screening. As dual staining is a subjective method, proper training may be required to ensure safe implementation in routine laboratories and reduce risk of misclassification. We determined concordance between novice evaluators and an expert, stratified by number of slides reviewed at three reading points.MethodsThe study was conducted at the Department of Pathology, Randers, Denmark. Women were eligible if they were aged ≥45, had been enrolled in one of two ongoing clinical studies, and had a dual stain slide available. Dual staining was performed using the CINtec plus assay. Slides were randomly selected from three reading points at which novice evaluators had reviewed <30, ~300, and ≥500 dual stain slides respectively. Level of concordance was estimated using Cohen's Kappa, κ.ResultsOf 600 eligible slides, 50 slides were selected for review as recommended by the manufacturer. Median age was 68 years (range: 58‐74). Overall concordance was good (κ = 0.68, 95% confidence interval [CI]: 0.60‐0.76), with an overall agreement of 84% (95% CI: 70.9%‐92.8%). Concordance improved with increasing number of slides reviewed at a given reading point, from a moderate concordance (κ = 0.47, 95% CI: 0.05‐0.90) after reviewing <30 slides to a good concordance (κ = 0.66, 95% CI: 0.20‐0.88) and a very good concordance (κ = 0.88, 95% CI: 0.66‐1.00) after reviewing ~300 and ≥500 slides, respectively.ConclusionsWhen interpreting dual stain slides from older women, concordance increased slightly as novice evaluators received more training and experience. Although further evaluation is warranted, these findings indicate that a significant amount of training and experience of novice evaluators may be needed to ensure accurate dual stain interpretation in this age group. Future studies should accurately describe training and experience of evaluators to enable a better comparison of concordance and diagnostic accuracy across studies.Trial registrationNCT04114968 and NCT04298957.

Accuracy of transvaginal sonoelastography for differential diagnosis between malignant and benign cervical lesions: A systematic review and meta‐analysis

AbstractBackgroundTo evaluate the performance of transvaginal sonoelastography (TVSE) for differential diagnosis between malignant and benign cervical lesions using a meta‐analysis.MethodsAn independent literature search was conducted on the English medical database, including PubMed, Embase and Medline, Cochrane Library, Web of Science, and OVID. The diagnostic accuracy of TVSE was compared with that of histopathology, which is the gold reference standard for diagnosis. The accuracy of TVSE was assessed by calculating the pooled sensitivity, specificity, diagnostic odds ratio, and area under the curve (AUC). The imaging mechanisms, assessment methods, and QUADAS scores were assessed with a meta‐regression analysis. A Deeks funnel plot was performed for evaluating publication bias.ResultsSix eligible studies reported a total sample of 615 cervical lesions (415 cancers, 200 benign lesions). TVSE showed a pooled diagnostic odds ratio of 21.42 (95% CI 13.65‐33.61), sensitivity of 0.87 (95% CI 0.84‐0.90), specificity of 0.79 (95% CI 0.72‐0.84), and an AUC of 0.892 (Q* = 0.822). The results of the meta‐regression analysis showed that the imaging mechanism (P = .253), the assessment method (P = .279), or QUADAS score (P = .205) did not affect the study heterogeneity.ConclusionTVSE has a relatively high and satisfactory value for differential diagnosis between malignant and benign cervical lesions. The diagnostic performance of strain elastography and shear wave elastography were similar and good. However, to accommodate heterogeneity and publication bias, high‐quality studies are required to further comparative effectiveness analyses to verify the efficacy of ultrasound detection.

Long noncoding RNA HCG11 inhibited growth and invasion in cervical cancer by sponging miR‐942‐5p and targeting GFI1

AbstractLong noncoding RNAs (lncRNAs) act as essential regulators in cancer tumorigenesis. Our study aimed to explore the underlying mechanism of lncRNA human leukocyte antigen complex group 11 (HCG11) in cervical cancer (CC) progression. Long noncoding RNA HCG11 was downregulated in CC. Functional assays demonstrated that lncRNA HCG11 inhibited CC cell proliferation and invasion. Then, we confirmed that lncRNA HCG11 could directly bind to miR‐942‐5p. Moreover, inhibition of miR‐942‐5p suppressed the growth and invasion of CC cells, and growth factor‐independent transcription repressor 1 (GFI1) gene was the target gene of miR‐942‐5p. Long noncoding RNA HCG11 increased the expression of GFI1 and suppressed cell proliferation and invasion by acting as a miR‐942‐5p sponge. Finally, the overexpression of lncRNA HCG11 suppressed the proliferation and metastasis of CC cells in vivo.

Implementing the 3T‐approach for cervical cancer screening in Cameroon: Preliminary results on program performance

AbstractOption recommended by World Health Organization (WHO) includes human papillomavirus (HPV) primary screening followed by visual inspection with acetic acid (VIA) triage. We implemented a program based on a 3T‐approach (Test‐Triage and Treat). Our objective was to verify the effectiveness of the program by defining a set of performance indices. A sensitization campaign was performed in Dschang (Cameroon) and women aged 30‐49 years were invited to participate for screening based on the 3T‐approach. Participants performed HPV self‐sampling (Self‐HPV), analyzed with the point‐of‐care Xpert HPV assay followed by VIA/VILI triage and treatment if required. Key performance indicators (KPIs) for screening, diagnosis, treatment and follow‐up were defined, and achievable targets were described for which the approach is likely to be running optimally. A total of 840 women with a mean age of 39.4±5.9 years participated. The KPIs included (i) the screening rate (8.4% at 7 months, target =20% at 12 months), (ii) HPV positivity rate (19.8%, expected range 18‐25%), (iii) compliance to referral to VIA/VILI and complete test (100%, target >90%), (iv) compliance to referral to thermal ablation (100%, target >90%), (v) VIA/VILI positivity rate (50.6%, expected range 45‐55%), (vi) a single visit from diagnostic to treatment (79.8%, target >80%), (vii) compliance to follow‐up at 1 month (96.4%, target >80%) and (viii) at 6 months (70.6%, target >80%). Program performance based on the single‐visit 3T‐approach corresponded to defined targets and preliminary results support adequateness of KPIs for periodic monitoring.

Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix based on population analyses

AbstractObjectiveWe aimed to assess the impact of the treatment modality on the outcome of small cell neuroendocrine cervical carcinoma (SCNEC) using the Surveillance Epidemiology and End Results (SEER) database.MethodsPatients from the SEER program between 1981 and 2014 were identified. Significant factors for cancer‐specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan‐Meier survival and Cox regression methods.ResultsA total of 503 SCNEC patients were identified. The 5‐year CSS and OS were 36.6% and 30.6%, respectively. The International Federation of Gynecology and Obstetrics (FIGO) stage I to IV distributions was 189 (37.6%), 108 (21.5%), 95 (18.9%), and 111 patients (22.0%), respectively. Within the patients with known treatment strategies, 177 (45.9%) were treated with radical surgery and 209 (54.1%) underwent primary radiotherapy. Local treatment strategies were independent prognostic factor for CSS and OS. The 5‐year CSS for radical surgery and primary radiotherapy was 50.0% and 27.9%, respectively (P < .001). The 5‐year OS for those who received radical surgery and primary radiotherapy was 57.8%, and 29.6%, respectively (P < .001). In FIGO stage I SCNEC, patients treated with radical surgery had superior CSS (P = .001) and OS (P = .003) than those with primary radiotherapy. However, in FIGO stage II and III SCNEC, there were no differences in CSS and OS with respect to different local treatment strategies. Our results also found that the addition of brachytherapy impacted OS in the FIGO stage III SENCE (P = .002). The 5‐year CSS and OS of patients with FIGO IV were only 11.7% and 7.1%, respectively.ConclusionsSCNEC is a rare disease with aggressive clinical behavior. The findings indicate that radical surgery should be suggested for early‐stage SCNEC and combining radiation therapy with brachytherapy should be suitable for patients with advanced stage.

Effectiveness and prognostic factors of apatinib treatment in patients with recurrent or advanced cervical carcinoma: A retrospective study

AbstractBackgroundApatinib is an oral anti‐angiogenic drug, its efficacy and prognosis in cervical carcinoma are unclear. This study evaluates the effectiveness and prognostic factors of apatinib in the treatment of recurrent or advanced cervical carcinoma.MethodsPatients with recurrent or advanced cervical cancer, who agreed to take apatinib, were recruited into this single‐center and retrospective study, and administrated apatinib with or without combination of chemo‐ or radio‐therapy until progressive disease (PD) or unacceptable toxicity.ResultsFrom March 2017 to February 2019, 53 patients were reviewed. Among them, 2 (3.77%) patients occurred complete response, 16 (30.19%) patients showed partial response, 27 (50.95%) patients had stable disease, and 8 (15.09%) patients had PD. The objective response rate and disease control rate (DCR) of these patients were 33.96% and 84.91%, respectively. The DCR of patients younger than 50, nonsquamous carcinoma, first‐line apatinib therapy, combined radiotherapy, lesions within radiation field, surgical history, and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 were significantly higher than other patients (p < 0.05). The median progression‐free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.43–7.57) and 8.0 months (95% CI: 6.52–9.48), respectively. The univariable and multivariable analysis showed that the patients with an ECOG performance status score of 2 and further line therapy were associated with poor prognosis in both PFS and OS (PFS: HR =8.35, p = 0.000; HR =6.66, p = 0.001; OS: HR = 7.40, p = 0.000; HR = 3.24, p = 0.039), respectively. The most common adverse effects (AEs) were hand‐foot syndrome (35.58%), hypertension (18.87%) and fatigue (15.09%). No grade 3 AEs and drug‐related death occurred.ConclusionThe efficacy and prognosis of patients who are in good general condition and first‐line apatinib combination therapy may be better than other patients. But further phase III clinical trials should be taken to prove this hypothesis.

Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124‐2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions

AbstractThe decision to treat a cervical squamous intraepithelial lesion (SIL) by loop electrosurgical excision procedure (LEEP) relies heavily on a colposcopy‐directed biopsy showing high‐grade (H)SIL. Diagnosis is often supported by p16, an immunohistochemical (IHC) biomarker of high‐risk (hr)HPV E7 gene activity. Additional potential markers include methylation of tumor suppressor genes FAM19A4/miR124‐2 in cervical cytology for advanced transforming HSIL and the IHC marker HPV E4 for productive, potentially regressing lesions. In 318 women referred for colposcopy, we investigated the relationship between staining patterns of p16 and E4 IHC in the worst biopsy, and the relation of these to FAM19A4/miR124‐2 methylation status in cytology. E4‐positive staining decreased with increasing SIL/CIN grade from 41% in LSIL to 3% in HSIL/CIN3. E4 positivity increased with grade of p16 when p16 expression was limited to the lower two third of the epithelium (r = 0.378), but fell with expression over. Loss of E4 expression in the worst lesion was associated with the methylation of FAM19A4/miR124‐2. We also examined whether these biomarkers can predict the histological outcome of the LEEP biopsy in a subgroup of 119 who underwent LEEP treatment. About 85% of women with ≥lower two third p16 staining/E4‐negative HSIL biopsies and 65% with limited p16 staining/E4‐positive HSIL biopsies had ≥HSIL in the LEEP specimen (P = .025). p16 expression in a biopsy is related both to viral production and transformation, while decreased E4 expression relates to methylation, indicating advanced HSIL. p16 expression in ≥2/3 of the epithelium and absent E4 indicate likely HSIL on a subsequent LEEP specimen.

