Technology in Cancer Research & Treatment

Suppression of NBS1 Upregulates CyclinB to Induce Olaparib Sensitivity in Ovarian Cancer

Background: Deficiencies in DNA damage repair responses promote chemotherapy sensitivity of tumor cells. The Nibrin homolog encoding gene Nijmegen Breakage Syndrome 1 (NBS1) is a crucial component of the MRE11-RAD50-NBN complex (MRN complex) and is involved in the response to DNA double-strand breaks (DSBs) repair that has emerged as an attractive strategy to overcome tumor drug resistance, but the functional relationship between NBS1 regulated DNA damage repair and cell cycle checkpoints has not been fully elucidated. Methods: In this study, lentivirus-mediated RNAi was used to construct NBS1-downregulated cells. Flow cytometry, qPCR, and immunohistochemistry were used to explore the regulatory relationship between NBS1 and CyclinB in vivo and in vitro. Results: Our findings suggest that NBS1 deficiency leads to defective homologous recombination repair. Inhibition of NBS1 expression activates CHK1 and CyclinB signaling pathways leading to cell cycle arrest and sensitizes ovarian cancer cells to Olaparib treatment in vitro and in vivo. NBS1-deficient ovarian cancer cells tend to maintain sensitivity to chemotherapeutic drugs through activation of cell cycle checkpoints. Conclusions: NBS1 may be a potential therapeutic target for epithelial ovarian cancer as it plays a role in the regulation of the DNA damage response and cell cycle checkpoints. Suppression of NBS1 upregulates CyclinB to induce Olaparib sensitivity in ovarian cancer.

3D-US and CBCT Dual-guided Radiotherapy for Postoperative Uterine Malignancy: A Primary Workflow Set-up

Introduction: The consistency of clinical target volume is essential to guiding radiotherapy with precision for postoperative uterine malignancy patients. By introducing a three-dimensional ultrasound system (3D-US) into image-guided radiation therapy (IGRT), this study was designed to investigate the initial workflow set-up, the therapeutic potential, and the adverse events of 3D-US and cone-beam computed tomography (CBCT) dual-guided radiotherapy in postoperative uterine malignancy treatment. Methods: From April 2021 to December 2021, postoperative uterine malignancy patients were instructed to follow the previously standard protocol of daily radiation treatment, particularly a 3D-US (Clarity system) guiding was involved before CBCT. Soft-tissue-based displacements resulting from the additional US-IGRT were acquired in the LT (left)/RT (right), ANT (anterior)/POST (posterior), and SUP (superior)/INF(inferior) directions of the patient before fractional treatment. Displacement distributions before and after treatment either from 3D-US or from CBCT were also estimated and compared subsequently, and the urinary and rectal toxicity was further evaluated. Results: All the patients completed radiation treatment as planned. The assessment of 170 scans resulted in a mean displacement of (0.17 ± 0.24) cm, (0.19 ± 0.23) cm, (0.22 ± 0.26) cm for bladder in LT/RT, ANT/POST, and SUP/INF directions. A mean deviation of (0.26 ± 0.22) cm, (0.58 ± 0.5) cm, and (0.3 ± 0.23) cm was also observed for the bladder centroid between the CBCT and computed tomography -simulation images in three directions. Paired comparison between these two guidance shows that the variations from 3D-US are much smaller than those from CBCT in three directions, especially in ANT/POST and SUP/INF directions with significance ( P = 0.000, 0.001, respectively). During treatment, and 0, 3, 6, 9, and 12 months after treatment, there was no severe urinary and rectal toxicity happened. Conclusion: A primary workflow of 3D-US and CBCT dual-guided radiotherapy has been established, which showed great therapeutic potential with mild to moderate urinary and rectal toxicity for postoperative uterine malignancy patients. But the clinical outcomes of this non-invasive technique need to be investigated further.