Significance of concurrent use of weekly cisplatin in carbon‐ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix: A propensity score‐matched analysis

AbstractBackgroundAlthough carbon‐ion radiotherapy (C‐ion RT) with concurrent chemotherapy (chemo‐C‐ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long‐term efficacy remains unclear. We evaluated the long‐term significance of concurrent weekly cisplatin and C‐ion RT for locally advanced AC of the uterine cervix.MethodsWe performed a pooled analysis of patients with stage IIB–IVA AC of the uterine cervix who underwent C‐ion RT alone or chemo‐C‐ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0‐2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage.ResultsThe matched cohort contained 26 patients who underwent C‐ion RT and 26 who underwent chemo‐C‐ion RT. The median age and follow‐up period were 57 (range, 28‐79) years and 34 (range, 2‐126) months, respectively. The 5‐year overall survival rate was significantly better in the chemo‐C‐ion RT group (72%) than in the C‐ion RT group (46%; P = .041). The 5‐year distant metastatic‐free rate was also significantly better in the chemo‐C‐ion RT group (66%) than in the C‐ion RT group (41%; P = .048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups.ConclusionsChemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit.

The potential population‐based impact of an HPV vaccination intervention in Colorado

AbstractBackgroundHuman papillomavirus (HPV) infection is the most common cause of cervical cancer and can be prevented with vaccination, but HPV vaccination rates remain low. An intervention to improve health care provider communication about vaccination has been shown to increase HPV vaccination rates in an initial trial in Colorado, where about 160 cases of cervical cancer are diagnosed each year.MethodsCensus data were combined with Colorado cancer and immunization registry data to identify clinics in locations that would most benefit from implementation of this intervention to improve HPV vaccination rates. ArcGIS Pro was used to map cervical cancer incidence, immunization rates, population data, and location of clinics participating in practice‐based research networks (PBRNs). Results from the provider communication intervention trial and published estimates of the number needed to vaccinate to prevent a case of cervical cancer were used to predict the number of cervical cancer cases prevented based on increased vaccination due to the intervention.ResultsNinety‐eight Colorado PBRN clinics were analyzed. For the 10 clinics with the highest predicted number of cervical cancer cases prevented, 5218 additional patients would be vaccinated and 43 cervical cancer cases prevented with implementation of the intervention. If implemented in all 98 clinics, the intervention would lead to 20 490 additional patients vaccinated (range 7‐658/clinic) and 171 cases of cervical cancer prevented (range 0.05‐5.48/clinic).ConclusionsGeographic data from cancer and immunization registries can inform the dissemination of evidence‐based practices like the provider communication intervention for HPV vaccination to maximize impact on public health.

Risk factors of cervical cancer after a negative cytological diagnosis in Polish cervical cancer screening programme

AbstractRisk factors of cervical cancer (CC) development are well investigated, however, those influencing the risk of a potential false negative cytology preceding diagnosis of an invasive CC are not. We have aimed to explore these factors according to the data from Organised Cervical Cancer Screening Programme (OCCSP) in Poland. A total of 2.36 million of Pap tests sampled in 2010–2012 within OCCSP were merged with the Polish National Cancer Registry to identify CC cases after abnormal cytology and after normal cytology within 3 years of screening. Of 1460 invasive CCs, 1025 were preceded by abnormal and 399 by normal cytology result. Multivariate logistic analysis indicated that the presence of microorganisms in the Pap (OR = 2.18, 95% CI 1.65–2.87), evaluation by smaller (below 9000 slides processed per year) laboratories (OR = 1.60, 95% CI 1.22–2.09) and non‐squamous histology of cancer increased the odds for a potential false negative result (OR = 3.39, 95% CI 2.37–4.85 for adenocarcinoma, OR = 1.99, 95% CI 1.11–3.55 for other types of carcinoma), whereas cervical ectropion, other macroscopic changes on the cervix and smoking decrease the odds for a potential false negative Pap test result preceding CC (OR = 0.61, 95% CI 0.45–0.82, OR = 0.41, 95% CI 0.25–0.67, OR = 0.60, 95% CI 0.46–0.78, respectively). Proper triage of women with microscopic signs of microorganisms in the Pap smear should be reconsidered and cytology should be assessed in laboratories processing over 9000 slides annually to decrease the odds for negative Pap test result in 2 years before CC diagnosis. Information on macroscopic changes on the cervix provided to cytomorphologist may reduce the risk of a potential false negative cytology result.

ROS1 Expression Correlates With Inguinal Lymph Node Affection in Vulvar Cancer Patients: A Retrospective Study

ABSTRACTPurposeSystemic treatment options for vulvar squamous cell carcinoma (VSCC) are limited. ROS1, a tyrosine kinase implicated, for example, in non‐small cell lung cancer (NSCLC), has recently shown responsiveness to tyrosine kinase inhibitors. This study investigated immunohistochemical ROS1 expression in VSCC to explore its potential as a future therapeutic target in this rare malignancy.MethodsIn this retrospective study, 48 patients with VSCC undergoing vulvectomy were included. Clinicopathological data were collected in a standardized manner. Immunohistochemistry (IHC) was used to assess ROS1 expression on an ordinal scale from 0 (absent staining) to 3 (> 50% of neoplastic cells demonstrated cytoplasmatic staining); levels 0 and 1 were considered negative, while 2 and 3 were rated as positive. After differences and correlations with clinicopathological parameters were evaluated between positive and negative tumors, we fitted logistic regression and survival models to assess the association of ROS1 with inguinal lymph node involvement and overall survival. Statistical analysis was conducted using GraphPad and Jamovi.ResultsROS1 IHC levels were associated with lymph node involvement [odds ratio (OR) 2.396, 95% confidence interval (CI) 1.034–5.555, logistic regression, p = 0.042]. ROS1 positive tumors demonstrated no difference in overall survival compared with negative ones [hazards ratio (HR) 0.837, 95% CI 0.283–2.479, log‐rank (Mantel‐Cox) test, p = 0.738].ConclusionROS1 expression was associated with inguinal lymph node involvement but not overall survival among VSCC patients. Further studies are required to elucidate the role of ROS1 in VSCC therapeutics.

Prognosis of high‐risk human papillomavirus‐related cervical lesions: A hidden Markov model analysis of a single‐center cohort in Japan

AbstractIntroductionPrevious studies have shown that individuals with human papillomavirus (HPV)‐related cervical lesions have different prognoses according to the HPV genotype. However, these studies failed to account for possible diagnostic misclassification. In this retrospective cohort study, we aimed to clarify the natural course of cervical lesions according to HPV genotype to account for any diagnostic misclassification.Materials and MethodsOur cohort included 729 patients classified as having cervical intraepithelial neoplasia (CIN). HPV was genotyped in all patients, who were followed up or treated for cervical lesions at the University of Tokyo Hospital from October 1, 2008 to March 31, 2015. Hidden Markov models were applied to estimate the diagnostic misclassification probabilities of the current diagnostic practice (histology and cytology) and the transitions between true states. We then simulated two‐year transition probabilities between true cervical states according to HPV genotype.ResultsCompared with lesions in patients with other HPV genotypes, lesions in HPV 16‐positive patients were estimated to be more likely to increase in severity (i.e., CIN3/cancer); over 2 years, 17.7% (95% confidence interval [CI], 9.3%–29.3%) and 27.8% (95% CI, 16.6%–43.5%) of those with HPV 16 progressed to CIN3/cancer from the true states of CIN1 and CIN2, respectively, whereas 55%–70% of CIN1/2 patients infected with HPV 52/58 remained in the CIN1/2 category. Misclassification was estimated to occur at a rate of 3%–38% in the current diagnostic practice.ConclusionThis study contributes robust evidence to current literature on cervical lesion prognosis according to HPV genotype and quantifies the diagnostic misclassification of true cervical lesions.

Comparison of survival, acute toxicities, and dose–volume parameters between intensity‐modulated radiotherapy with or without internal target volume delineation method and three‐dimensional conformal radiotherapy in cervical cancer patients: A retrospective and propensity score‐matched analysis

AbstractBackgroundTo evaluate whether the use of the internal target volume (ITV) delineation method improves the performance of intensity‐modulated radiotherapy (IMRT) and three‐dimensional conformal radiotherapy (3DCRT) in terms of survival, acute toxicities, and dose–volume parameters.MethodsA total number of 477 cervical cancer patients who received concurrent chemoradiotherapy (CCRT) from January 2012 to December 2016 were retrospectively analyzed. They were divided into four groups: the non‐ITV (N‐ITV) + IMRT, ITV + IMRT, N‐ITV + 3DCRT, and ITV + 3DCRT groups, with 76, 41, 327, and 33 patients, respectively. Survival analysis was performed with the Kaplan–Meier and the log‐rank tests, and acute toxicity analysis was performed with the chi‐squared test and the binary logistic regression test. Using the propensity score matching (PSM) method, 92 patients were matched among the four groups, and their dose–volume parameters were assessed with the Kruskal–Wallis method.ResultsThe median follow‐up time was 49 months (1–119) for overall survival (OS). The 5‐year OS rate was 66.4%. The ITV delineation method was an independent prognostic factor for OS (HR [95% CI]: 0.52 [0.27, 0.98], p = 0.044) and progression‐free survival (PFS) (HR [95% CI]: 0.59 [0.36, 0.99], p = 0.045). The ITV + IMRT group had the lowest incidence rate (22%) and the N‐ITV + IMRT group had the highest incidence rate of grade ≥3 hematological toxicity (HT) (46.1%) among the four groups. The pelvic bone marrow relative V10, V20, and V30 in the N‐ITV + IMRT group was higher than those in the ITV + IMRT and N‐ITV + 3DCRT groups (p < 0.05).ConclusionsThe use of ITV for IMRT treatment planning was associated with improved overall survival and progression‐free survival, with lower HT rate.

A screening assistance system for cervical cytology of squamous cell atypia based on a two‐step combined CNN algorithm with label smoothing

AbstractBackgroundAlthough many cervical cytology diagnostic support systems have been developed, it is challenging to classify overlapping cell clusters with a variety of patterns in the same way that humans do. In this study, we developed a fast and accurate system for the detection and classification of atypical cell clusters by using a two‐step algorithm based on two different deep learning algorithms.MethodsWe created 919 cell images from liquid‐based cervical cytological samples collected at Sapporo Medical University and annotated them based on the Bethesda system as a dataset for machine learning. Most of the images captured overlapping and crowded cells, and images were oversampled by digital processing. The detection system consists of two steps: (1) detection of atypical cells using You Only Look Once v4 (YOLOv4) and (2) classification of the detected cells using ResNeSt. A label smoothing algorithm was used for the dataset in the second classification step. This method annotates multiple correct classes from a single cell image with a smooth probability distribution.ResultsThe first step, cell detection by YOLOv4, was able to detect all atypical cells above ASC‐US without any observed false negatives. The detected cell images were then analyzed in the second step, cell classification by the ResNeSt algorithm, which exhibited average accuracy and F‐measure values of 90.5% and 70.5%, respectively. The oversampling of the training image and label smoothing algorithm contributed to the improvement of the system's accuracy.ConclusionThis system combines two deep learning algorithms to enable accurate detection and classification of cell clusters based on the Bethesda system, which has been difficult to achieve in the past. We will conduct further research and development of this system as a platform for augmented reality microscopes for cytological diagnosis.

Malignancies diagnosed before and after anal squamous cell carcinomas: A SEER registry analysis

AbstractBackgroundIncreased risk of a second primary malignancy (SPM) before or after diagnosis of anal squamous cell carcinoma (ASCC) has been reported in a previous single‐institution study. We hypothesize that patients diagnosed with ASCC are at increased risk for developing SPMs before or after the diagnosis of ASCC. The primary objective of this study was to identify the diagnoses of cancer most likely to occur as SPMs before or after ASCC.MethodsThis work employs the Surveillance, Epidemiology, and End Results (SEER) Program registry data to conduct a US‐population‐based study of patients diagnosed with ASCC between 1975 and 2016. In patients diagnosed with ASCC, we evaluated the risk of SPMs and the risk of developing ASCC as an SPM after another cancer using standardized incidence ratios (SIR) for all SPMs by calculating the ratio of observed events in the ASCC cohort compared to expected (O/E) events in a matched reference cohort of the general population.ResultsA total of 7,594 patients with primary ASCC were included. Patients with ASCC were at increased risk of the diagnosis of an SPM (SIR = 1.45), particularly cancers of the lung, vulva, oropharynx, or colon. Patients with ASCC had an increased rate of previous malignancy (SIR = 1.23), especially Kaposi sarcoma or vulvar cancer. Overall elevated incidence of SPMs was unrelated to prior radiation treatment. Radiation treatment was associated with increased risk for SPMs in the female genital system but appeared protective against prostate cancer as SPMs.ConclusionsOur findings support increased surveillance and screening for second malignancies in patients with these diagnoses, as patients with ASCC are often either survivors of a prior cancer diagnosis or are at increased risk of developing later malignancies.

At what age should the Uyghur minority initiate cervical cancer screening if screened using careHPV

AbstractBackgroundThe careHPV test as a primary screening method for cervical cancer has been proven to be the best option for Uyghur women in Xinjiang in a previous study. In this research, we aim to discuss the appropriate age for Uyghur women in Xinjiang to be screened for cervical cancer using careHPV.MethodsEleven thousand women aged 20–69 years old (mean age 38.93 ± 9.74) from South Xinjiang were screened using careHPV and liquid‐based cytology, and the positive results were referred for colposcopy and cervical biopsy. A questionnaire regarding basic social characteristics, sexual practices, and reproductive history was administered to each woman. The age‐specific prevalence of HPV positivity, cytology abnormality, and cervical intraepithelial neoplasia (CIN) 2+ in ≥25, ≥30, and ≥35 age groups were analyzed, and the diagnostic value of careHPV in the three age groups was evaluated. The chi‐squared test was used to compare the differences between age groups. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve were calculated.ResultsThe women were mostly married (76.3%) and delivered at 15–19 years of age (61.4%). The HPV infection rate was 9.15% and detection rates of CIN2+ and invasive cervical cancer were 1.53% (1530/100,000) and 0.25% (250/100,000), respectively. The first peak of HPV(+) appeared at the age of 30–34, while CIN2+ appeared at 35–39. CareHPV performed similarly well in the three age groups.ConclusionBased on the results of our study, Uyghur women in Xinjiang should be recommended to initiate cervical cancer screening at the age of 30 years when screened using careHPV.

A modified delineation method of para‐aortic nodal clinical target volume in patients with locally advanced cervical cancer

AbstractPurposeTo validate the nodal center coverage (NCC) of the three mainstream delineation methods of para‐aortic nodal clinical target volume (CTV) and propose a modified delineation method of para‐aortic nodal CTV in prophylactic extended‐field irradiation (EFI) of cervical cancer.MethodsA total of 106 patients with para‐aortic lymph nodes (PALNs) identified on PET/CT were included at Peking Union Medical College Hospital between 2011 and 2020. PALNs were classified as left lateral para‐aortic (LLPA), aorto‐caval (AC), and right para‐caval (RPC). Distances from the nodal center to the aorta and inferior vena cava (IVC) were measured. The NCC of the three mainstream delineation methods of para‐aortic nodal CTV (CTV‐K, CTV‐S, and CTV‐D) and a modified CTV (CTV‐M) was calculated. Radiotherapy plans were created based on 4 CTVs for 10 selected patients who received prophylactic EFI. The chi‐squared test and the Student's t‐test were performed.ResultsWe identified 344 PALNs (216 LLPA, 101 AC, and 27 RPC) in 106 patients. Mean distance from the nodal center to the aorta was 9.6 mm in the LLPA and 7 mm in the AC and from the nodal center to the IVC was 5.6 mm in the AC and 5.6 mm in the RPC. CTV‐D improved the NCC of 98% compared with 92% for CTV‐K (p = 0.002) and 95% for CTV‐S (p = 0.046). CTV‐M provided the same satisfactory NCC as CTV‐D (97% vs. 98%, p = 0.485). The V50Gy to the duodenum, the Dmean to the bilateral kidneys, and the V45Gy to the small bowel were significantly lower on the CTV‐M‐based plan than on the CTV‐D‐based plan (p = 0.001, 0.011, and 0.001, respectively).ConclusionCTV‐D provided more satisfactory NCC than CTV‐K and CTV‐S. CTV‐M provided the same satisfactory NCC as CTV‐D and reduced the dose to the critical structures.

Adherence to follow‐up after the exit cervical cancer screening test at age 60–64: A nationwide register‐based study

AbstractBackgroundIn Denmark, human papillomavirus (HPV) testing has replaced cytology in primary cervical cancer screening for women aged 60–64; at this age, women are invited for the last (exit) screening test within the national organized program.AimWe investigated the adherence of these women to the recommended follow‐up after a non‐negative (positive or inadequate) HPV test and the overall resource use during that follow‐up.Materials & MethodsWe included all 2926 women aged 60–64 years with nonnegative HPV screening tests between March 2012 and December 2016. All relevant follow‐up tests and procedures were retrieved until the end of 2020 from the highly complete Danish administrative health registers, and the data were linked at the individual level. We determined the extent to which the adherence patterns followed the national recommendations for follow‐up and estimated the total numbers of tests and diagnostic procedures utilized during the entire process.ResultsIn total, only 26% of women had follow‐up in accordance with the recommendations; 4% had no follow‐up, 46% had insufficient follow‐up, and 24% had more follow‐up than recommended. We estimated that 17% of women remained in follow‐up for longer than 4 years. The average numbers of diagnostic tests and procedures used after positive HPV screening were higher than expected, even among women who had insufficient follow‐up, that is, those who received less invasive procedures than recommended, or experienced delays in receiving those procedures.ConclusionTo conclude, we found that the patterns of follow‐up of women with nonnegative primary HPV screening tests at 60–64 often diverged from the recommendations. Addressing these inconsistencies in follow‐up by providing evidence for optimal clinical management should help improve the quality of screening programs and secure an equal and reliable follow‐up care service for all women.

Age‐specific prevalence of human papillomavirus and abnormal cytology at baseline in a diverse statewide prospective cohort of individuals undergoing cervical cancer screening in Mississippi

AbstractBackgroundMississippi (MS) has among the highest rates of cervical cancer incidence and mortality in the United States, with disproportionately higher rates among Blacks compared to Whites. Here, we evaluate the prevalence of high‐risk human papillomavirus (HPV) and abnormal cytology in a representative baseline sample from a diverse statewide cohort of individuals attending cervical screening in MS from the STRIDES Study (STudying Risk to Improve DisparitiES in cervical cancer).MethodsWe included individuals aged 21–65 years undergoing screening at the University of Mississippi Medical Center (UMMC) and the Mississippi State Department of Health (MSDH) from May to November 2018. We calculated age‐specific HPV prevalence, overall and by partial HPV16/18 genotyping, and abnormal cytology by race.ResultsA total of 6871 individuals (mean age 35.7 years) were included. HPV prevalence was 25.6% and higher in Blacks (28.0%) compared to Whites (22.4%). HPV prevalence was significantly higher in Blacks aged 21–24 years (50.2%) and 30–34 years (30.2%) compared to Whites in the same age groups (32.1% and 20.7%; p < 0.0001, respectively). The prevalence of high‐grade cytologic abnormalities, a cytologic sign of cervical precancer, peaked earlier in Blacks (ages 25–29) compared to Whites (35–39). For comparison, we also analyzed HPV prevalence data from the National Health and Nutrition Examination Survey (NHANES, 2013–2016) and observed similar racial differences in HPV prevalence among women aged 21–24 years.ConclusionsOur findings suggest that Blacks undergoing cervical cancer screening in MS have higher prevalence of other high‐risk 12 HPV types at younger ages and experience an earlier peak of high‐grade cytologic abnormalities compared to Whites.

Cervical cancer screening uptake and determinant factors among women in Ambo town, Western Oromia, Ethiopia: Community‐based cross‐sectional study

Abstract Background Cervical cancer is the second most common cancer and the leading cause of cancer‐related death in Ethiopian women. About 77.6% of women died of 6294 new cases reported in 2019. Early screening for cervical cancer has substantially reduced morbidity and mortality attributed to it. In Ethiopia, most of the women visit the health facilities at the late stage of the disease in which the offered intervention is not promising. Therefore, we aimed to assess the level of cervical cancer screening uptake and its determinant among women of Ambo town, Ethiopia. Methods Community‐based cross‐sectional study was conducted among 422 women aged 20–65 years. An interviewer‐administered questionnaire was used to collect the data. Data were analyzed using SPSS version 25. Estimates were presented using an odds ratio (OR) with 95% CI. Statistical significance was declared at a p  value of <0.05. Results In the present study, 392 women were participated giving a response rate of 93%. Only 8.7% (34) of the study participants were received cervical cancer screening in their lifetime. Being in the age group of 30–39 years (AOR = 3.2, 95% CI: 1.22, 8.36), having cervical cancer‐related discussions with a healthcare provider (AOR = 3.5; 95% CI: 1.17, 10.7), and knowing the availability of cervical cancer screening service (AOR = 2.8; 95% CI: 1.03, 7.87) were significantly associated with uptake of cervical cancer screening. Conclusion In this study, cervical cancer screening uptake is very low. Our study identifies clues for determinants of cervical cancer screening uptake. Thus, further studies using a better study design might be helpful to explore determinants of low utilization of CC screening services and suggest an appropriate intervention that increases CC screening uptake in the study area.

Prognostic impact of hepatitis B virus infection in patients with primary cervical cancer

AbstractBackgroundHepatitis B virus (HBV) infection has been associated with an increased risk of a few malignancies. However, the prognostic impact of HBV infection remains unclear in cervical cancer.ObjectiveTo explore the association between HBV infection and survival outcomes of patients with primary cervical cancer, using overall survival (OS) and disease‐free survival (DFS) as primary endpoints.MethodsThis analysis was performed retrospectively with newly diagnosed cervical cancer patients admitted to the Department of Gynecologic Oncology at the Sun Yat‐sen Memorial Hospital of Sun Yat‐sen University from June 2013 to October 2019, who were enrolled and followed up. The Kaplan–Meier method and Cox proportional hazard analysis were used to examine the performance of HBV infection in predicting OS and DFS.ResultsPatients were followed up for a median of 37.17 months (95% CI, 34.69–39.65). Among the 695 patients, 87 (12.5%) were serologically positive for hepatitis B surface antigen (HBsAg), and 276 (39.7%) had a prior history of HBV infection. There was no significant difference between HBsAg‐positive group and HBsAg‐negative patients concerning OS or DFS. Multivariate analysis showed prior HBV infection was an independent favorable prognosticator for OS (HR, 0.335; 95% CI, 0.153–0.0.734; p = 0.006) and DFS (HR, 0.398; 95% CI, 0.208–0.691; p = 0.002).ConclusionWe provide the first clinical evidence that suggests prior HBV infection as an independent favorable prognostic factor for patients with primary cervical cancer.

Cost‐effectiveness analysis of primary human papillomavirus testing in cervical cancer screening: Results from the HPV FOCAL Trial

AbstractThe Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population‐based Cervix Screening Program in British Columbia, Canada. We conducted a cost‐effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high‐grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid‐based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co‐testing at the 48‐month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of ‐$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC‐based testing every 2 years for cervical cancer screening at a lower cost.

Effectiveness of various human papillomavirus vaccination strategies: A community randomized trial in Finland

AbstractIntroductionWe conducted a community‐randomized trial (NCTBLINDED) in Finland to assess gender‐neutral and girls‐only vaccination strategies with the AS04‐adjuvanted human papillomavirus (HPV)‐16/18 (AS04‐HPV‐16/18)vaccine.MethodsGirls and boys (12−15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04‐HPV‐16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04‐HPV‐16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV‐16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04‐HPV‐16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co‐primary objectives were overall effectiveness following gender‐neutral or girls‐only vaccination.ResultsOf 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: −19.0, 51.1; P = 0.232) with gender‐neutral vaccination. Following girls‐only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04‐HPV‐16/18 vaccine was high in both sexes.ConclusionsThis study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

Identification of a novel six‐gene signature with potential prognostic and therapeutic value in cervical cancer

AbstractIntroductionCervical cancer has high mortality, high recurrence and poor prognosis. Although prognostic biomarkers such as clinicopathological features have been proposed, their accuracy and precision are far from satisfactory. Therefore, novel biomarkers are urgently needed for disease surveillance, prognosis prediction and treatment selection.MaterialsDifferentially expressed genes (DEGs) between cervical cancer and normal tissues from three microarray datasets extracted from the Gene Expression Omnibus platform were identified and screened. Based on these DEGs, a six‐gene prognostic signature was constructed using cervical squamous cell carcinoma and endocervical adenocarcinoma data from The Cancer Genome Atlas. Next, the molecular functions and related pathways of the six genes were investigated through gene set enrichment analysis and co‐expression analysis. Additionally, immunophenoscore analysis and the QuartataWeb Server were employed to explore the therapeutic value of the six‐gene signature.ResultsWe discovered 178 overlapping DEGs in three microarray datasets and established a six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) prognostic signature with stable and excellent performance in predicting overall survival in different subgroups. Intriguingly, the six‐gene signature was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature might be used for predicting response to immune checkpoint inhibitors (ICIs) and the six genes may serve as new drug targets for cervical cancer.ConclusionOur study established a novel six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) signature that was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature was indicative of aggressive features of cervical cancer and therefore might serve as a promising biomarker for predicting not only overall survival but also ICI treatment effectiveness. Moreover, three genes (UPP1, ISG20 and GLTP) within the six‐gene signature have the potential to become novel drug targets.

Letter to the Editor Re: A population study of screening history and diagnostic outcomes of women with invasive cervical cancer

Preoperative magnetic resonance imaging criteria for predicting lymph node metastasis in patients with stage IB1‐IIA2 cervical cancer

AbstractObjectiveThis study aimed to identify patients with stage IB1‐IIA2 cervical cancer at low risk for lymph node metastasis (LNM) using preoperative magnetic resonance imaging (MRI) parameters.MethodsClinical and MRI data of patients with stage IB1‐IIA2 cervical cancer who underwent radical surgery between 2010 and 2015 were retrospectively reviewed. Clinical stage IB1‐IIA2 cervical cancer was diagnosed according to the 2009 International Federation of Gynecology and Obstetrics staging system. The low‐risk criteria for LNM were identified using logistic regression analysis. The performance of the logistic regression analysis was estimated through receiver operating characteristic curve analysis.ResultsOf 453 patients, 105 (23.2%) exhibited pathological LNM (p‐LNM). The maximal tumor diameter (adjusted odds ratio [aOR], 1.586; 95% confidence interval [CI], 1.312–1.916; p < 0.001) and LNM (aOR, 2.384; 95% CI, 1.418–4.007; p = 0.001) on preoperative MRI (m‐LNM) were identified as independent risk factors for p‐LNM using a multivariate logistic analysis. The p‐LNM rate was 4.0% for low‐risk patients (n = 124) identified using the current criteria (maximal tumor diameter <3.0 cm and no sign of m‐LNM). The 5‐year disease‐free survival rate of low‐risk patients was significantly greater than the rate of patients with a maximal tumor diameter ˃3.0 cm and/or signs of m‐LNM (90.4% vs. 82.1%; p = 0.033).ConclusionsThe low‐risk criteria for p‐LNM were a maximal tumor diameter <3.0 cm and no sign of m‐LNM. Patients with stage IB1‐IIA2 cervical cancer at low risk for m‐LNM could be candidates for radical surgery; hence, they have a lesser need for adjuvant chemoradiotherapy, thus avoiding the severe comorbidities it causes.

Prognostic significance of poorly differentiated histology and impact of adjuvant chemotherapy in early squamous cell carcinoma of cervix uteri

AbstractObjectiveThis study is to determine whether the addition of cisplatin‐based chemotherapy after radical hysterectomy will improve the survival of low‐risk squamous cervical carcinoma with poor differentiation.MethodsPatients with low‐risk squamous cervical cancer (FIGO IA2–IIA, absent high‐ and intermediate‐risk factors after pathological evaluation) were eligible for this study. As first, the prognostic relevance of G3 versus G1/G2 among patients with low‐risk squamous cervical cancer was analyzed, then, the oncological results of postoperative chemotherapy among low‐risk squamous cervical cancer with poor differentiation was explored.ResultsTotally, there were 367 low‐risk squamous cervical cancer patients, of whom 161 were poor‐differentiated (47 in the chemotherapy group and 114 in the nonchemotherapy group), with a median follow‐up time of 56 months. Patients with G3 displayed a significantly worse overall survival (p = 0.035), and a higher recurrence rate (p = 0.014) than patients with G1/G2. Compared with the nonchemotherapy group, the hazard ratios (95%CI) for recurrence‐free survival in the chemotherapy group was 0.24 (0.06–0.93), (p = 0.038). No difference in overall survival was observed between the chemotherapy group and the nonchemotherapy group.ConclusionsThe addition of cisplatin‐based chemotherapy following surgery significantly improved recurrence‐free survival for low‐risk, poor differentiation, and early stage squamous cervical cancer patients.

The immune landscape during the tumorigenesis of cervical cancer

AbstractObjectiveDeciphering the determinants of the intralesional immune reaction in cervical carcinogenesis may be conducive to improving the understanding of the disease and then improve outcomes.MethodsPublic gene‐expression data and full clinical annotation were searched in Gene Expression Omnibus in the joint analysis of the array‐based four eligible cohorts. The infiltrating estimation was quantified using microenvironment cell populations‐counter algorithm and absolute‐mode CIBERSORT and verified by flow cytometry analysis. An unsupervised classification on immune genes strongly associated with progression, designated by linear mixed‐effects regression. We determined immune response and signaling features of the different developmental stages and immune phenotypes by functional annotation and systematically correlated the expression of immune checkpoints with cell‐infiltrating characteristics.ResultsWe identified the lesion‐intrinsic immunosuppression mechanism was triggered at precancerous stages, such as genome instability and mutation, aerobic glycolysis, activation of proto‐oncogene pathways and so forth. Predominant innate and adoptive cells were increasing from normalcy to cancer (B cell, total T cell, regulatory T cells [Tregs], monocytes, neutrophils, and M2‐like macrophages) together with the decrease of CD4+ T cell and CD8+ T cell through the development of cervical cancer. Immune escape initiated on the expression of immunosuppressive molecules from high‐grade squamous intraepithelial lesions (HSIL) and culminated in squamous cell carcinoma (SCC). Of note, the expression of immune checkpoints was escalated in the immune‐hot and immune‐warm phenotype largely encompassed by HSIL and SCC under the stress of both activated and suppressive immune responses.ConclusionsImmune surveillance is unleashing from low‐grade squamous intraepithelial lesions onwards and immune‐suppression mechanisms are triggered in HSIL. Thorough knowledge of the immune changing pattern during cervical tumorigenesis contributes to finding the potential therapeutic targets to susceptive patients towards immune checkpoints inhibitors.

Diagnostic value of high‐risk human papillomavirus viral load on cervical lesion assessment and ASCUS triage

AbstractThis study aims to evaluate HR‐HPV viral load in the cervical lesion assessment and its diagnostic value on the triage of ASCUS. The three‐step protocol for cervical cancer screening was carried out in 5171 patients from June 2017 to August 2019, and 1620 histopathological results were obtained. The positive rate of HR‐HPV and TCT increased with the aggravation of pathological grades of cervical lesions. The sensitivity and specificity of HR‐HPV (DH3) to detect CIN II+ were 91.91% and 84.46%, respectively. In comparison, the corresponding results of the cytology test were 80.51% and 83.12%. HPV16/18 viral load was positively correlated with the grade of cervical lesions (p < 0.001, r = 0.321). The diagnostic efficiency of AUC by applying HPV16/18 viral load was 0.682 for the diagnosis of CIN II+. The optimal HPV16/18 viral load for predicting CIN II+ was 6.80 RLU/CO (relative light units/cut‐off), with corresponding sensitivity of 48.6%, specificity of 79.7%, and Youden index of 0.283. In the ASCUS population, viral loads were statistically different in HPV16/18 and the other 12 HR‐HPV when compared cervicitis group with CIN I group and CIN II+ group (all p < 0.05). Statistical differences were detected concerning HPV16/18 viral load, contact bleeding status, and smoking status when compared cervicitis group with CIN I group and CIN II+ group (p < 0.05), with a corresponding odds ratio of 1.004, 1.533, and 5.513, respectively. Our findings suggest that HR‐HPV viral load can be regarded as a useful tool to predict the grade of cervical lesions for ASCUS triage.ClinicalTrials.gov ID: NCT03178136.

Consistency of the S5 DNA methylation classifier in formalin‐fixed biopsies versus corresponding exfoliated cells for the detection of pre‐cancerous cervical lesions

AbstractMethylation biomarkers are promising tools for diagnosis and disease prevention. The S5 classifier is aimed at the prevention of cervical cancer by the early detection of cervical intraepithelial neoplasia (CIN). S5 is based on pyrosequencing a promoter region of EPB41L3 and five late regions of HPV types 16, 18, 31, and 33 following bisulfite conversion of DNA. Good biomarkers should perform well in a variety of sample types such as exfoliated cells, fresh frozen or formalin‐fixed paraffin‐embedded (FFPE) materials. Here, we tested the performance of S5 on 315 FFPE biopsies with paired exfoliated cervical samples using four different conversion kits (Epitect Bisulfite, Epitect Fast Bisulfite, EZ DNA Methylation, and EZ DNA Methylation‐Lightning). The S5 values from FFPE biopsies for all kits were significantly correlated with those obtained from their paired exfoliated cells. For the EZ DNA Methylation kit, we observed an average increased methylation of 4.4% in FFPE. This was due to incomplete conversion of DNA (73% for FFPE vs. 95% for cells). The other kits had a DNA conversion rate in FFPE similar to the cells (95%–97%). S5 performed well at discriminating <CIN2 lesions from CIN2+ lesions on the FFPE with all kits given optimized adjustments to the cut‐off. The area under the curve (AUC) for S5 on FFPE was not significantly different from the paired cells (0.74–0.79 vs. 0.81). The best sensitivity and specificity were obtained for EZ DNA Methylation after the adjustment of the cut‐off to reflect its lower conversion rate. Consistent methylation results can be obtained from FFPE material regardless of the conversion kit used. The S5 classifier performed as well on FFPE material as on exfoliated cells with adjusted cut‐off allowing easier clinical implementation.

The accuracy of HPV genotyping in isolation and in combination with CD4 and HIV viral load for the identification of HIV‐infected women at risk for developing cervical cancer

AbstractBackgroundHuman papillomavirus (HPV) genotype testing has limited utility to identify human immunodeficiency virus‐infected (HIV+) women's risk for developing cervical cancer (CC) due to high positivity rate of high‐risk (HR) HPVs. We investigated the accuracy of HPV testing in isolation/in combination with CD4 and HIV viral load (VL) to identify HIV+ women at risk for developing CC.MethodsStudy consisted of 344 HIV+ women on combination antiretroviral therapy (cART), tested for cervical cytology/HPV using the Cobas test and had data on absolute CD4 count and VL measurements. We calculated the positive predictive value (PPV) and negative predictive value (NPV) of HPV testing, pre‐, post‐cART, and current CD4 and VL in isolation and in combinations to identify those with or free of higher than atypical squamous cells of unknown significance (ASCUS+) or low‐grade intraepithelial lesions (LSIL+).ResultsHPV test in combination with pre‐/post‐cART or current CD4 counts and VL had higher PPVs compared to HPV test alone for identifying ASCUS+ or LSIL+. PPV of HPV‐CD4 combinations yielded higher PPVs compared to HPV‐VL combinations. The NPVs with pre‐, post‐cART, or current CD4 count and VL in isolation or in combinations were comparable to that of HPV test alone.ConclusionsOur results provide a more accurate tool for managing HIV+ women by combining Cobas HPV with CD4 and VL, especially those who had an undesirable pre‐cART CD4 and VL status. Our results also indicate the usefulness of CD4 and VL measurements to identify those at lower risk in the absence of HPV testing.

Polymorphic variants INSIG2 rs6726538, HLA‐DRB1 rs9272143, and GCNT1P5 rs7780883 contribute to the susceptibility of cervical cancer in the Bangladeshi women

AbstractObjectiveCervical cancer is a gynecological health problem, affecting nearly 500,000 women each year worldwide. Genome‐wide association studies have revealed multiple susceptible genes and their polymorphisms for cervical carcinoma risk. We have carried out this case‐control study to investigate the association of INSIG2 rs6726538 (A; T), HLA‐DRB1 rs9272143 (T; C), and GCNT1P5 rs7780883 (G; A) with cervical cancer.MethodsThe present study recruited 234 cervical cancer patients as cases and 212 healthy females as controls. We have applied the tetra‐primer amplification refractory mutation system polymerase chain reaction (T‐ARMS‐PCR) method for genotyping.ResultsThe SNP rs6726538 was significantly associated with increased risk of cervical cancer in all genetic models (AT vs. AA: OR = 3.30, 95% CI = 2.19–4.97, p < 0.0001; TT vs. AA: OR = 8.72, 95% CI = 3.87–19.7, p < 0.0001; AT+TT vs. AA: OR = 3.87, 95% CI = 2.61–5.73, p < 0.0001; T vs. A: OR = 2.97, 95% CI = 2.20–4.01, p < 0.0001) except the recessive model which showed a significantly reduced risk (TT vs. AA+AT: OR = 0.20, 95% CI = 0.09–0.44, p = 0.0001). rs9272143 showed significantly reduced risk for the additive model 1, dominant model, and allelic model (TC vs. TT: OR = 0.46, 95% CI = 0.31–0.70, p = 0.0004; TC+CC vs. TT: OR = 0.47 95% CI = 0.32–0.70, p = 0.0002; C vs. T: OR = 0.56, 95% CI = 0.40–0.78, p = 0.0006, respectively). The third variant, rs7780883, was significantly associated with increased risk in additive model 2, dominant, and allelic models (AA vs. GG: OR = 5.08, 95% CI = 2.45–10.5, p < 0.0001; GA+AA vs. GG: OR = 1.54, 95% CI = 1.06–2.24, p = 0.0237; A vs. G: OR = 1.88, 95% CI = 1.34–2.52, p < 0.0001, consecutively), whereas recessive model reduced the risk of cervical cancer (AA vs. GG+GA: OR = 0.20, 95% CI = 0.09–0.41, p < 0.0001). Other models of these SNPs were not associated with cervical cancer. All significant associations for three SNPs withstand after Bonferroni correction except the additive model 2 of rs7780883.ConclusionOur study concludes that INSIG2 rs6726538, HLA‐DRB1 rs9272143, and GCNT1P5 rs7780883 polymorphisms may contribute to the development of cervical cancer in the Bangladeshi population.

Novel prognostic nomograms in cervical cancer based on analysis of 1075 patients

AbstractObjectiveTo explore the factors affecting the prognosis of cervical cancer (CC), and to construct and evaluate predictive nomograms to guide individualized clinical treatment.MethodsThe clinicopathological and follow‐up data of CC patients from June 2013 to December 2019 in Sun Yat‐sen Memorial Hospital of Sun Yat‐sen University were retrospectively analyzed. Log‐rank test was used for univariate survival analysis, and Cox multivariate regression was used to identify independent prognostic factors, based on which nomogram models were established and evaluated in multiple aspects.ResultsPatients were randomly assigned into the training (n = 746) and validation sets (n = 329). Survival analysis of the training set identified cervical myometrial invasion, parametrial involvement, and malignant tumor history as prognosticators of postoperative DFS and pathological type, cervical myometrial invasion, and history of STD for OS. C‐index was 0.799 and 0.839 for the nomograms for DFS and OS, respectively. Calibration curves and Brier scores also indicated high performance. Importantly, decision curve analysis suggested great clinical applicability of these nomograms.ConclusionsIn this study, we analyzed a cohort of 1075 CC patients and identified DFS‐ or OS‐associated clinicohistologic characteristics. Two nomograms were subsequently constructed for DFS and OS prognostication, respectively, and showed high performance in terms of discrimination, calibration, and clinical applicability. These models may facilitate individualized treatment and patient selection for clinical trials. Future investigations with larger cohorts and prospective designs are warranted for validating these prognostic models.

hsa‐mir‐133a‐2 promotes the proliferation and invasion of cervical cancer cells by targeting the LAMB3‐mediated PI3K/ATK pathway

AbstractObjectiveCervical cancer, one of the common types of malignant tumors progressed in women, is on the rise in developing countries. Numerous previous studies have demonstrated that hsa‐mir‐133a‐2 miRNA is abnormally expressed in cervical cancer cells. However, its fundamental mechanism in cervical cancer needs to be further clarified. Our study set out to investigate the effect of hsa‐mir‐133a‐2 on the phenotypes of cervical cancer cells as well as any potential molecular processes involved in the proliferation and invasion of cervical cancer cells.MethodsThe Cancer Genome Atlas‐cervical squamous cell carcinoma and endocervical adenocarcinoma(TCGA‐CESC) was adopted in order to verify the expression of hsa‐mir‐133a‐2 in cervical cancer tissues and to identify its potential targets. The interaction between Laminin subunit beta‐3(LAMB3) and hsa‐mir‐133a‐2 was verified by TargetScan database as well as Luciferase reporter assay. The Cell Counting Kit‐8 (CCK8) and transwell methods were utilized to assess the influence of hsa‐mir‐133a‐2 on the proliferation and invasion characteristics of cervical cancer cells. We studied the role that hsa‐mir‐133a‐2 plays in cervical cancer progression through Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis as well as Western Blot (WB) experiment.ResultsDown‐regulation of hsa‐mir‐133a‐2 was detected in cervical cancer tissues. It directly targeted LAMB3 and negatively regulated LAMB3 expression. The overexpression of hsa‐mir‐133a‐2 has a significant inhibiting effect on cervical cancer cell proliferation and invasion. The overexpression of hsa‐mir‐133a‐2 significantly inhibits the proliferation and invasion of cervical cancer cells. Moreover, the LAMB3 was able to up‐regulate the phosphorylation levels of AKT and phosphatidylinositol 3‐kinase (PI3K) protein in cervical cancer cells. hsa‐mir‐133a‐2 could also modulate the PI3K/AKT signaling pathway by targeting LAMB3.Conclusionhsa‐mir‐133a‐2 inhibits cervical cancer cell proliferation and invasion by indirectly regulating the PI3K/AKT signaling pathway, providing us with a new clinical treatment strategy for cervical cancer.

Adherence to Guideline‐Recommended cancer screening among Utah cancer survivors

AbstractBackgroundAdherence to cancer screening is important for cancer survivors because they are at high risk of subsequent cancer diagnoses or recurrence. We assessed adherence to breast, cervical, and colorectal cancer‐(CRC)‐screening guidelines and evaluated demographic disparities among a population‐based sample of survivors.MethodsA representative sample of Utah survivors diagnosed from 2012–2018 with any reportable invasive cancer was selected from central cancer registry records for a survey about survivorship needs. We estimated the proportion of eligible survivors adhering to U.S. Preventive Services Task Force screening guidelines and calculated risk ratios and 95% confidence intervals. Analyses were age‐adjusted and weighted to account for sample design and nonresponse.ResultsAnd 1421 survivors completed the survey (57.2% response rate). Screening adherence was 74.4% for breast, 69.4% for cervical, and 79.7% for CRC. Rural residents were more likely to adhere to breast cancer screening than urban residents (86.1% vs. 72.7%; adjusted RR = 1.19, CI = 1.05, 1.36). Higher educational attainment was associated with increased adherence to cervical and colorectal cancer screening. Younger age was associated with greater adherence to cervical cancer screening (p = 0.006) but lower adherence to CRC screening (p = 0.003). CRC screening adherence was lower among the uninsured and those without a primary care provider (45.6%) compared to those with a regular provider (83.0%; adjusted RR = 0.57, CI = 0.42, 0.79).ConclusionsSurveys based on samples from central cancer registries can provide population estimates to inform cancer control. Findings demonstrate work is needed to ensure all Utah cancer survivors obtain recommended cancer screenings. Efforts should focus particularly on increasing uptake of breast and cervical cancer screening and reducing demographic disparities in CRC screening.PrecisDespite high risk for subsequent cancer diagnosis, Utah cancer survivors are not all obtaining recommended breast, cervical, and colorectal cancer screenings. This presents a significant healthcare gap.

The pathological risk score: A new deep learning‐based signature for predicting survival in cervical cancer

AbstractPurposeTo develop and validate a deep learning‐based pathological risk score (RS) with an aim of predicting patients' prognosis to investigate the potential association between the information within the whole slide image (WSI) and cervical cancer prognosis.MethodsA total of 251 patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IA1–IIA2 cervical cancer who underwent surgery without any preoperative treatment were enrolled in this study. Both the clinical characteristics and WSI of each patient were collected. To construct a prognosis‐associate RS, high‐dimensional pathological features were extracted using a convolutional neural network with an autoencoder. With the score threshold selected by X‐tile, Kaplan–Meier survival analysis was applied to verify the prediction performance of RS in overall survival (OS) and disease‐free survival (DFS) in both the training and testing datasets, as well as different clinical subgroups.ResultsFor the OS and DFS prediction in the testing cohort, RS showed a Harrell's concordance index of higher than 0.700, while the areas under the curve (AUC) achieved up to 0.800 in the same cohort. Furthermore, Kaplan–Meier survival analysis demonstrated that RS was a potential prognostic factor, even in different datasets or subgroups. It could further distinguish the survival differences after clinicopathological risk stratification.ConclusionIn the present study, we developed an effective signature in cervical cancer for prognosis prediction and patients' stratification in OS and DFS.

Artificial intelligence assisted cytological detection for early esophageal squamous epithelial lesions by using low‐grade squamous intraepithelial lesion as diagnostic threshold

AbstractBackgroundManual cytological diagnosis for early esophageal squamous cell carcinoma (early ESCC) and high‐grade intraepithelial neoplasia (HGIN) is unsatisfactory. Herein, we have introduced an artificial intelligence (AI)‐assisted cytological diagnosis for such lesions.MethodsLow‐grade squamous intraepithelial lesion or worse was set as the diagnostic threshold for AI‐assisted diagnosis. The performance of AI‐assisted diagnosis was evaluated and compared to that of manual diagnosis. Feasibility in large‐scale screening was also assessed.ResultsAI‐assisted diagnosis for abnormal cells was superior to manual reading by presenting a higher efficiency for each slide (50.9 ± 0.8 s vs 236.8 ± 3.9 s, p = 1.52 × 10−76) and a better interobserver agreement (93.27% [95% CI, 92.76%–93.74%] vs 65.29% [95% CI, 64.35%–66.22%], p = 1.03 × 10−84). AI‐assisted detection showed a higher diagnostic accuracy (96.89% [92.38%–98.57%] vs 72.54% [65.85%–78.35%], p = 1.42 × 10−14), sensitivity (99.35% [95.92%–99.97%] vs 68.39% [60.36%–75.48%], p = 7.11 × 10−15), and negative predictive value (NPV) (97.06% [82.95%–99.85%] vs 40.96% [30.46%–52.31%], p = 1.42 × 10−14). Specificity and positive predictive value (PPV) were not significantly differed. AI‐assisted diagnosis demonstrated a smaller proportion of participants of interest (3.73%, [79/2117] vs.12.84% [272/2117], p = 1.59 × 10−58), a higher consistence between cytology and endoscopy (40.51% [32/79] vs. 12.13% [33/272], p = 1.54 × 10−8), specificity (97.74% [96.98%–98.32%] vs 88.52% [87.05%–89.84%], p = 3.19 × 10−58), and PPV (40.51% [29.79%–52.15%] vs 12.13% [8.61%–16.75%], p = 1.54 × 10−8) in community‐based screening. Sensitivity and NPV were not significantly differed. AI‐assisted diagnosis as primary screening significantly reduced average cost for detecting positive cases.ConclusionOur study provides a novel cytological method for detecting and screening early ESCC and HGIN.

Comparison of recurrence patterns in cervical cancer patients with positive lymph nodes versus negative

AbstractPurposeThe aim of this study was to compare patterns of recurrence in 2009 FIGO Stage IB‐IIA (T1bN0M0‐T2aN0M0) cervical cancer patients with cN0 and cN1.MethodsThe epidemiological and clinical data of 1352 patients who had undergone radical hysterectomy and systematic lymphadenectomy with cervical cancer treated from January 2008 to April 2019 at a tertiary teaching hospital were retrospectively collected. The primary aim was to discover the lymph node status‐dependent patterns and time of recurrence.ResultsTumor recurrence and death were significantly less common in patients with cN0 than cN1. In addition, the length of time to recurrence (median 60 months cN0 vs. 43 months cN1, p < 0.001) and death (median 84 months cN0 vs. 68 months cN1 p < 0.001) were significantly longer in cN0 versus cN1 patients. The cumulative rate of relapse also showed a significant difference between cN0 and cN1 groups, especially the 1‐year relapse rate (2.14% vs. 10.78%). Of the patients who recurred, there was no difference in number of recurrent sites between cN0 and cN1 groups (solitary metastases:35.8% of cN0 and 35.6% of cN1; multiple metastases: 64.2% of cN0 and 64.4% of cN1). Similarly, there was no statistical difference in recurrence sites of cervical cancer between cN0 and cN1 groups based on three categories, (p = 0.646). However, in the six categories, patients' vaginal vaults with negative lymph nodes were more prone to recurrence, while the distribution of other recurrence sites showed no significant difference between the two groups.ConclusionsThere is a significant improvement of relapse‐free survival in the cN0 group, and the recurrence time of cN0 patients is significantly delayed than cN1 group. However, except for the risk of metastasis of the vaginal vault, the site of relapse remains similar.

Age‐specific prevalence and genotype distribution of human papillomavirus in women from Northwest China

AbstractBackgroundHuman papillomavirus (HPV) is the leading cause of cervical cancer with more than 200 genotypes. Different genotypes have different potentials in causing premalignant lesions and cervical cancers. In this study, we investigated the age‐specific prevalence and genotype distribution of HPV genotypes in Northwest China.Materials and MethodsWe recruited 145,918 unvaccinated women from Northwest China for population‐based HPV DNA screening test during June 2015 to December 2020. And a lab‐based test was performed for each volunteer by flow fluorescent technology to identify the genotypes of HPV.ResultsThe overall infection rate of HPV was 22.97%. With the participants divided into 12 groups according to age, a bimodal curve of infection rate was obtained. And the two peaks appeared in the younger than 20 group and 61–65 group, respectively. The five most common HPV genotypes included HPV 16, 58, 52, 53 and 61 in all participants, which were in descending order of frequency. Among women younger than 25 years old, HPV 6 and 11 were more common and even higher than some genotypes mentioned above. Among women older than 65 years old, HPV 18 and 66 were more common than or as high as the six most common genotypes in all populations. Additionally, the distribution of single and multiple infections in each age group was also different.ConclusionThe baseline prevalence and genotype distribution of HPV in Northwest China was uncovered for the first time. Age was related to the epidemiology of different HPV genotypes. All the results would be of great significance for future healthcare services.

The exon 12‐containing LHX6 isoforms promote cervical cancer cell proliferation by regulating the MAPK signaling pathway

AbstractLIM homeobox 6 (LHX6) has been reported to be downregulated and inhibits cell proliferation in various cancers. Alternative splicing of LHX6 leads to six annotated isoforms, which can be found in the NCBI database. However, the expression patterns and potential roles of these isoforms remain poorly characterized in cervical cancer. Here, we demonstrated that the LHX6 isoforms containing exon 12 (LHX6EX(+12) group) and isoforms lacking exon 12 (LHX6EX(–12) group) were differentially expressed in cervical tissue by qRT‐PCR. The mRNA expression level of LHX6EX(+12) group was higher than that of LHX6EX(−12) group in cervical cancer tissue. Knockdown of LHX6EX(+12) group and all LHX6 isoforms (LHX6All group) inhibited cell growth, increased cell apoptosis, and induced cell cycle arrest from G0/G1 phase to S phase in vitro. Consistently, overexpression of the LHX6EX(+12) group promoted cervical cancer cell proliferation in vitro. In contrast, no significant differences in cell proliferation were found between LHX6EX(−12) isoform knockdown group and its control. RNA‐sequencing suggested that the LHX6EX(+12) isoform group might exert its cancer‐promoting effects in cervical cancer via regulating MAPK signaling pathway. Downregulation of the LHX6EX(+12) group significantly suppressed the phosphorylation of MRK, ERK, JNK, and P38 at the protein level. We also identified some unique biological processes and signaling pathways in which each isoform group might be involved. In summary, our results indicated that LHX6EX(+12) isoform group was the dominant oncogenic type of LHX6 in cervical cancer, which may be a new biomarker and a potential precise therapeutic target for cervical cancer in the future.

Secondary cancers after carbon‐ion radiotherapy and photon beam radiotherapy for uterine cervical cancer: A comparative study

AbstractBackgroundThere are limited studies on the risk of secondary cancers after carbon‐ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period.MethodsThis retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated.ResultsThe analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person‐years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6–2.1) in the CIRT group and 1.4 (95% CI, 1.0–2.1) in the photon RT group. The 10‐year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0–21.5) in the CIRT group and 9.4% (95% CI, 6.2–14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268).ConclusionsThe incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long‐term observation is warranted.

Depression before and after diagnostic procedures among women with abnormal finding of Papanicolaou screening test

AbstractBackgroundSome studies did find significant differences in the level of depression of women while undergoing diagnostic evaluation of an abnormal Papanicolaou screening smear, but findings were not consistent. This study aimed to assess prevalence and correlates of depression in women with abnormal cervical screening results before and after diagnostic procedures.MethodsA cross‐sectional study was carried out during 2017 in a cohort of women with positive Papanicolaou screening test before and after diagnostic procedures (colposcopy/biopsy/endocervical curettage) at the university Clinical Centre Kragujevac, Serbia. Women completed a questionnaire about demographics, lifestyle, and other factors of interest. Also, questionnaire “Hospital Anxiety and Depression Scale” (HADS) was used immediately before and 2–4 weeks after the diagnostic procedures: a score of ≥8 on HADS‐D and HADS‐A subscales indicated depression and anxiety, respectively. Multivariate logistic regression was applied in the data analysis.ResultsThe study comprised 172 women, giving a response rate of 72.3%. The mean age of the participants was 47.8 ± 11.1 years (range 23–65). The frequency of depressive symptoms was significantly higher after diagnostic procedures (48.3%) than before diagnostic procedures (37.2%) (p = 0.038). Before diagnostic procedures, older age (OR = 1.60; 95% CI = 1.09–2.34; p = 0.017), and level of anxiety according to the HADS‐A subscale (OR = 1.61; 95% CI = 1.38–1.88; p < 0.001) were significant independent predictors of depression. After diagnostic procedures, significant independent predictors of depression were urban place of residence (OR = 0.12; 95% CI = 0.03–0.47; p = 0.002) and level of anxiety according to the HADS‐A subscale (OR = 1.85; 95% CI = 1.54–2.21; p < 0.001).ConclusionOur study showed that older age, rural residence, and anxiety play a role in shaping the risk of depression among women undergoing additional diagnostic procedures after receiving an abnormal Papanicolaou screening result.

COVID‐19 and inequities in colorectal and cervical cancer screening and diagnosis in Washington State

AbstractIntroductionStudies have shown that cancer screenings dropped dramatically following the onset of the coronavirus diseases 2019 (COVID‐19) pandemic. In this study, we examined differences in rates of cervical and colorectal cancer (CRC) screening and diagnosis indicators before and during the first year of the COVID‐19 pandemic.MethodologyWe used retrospective data from a large healthcare system in Washington State. Targeted screening data included completed cancer screenings for both CRC (colonoscopy) and cervical cancer (Papanicolaou test (Pap test)). We analyzed and compared the rate of uptake of colorectal (colonoscopies) and cervical cancer (Pap) screenings done pre‐COVID‐19 (April 1, 2019–March 31, 2020) and during the pandemic (April 1, 2020–March 31, 2021).ResultsA total of 26,081 (12.7%) patients underwent colonoscopies in the pre‐COVID‐19 period, compared to only 15,708 (7.4%) patients during the pandemic, showing a 39.8% decrease. A total of 238 patients were referred to medical oncology for CRC compared to only 155 patients during the first year of the pandemic, a reduction of 34%. In the pre‐COVID‐19 period, 22,395 (10.7%) women were administered PAP tests compared to 20,455 (9.6%) women during the pandemic, for a 7.4% reduction. period 1780 women were referred to colposcopy, compared to only 1680 patients during the pandemic, for a 4.3% reduction.ConclusionInterruption in screening and subsequent delay in diagnosis during the pandemic will likely lead to later‐stage diagnoses for both CRC and cervical cancer, which is known to result in decreased survival.ImpactThe results emphasize the need to prioritize cancer screening, particularly for those at higher risk.

Effect of modified no‐touch laparoscopic radical hysterectomy on outcomes of early stage cervical cancer: A retrospective cohort study

AbstractObjectivesWe aimed to compare the prognosis of modified no‐touch laparoscopic radical hysterectomy (MLRH) and laparoscopic radical hysterectomy (LRH) on survival in patients with early stage cervical cancer.Materials and MethodsThe clinicopathological data of patients with stage IB1 and IIA1 cervical cancer, who underwent radical surgery between 2014 and 2019, were retrospectively reviewed. The 5‐year disease‐free survival (DFS) and overall survival (OS) were compared between the MLRH and LRH groups using the Kaplan–Meier method. Independent prognostic factors for 5‐year DFS and OS were identified using multivariate, forward, stepwise Cox proportional hazards regression models.ResultsA total of 223 patients with stage IB1 and IIA1 cervical cancer were included. Kaplan–Meier analysis revealed that the 5‐year DFS and OS rates in the MLRH (n = 81) group were significantly higher than those in the LRH group (n = 142) (DFS, 94.5% vs. 78.8%, p = 0.007; OS, 96.7% vs. 87.6%, p = 0.033). No significant differences were identified between the two groups in terms of operative time, blood loss, transfusion requirement, and intraoperative or postoperative complications. MLRH was an independent prognostic factor associated with increased 5‐year DFS (adjusted hazard ratio [HR], 0.202; 95% confidence interval [CI], 0.069–0.594; p = 0.004) and 5‐year OS (adjusted HR, 0.163; 95% CI, 0.035–0.748; p = 0.020).ConclusionThe oncologic outcomes were superior with MLRH than with LRH in patients with stage IB1 and IIA1 cervical cancer. Contact of cervical tumor cells with the pelvic cavity likely explains the worse prognosis associated with LRH.

The Efficacy and Safety of Folate Receptor α‐Targeted Antibody‐Drug Conjugate Therapy in Patients With High‐Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers: A Systematic Review and Meta‐Analysis

ABSTRACT Background Antibody‐drug conjugates (ADC) have emerged as a highly promising systemic option in the treatment of recurrent ovarian cancer. The present study aimed to evaluate the treatment efficacy of folate receptor α (FRα)‐targeting ADCs, associated treatment‐related adverse events (TRAEs), and their impact on treatment safety. Methods We conducted an electronic search to identify prospective trials of single‐agent ADCs targeting FRα and those combined with chemotherapy in recurrent ovarian cancer. Information regarding the objective response rate (ORR) and TRAEs was collectively analyzed, and differences in subgroups based on FRα receptor expression levels were investigated. The protocol was registered with PROSPERO (CRD42023491151). Results Ten studies with a total of 940 patients (859 treated with Mirvetuximab soravtansine‐gynx (MIRV)), 45 with Farletuzumab Ecteribulin (MORAb‐202), and 36 with Luveltamab Tazevibulin (STRO‐002) were included in this meta‐analysis. Based on the pooled data, the ORR of the entire cohort was 37% (95% CI: 0.30–0.43), while that of the high‐FRα expression group was 34% (95% CI: 0.26–0.42). The incidence of grade ≥ 3 adverse events was 27% (95% CI: 0.19–0.36). Conclusion FRα‐targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second‐line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

Nocardia rubra cell‐wall skeleton influences the development of cervical carcinoma by promoting the antitumor effect of macrophages and dendritic cells

AbstractBackgroundAs an immune enhancer, Nocardia rubra cell‐wall skeleton (Nr‐CWS) has been used to treat persistent human papillomavirus infection and cervical precancerous lesions. However, it is still unclear whether it can be used to treat cervical carcinoma.MethodsIn our study, the aim was to determine whether Nr‐CWS affects the apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages in vivo and in vitro.ResultsThe experimental results showed that Nr‐CWS can promote the activity of dendritic cells and macrophages and reduce their apoptosis. It also increased the cytokines IL‐6, IL‐12, TNF‐ɑ, and IL‐1β secreted by dendritic cells and macrophages and reduced their PD‐L1 expression. In vitro, Nr‐CWS inhibited the proliferation, colony forming ability of HeLa and SiHa cervical carcinoma cell lines cultured with macrophages, and more cells were blocked in G2/M phase. Nr‐CWS promoted TNF‐ɑ/TNFR1/caspase‐8‐mediated apoptosis by increasing macrophages secretion of TNF‐ɑ and inhibited cell migration and invasion regulated by the WNT/β‐catenin‐EMT pathway. Nr‐CWS also reduced the expression of the cervical carcinoma genes E6 and E7 thereby increasing expression of p53 gene and decreasing expression of PD‐L1 gene. In vivo, Nr‐CWS inhibited tumor growth and decreased the expression of E6, E7, PD‐L1, P16, Ki67, and PCNA in tumors.ConclusionsTherefore, our results suggest that Nr‐CWS can promote apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages.

The distribution and pathogenic risk of non‐9‐valent vaccine covered HPV subtypes in cervical lesions

AbstractHuman papillomavirus (HPV) infection is the main cause of female precancerous lesions and cervical cancer. The development and application of HPV prophylactic vaccines have been recognized as a major effective intervention for the control of cervical lesions. However, the infection rate and clinical characters of non‐9‐valent vaccine covered HPV subtypes are still worth studying. In this retrospective study, we included patients diagnosed and treated in the Department of Gynecology of Shanghai General Hospital between January 2017 and February 2021. The clinical features of non‐9‐valent vaccine covered HPV subtypes were explored in 2179 patients who have normal results, 338 patients with cervical intraepithelial neoplasia 1 (CIN1), and 153 patients with ≥CIN2. Univariate analysis showed that compared to the normal cervix group, age ≥50, pregnancy ≥5, delivery ≥3, menopause, no condom use, and cervical transformation zone type III were risk factors for CIN1 or ≥CIN2 (p < 0.05). Thirty‐one percent of CIN1 and 26% of ≥CIN2 were attributed to HPV51, HPV53, HPV56, and HPV68. Multivariate analysis revealed that HPV53, HPV81, age, menopause, cervical transformation area and involved glands were independent risk factors for ≥CIN2 group compared to the CIN1 group (p < 0.05). Additionally, among the 14 non‐9‐valent vaccine covered HPV subtypes, the infection rates of HPV53, 56, 51, and 68 were higher in this study. In conclusion, our study demonstrated the distribution and pathogenic risk of non‐9‐valent vaccine covered HPV subtypes in cervical lesions. These findings might supply a foundation for optimizing cervical cancer prevention in the post‐vaccine era.

A Retrospective Study on the Clinicopathological Characteristics and Prognostic Analysis of Gynecologic Neuroendocrine Carcinoma

ABSTRACT Background Gynecologic neuroendocrine carcinomas (NECs) are rare, highly aggressive malignancies with early metastatic potential and limited evidence to guide optimal management across different primary sites. Aims To characterize the clinicopathological features, treatment patterns, survival outcomes, and prognostic factors of gynecologic NECs (cervix, endometrium, and ovary) treated at a single tertiary center over a 10‐year period. Materials and Methods This observational, single‐center retrospective cohort study included patients diagnosed with gynecologic NEC at Women's Hospital, Zhejiang University School of Medicine, between January 2013 and August 2023. Clinicopathological data, treatment modalities, recurrence, and follow‐up outcomes were collected. Progression‐free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods. Prognostic factors were assessed using log‐rank tests and multivariable Cox proportional hazards models. Results A total of 52 patients were identified, of whom 78.8% had cervical NEC. Primary surgery was performed in 90.4% of patients; adjuvant chemotherapy and radiotherapy were administered in 65.4% and 51.9%, respectively. Among cervical NEC cases with HPV testing, 69.7% were HPV16/18‐positive. Immunohistochemical (IHC) showed high positivity for synaptophysin (95.3%) and chromogranin A (72.7%); Ki‐67 exceeded 50% in 89.1% of evaluated cases. Median PFS for cervical NEC was 29 months; stage I cervical NEC showed a 5‐year PFS of 51.6% and 5‐year OS of 68.4%. Poorer prognosis was associated with FIGO stage ≥ IB3, mixed neuroendocrine‐non‐neuroendocrine neoplasm (MiNEN) with squamous cell carcinoma, tumor size > 4 cm, and lymph node metastasis. On multivariable analysis of cervical NEC, MiNEN with squamous cell carcinoma remained an independent predictor of reduced PFS (HR = 6.97, 95% CI: 1.60–30.31; p  = 0.010). Discussion Despite multimodal treatment, gynecologic NECs showed poor outcomes. The identification of MiNEN with squamous cell carcinoma as an independent adverse factor for PFS suggests histologic composition may meaningfully affect prognosis and warrants validation in larger, multicenter cohorts. Conclusion Cervical NEC was the predominant subtype, most patients underwent surgery with adjuvant therapy, and survival was strongly stage‐dependent. MiNEN with squamous cell carcinoma independently predicted worse PFS, highlighting a potential high‐risk subgroup and reinforcing the need for multicenter prospective studies and more effective, potentially targeted treatment approaches for gynecologic NECs.

Chemotherapy‐Induced Myelosuppression in Patients With gBRCA ‐m Epithelial Ovarian Cancer: A Retrospective Study

ABSTRACT Background Existing evidence indicates that germline BRCA mutation (gBRCA‐m) may increase chemotherapy sensitivity and toxicity. However, its role in chemotherapy‐induced myelosuppression (CIM) remains unclear. We conducted this study to investigate the influence of gBRCA‐m on CIM incidence and severity in patients with epithelial ovarian carcinoma (EOC). Methods Patients with EOC treated at the First Affiliated Hospital of Nanjing Medical University from January 2018 to August 2023 were classified into two groups: gBRCA‐m and gBRCA wild‐type. Chemotherapy regimen and myelosuppression data were retrospectively reviewed. Multivariate analysis assessed the association between gBRCA‐m and CIM incidence and severity in patients with EOC receiving first‐line chemotherapy. Results Sixty six (27%) of 242 included patients were gBRCA‐m carriers. The median times to myelosuppression onset and the most severe occurrence were significantly shorter for patients with gBRCA‐m (6.0 vs. 27.0 days, p  < 0.001; 73.5 vs. 121.0 days, p  < 0.001). Patients with gBRCA‐m had a greater likelihood of Grade IV (GIV) myelosuppression at onset (aOR = 5.585, 95% CI = 1.621–19.241). During the most severe myelosuppression, patients with gBRCA‐m experienced more pronounced decreases in white blood cells (1.83 × 10 9 vs. 2.33*10 9  cells/L, p  = 0.002), neutrophils (0.73 × 10 9 vs. 1.08 × 10 9  cells/L, p  = 0.001), haemoglobin levels (90.41 vs. 94.14 g/L, p  = 0.017) and platelets (81.62 × 10 9 vs. 97.63 × 10 9  cells/L, p  = 0.001) and were more prone to febrile GIV myelosuppression (aOR = 2.882, 95% CI = 1.071–7.754). The incidences of chemotherapy dose reduction (aOR = 4.322, 95% CI = 2.048–9.124) and delay (aOR = 6.045, 95% CI = 2.266–16.126) were significantly greater in patients with gBRCA‐m. An analysis across all chemotherapy cycles indicated that patients with gBRCA‐m had greater risks of GIII (aOR = 2.356, 95% CI = 1.770–3.137), GIV (aOR = 2.324, 95% CI = 1.685–3.207) myelosuppression and GIV myelosuppression with fever (aOR = 2.097, 95% CI = 1.077–4.083), as well as a greater incidence of chemotherapy dose reduction (aOR = 2.606, 95% CI = 1.785–3.805) and delay (aOR = 4.118, 95% CI = 2.213–7.663). Conclusions EOC patients with gBRCA‐m experienced earlier and more severe CIM, highlighting the need for careful monitoring and tailored management.

Targeting Autophagy in Ovarian Cancer: The Emerging Role of Ginsenosides

ABSTRACT Background Ovarian cancer, the third most prevalent gynecological malignancy, is frequently diagnosed at an advanced stage owing to its asymptomatic early progression. Despite the application of conventional therapies, clinical management remains limited by adverse effects and the development of drug resistance. Therefore, the identification of novel therapeutic targets and strategies is urgently needed. Autophagy, a tightly regulated cellular degradation process, plays a dual and context‐dependent role in cancer progression and chemoresistance and has emerged as a promising therapeutic target in ovarian cancer. Ginsenosides, the major bioactive constituents of ginseng, exhibit significant anticancer activity in a variety of tumors. Methods A literature review was conducted to summarize current studies on autophagy regulation in ovarian cancer and the structural characteristics and pharmacological activities of ginsenosides, with particular attention to the molecular mechanisms through which ginsenosides modulate autophagy and their potential therapeutic implications in ovarian cancer. Results Ginsenosides can modulate autophagy through multiple mechanisms, including activation of the AMPK/mTOR signaling pathway, induction of reactive oxygen species (ROS) accumulation, and regulation of autophagy‐related genes (ATGs), ultimately contributing to tumor suppression. Moreover, ginsenosides have demonstrated notable anticancer effects in ovarian cancer, further highlighting their potential clinical value. Conclusion This review provides a comprehensive overview of current knowledge regarding autophagy regulation in ovarian cancer, summarizes the structural and pharmacological characteristics of ginsenosides, and discusses their emerging role as autophagy‐targeting agents, particularly in the treatment of this malignancy. Collectively, these insights offer a new perspective for the development of autophagy‐based precision therapies for ovarian cancer.

Risk of Breast and Ovarian Cancer After Prophylactic Mastectomy and Salpingo‐Oophorectomy in BRCA1 /2 Germline Variant Carriers: A Retrospective Cohort Study From a Single German Center

ABSTRACT Background As the data on BRCA1/2 ‐associated breast and ovarian cancer prevalence after prophylactic surgery has not been exhaustively investigated yet, we aimed to evaluate the cancer prevalence in a single center cohort of BRCA1 and BRCA2 carriers after conducting prophylactic mastectomy, as well as prophylactic bilateral salpingo‐oophorectomy (PBSO) respectively. Methods We included 875 women that were tested positive for a germline variant in the BRCA1/BRCA2 gene (gPV) between 2002 and 2022 at the Center of Hereditary Breast and Ovarian Cancer of the Technical University Munich Germany. Mean follow up was 7.2 years (range 0–44 years; 95% CI: 6.70 to 7.70). We differentiated breast and/or ovarian cancer diseased ( n  = 643) and non‐diseased BRCA1/2 carriers ( n  = 232). Results Our analysis confirmed the effectiveness of prophylactic surgeries in genetically predisposed women with a gPV in the BRCA1 /2 gene. We observed no breast cancer after prophylactic bilateral mastectomy, 2 contralateral breast cancer diseases after contralateral prophylactic mastectomy and 1 extraovarian serous adenocarcinoma after PBSO. Within the entire study collective, a total of 293 have undergone PBSO, with 6 women having an incidental finding of ovarian cancer and STIC respectively (=2.0%; 1.7% gBRCA1 and 0.3% gBRCA2 ). Our data suggests that, particularly regarding ipsilateral secondary cancer (ISC), higher oncological safety can be achieved through mastectomy rather than breast‐conserving surgery (BCS). In the group of patients who had a second breast cancer and were treated with BCS during their first cancer, 18.3% showed an ISC. Within the patients who were first treated with a mastectomy, only 4.3% showed an ISC. Conclusions Prophylactic surgeries demonstrate high oncological effectiveness in gPV BRCA1/2 carriers. In particular, mastectomy may provide greater protection against ISC compared with BCS. Further studies will have to be conducted to compare ipsilateral cancer prevalence after breast‐sparing surgery and mastectomy.

Ovarian Cancer and High Body‐Mass Index: A Global Burden of Disease Database Study From 1990 to 2021

ABSTRACT Background Excess adiposity has been recognized as a significant modifiable risk factor for ovarian cancer (OC), but the epidemiology of OC attributable to high BMI remain largely unknown. Methods Utilizing comprehensive data from the Global Burden of Disease 2021 study, this investigation quantifies the epidemiological impact of elevated body mass index (BMI) on OC. Results Our study demonstrated a striking 17,344 mortality cases attributable to BMI in 2021, with a 153.2% increase compared to 1990. The age‐standardized mortality rate (ASMR) and disability‐adjusted life years (DALYs) rate associated with excessive BMI rose from 0.18 per 100,000 (95% UI: −0.04–0.33) and 4.57 per 100,000 (95% UI: 0.94–8.6) in 1990 to 0.2 per 100,000 (95% UI: 0.05–0.36) and 5.46 per 100,000 (95% UI: 1.3–9.62) in 2021, respectively, with DALYs showing a 152.6% increase during this period. Notably, geriatric populations and low‐income nations exhibited disproportionately elevated mortality and DALY counts in 2021. The Bayesian age‐period‐cohort (BAPC) predictive modeling framework was used to quantify the average yearly rate of the obesity‐related OC and demonstrated a continued rise in both incidence and mortality rates over the next 25‐year period. Conclusion These findings highlight metabolic dysfunction as a critical public health challenge in OC pathogenesis, emphasizing the urgent need to address modifiable metabolic determinants and associated conditions.

Association of Neighborhood Social Vulnerability With Metastatic Cancer at Diagnosis

ABSTRACT Background Relationships between socioeconomic factors and metastatic cancer at diagnosis have not been well studied. Using CDC's Social Vulnerability Index (SVI) we studied the association of metastatic cancer at initial diagnosis with 16 social factors and their interaction with insurance status. Methods California and Texas cancer registries, merged with the SVI database, were used to identify adult patients diagnosed with breast, colorectal, liver, lung, ovarian, pancreatic, or prostate cancer from 2015 to 2019. To determine the association of SVI with metastatic cancer at initial diagnosis, multivariable binary logistic regression analyses were performed. Results Of the 654,016 patients included, 149,476 (21.5%) were diagnosed with metastatic cancer at diagnosis. Overall, the adjusted odds of metastasis at diagnosis increased by 5% for every 10 unit increase in SVI. Stratified by cancer type, the odds (95% confidence interval) of metastatic cancer at diagnosis were: breast 1.04 (1.03–1.05), colorectal 1.01 (1.01–1.02), liver 1.03 (1.02–1.05), lung 1.01 (1.01–1.02), pancreatic 1.02 (1.01–1.03), prostate 1.06 (1.05–1.07). Interaction analysis of insurance with SVI revealed that the marginal effect of the association between SVI and the risk of metastasis at initial diagnosis increased most substantially as SVI increased for patients who had insurance. It was relatively constant for uninsured and Medicaid patients, who had the overall highest average risk. Conclusions Increased neighborhood social vulnerability is associated with an increased risk of metastatic cancer at initial diagnosis. While uninsured patients or those on Medicaid had a higher risk, patients with other insurance types experienced the largest increases in risk associated with increasing SVI.

Effectiveness of Positive Psychology Interventions for Cancer Survivors: A Systematic Review and Meta‐Analysis

ABSTRACT Objectives This systematic review aimed to evaluate the effectiveness of positive psychology interventions (PPIs) that are theoretically grounded and tailored to individuals across various stages and types of cancer. Methods Adhering to PRISMA guidelines, a comprehensive search of peer‐reviewed and gray literature was conducted across seven databases and supplementary sources, including Google and Google Scholar. Meta‐analyses were performed using standardized mean differences (Hedges' g ) to assess the impact of PPIs on various psychological, physiological, and quality of life (QOL) outcomes. The methodological quality of included studies was appraised using the McMaster Critical Appraisal Tool, and the overall body of evidence was graded using the NHMRC FORM framework. Results Eighteen studies involving 1382 participants were included. PPIs significantly improved psychological wellbeing domains such as post‐traumatic growth, positive emotions, engagement, meaning, and positive relationships, with effect sizes ranging from moderate to large ( p  < 0.05). Improvements were also observed in QOL and sexual functioning, though these outcomes were assessed in fewer studies. In contrast, limited or inconsistent effects were noted for accomplishment, psychological distress, physical functioning, and pain. High heterogeneity across studies highlighted variability in intervention designs and participant populations. Conclusions PPIs hold promise as an integrative approach to psycho‐oncology care in enhancing psychological wellbeing among cancer survivors. While their effects on psychological distress and specific concerns like sexual dysfunction warrant further research, PPIs represent a valuable framework for supporting the multifaceted needs of cancer survivors. Standardization of interventions and integration into multidisciplinary care models are recommended to maximize their clinical utility.

Hepatocyte nuclear factor 1 beta: A perspective in cancer

AbstractHepatocyte nuclear factor 1 beta (HNF1 β/B) exists as a homeobox transcription factor having a vital role in the embryonic development of organs mainly liver, kidney and pancreas. Initially described as a gene causing maturity‐onset diabetes of the young (MODY), HNF1β expression deregulation and single nucleotide polymorphisms in HNF1β have now been associated with several tumours including endometrial, prostate, ovarian, hepatocellular, renal and colorectal cancers. Its function has been studied either as homodimer or heterodimer with HNF1α. In this review, the role of HNF1B in different cancers will be discussed along with the role of its splice variants, and its emerging role as a potential biomarker in cancer.