CircAGFG1 Promotes Ovarian Cancer Progression Through the miR-409-3 p/ZEB1 Axis

Objectives Circular RNAs (circRNAs) serve a crucial regulatory role in ovarian cancer (OC). Circular RNA ArfGAP with FG repeats 1 (circAGFG1) has been shown to be involved in promoting the progression of several cancers, containing triple-negative breast cancer, esophageal cancer and colorectal cancer. However, the function of circAGFG1 in OC is unclear. Methods Quantitative real-time reverse transcription PCR (RT-qPCR) was conducted to determine the expression levels of circAGFG1 and miR-409-3p. The proliferation and metastasis of cells were determined by colony formation assays, EdU assays, transwell assays and wound healing assays. In addition, a dual-luciferase reporter assay was performed to validate the mechanism between circAGFG1, miR-409-3p, and ZEB1. Results Our data suggested that circAGFG1 was significantly overexpressed in OC tissues compared to normal ovarian epithelial tissues. Overexpression of circAGFG1 was correlated with intraperitoneal metastasis, tumor recurrence and advanced stage. Additionally, circAGFG1 overexpression revealed a poor prognosis in OC patients. Knockdown of circAGFG1 suppressed the proliferation, invasion and migration of OC cells. Mechanistically, circAGFG1 acted as a sponge of miR-409-3p to enhance the expression level of zinc finger E-box binding homeobox 1 (ZEB1), thereby conferring OC cell proliferation, invasion and migration. Importantly, re-expression of ZEB1 effectively reversed the effects of circAGFG1 knockdown on OC cells. Conclusions In summary, our study indicated that circAGFG1 may act as a prognostic biomarker and potential therapeutic target for patients with OC.

Body Mass Index and Risk of Female Reproductive System Tumors Subtypes: A Meta-Analysis Using Mendelian Randomization

Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577–1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216–1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.

piR-1919609 Is an Ideal Potential Target for Reversing Platinum Resistance in Ovarian Cancer

Purpose PIWI-interacting RNAs (piRNAs) are a type of noncoding small RNA that can interact with PIWI-like RNA-mediated gene silencing (PIWIL) proteins to affect biological processes such as transposon silencing through epigenetic effects. Recent studies have found that piRNAs are widely dysregulated in tumors and associated with tumor progression and a poor prognosis. Therefore, this study aimed to investigate the effect of piR-1919609 on the proliferation, apoptosis, and drug resistance of ovarian cancer cells. Methods In this study, we used small RNA sequencing to screen and identify differentially expressed piRNAs in primary ovarian cancer, recurrent ovarian cancer, and normal ovaries. A large-scale verification study was performed to verify the expression of piR-1919609 in different types of ovarian tissue, including ovarian cancer tissue and normal ovaries, by RT–PCR and to analyze its association with the clinical prognosis of ovarian cancer. The expression of PIWILs in ovarian cancer was verified by RT–PCR, Western blotting and immunofluorescence. The effects of piR-1919609 on ovarian cancer cell proliferation, apoptosis and drug resistance were studied through in vitro and in vivo models. Results (1) piR-1919609 was highly expressed in platinum-resistant ovarian cancer tissues (p < 0.05), and this upregulation was significantly associated with a poor prognosis and a shorter recurrence time in ovarian cancer patients (p < 0.05). (2) PIWIL2 was strongly expressed in ovarian cancer tissues (p < 0.05). It was expressed both in the cytoplasm and nucleus of ovarian cancer cells. (3) Overexpression of piR-1919609 promoted ovarian cancer cell proliferation, inhibited apoptosis, and promoted tumor growth in nude mice. (4) Inhibition of piR-1919609 effectively reversed ovarian cancer drug resistance. Conclusion In summary, we showed that piR-1919609 is involved in the regulation of drug resistance in ovarian cancer cells and might be an ideal potential target for reversing platinum resistance in ovarian cancer.

Comprehensive Genomic and Immunohistochemical Profiling to Predict Prognosis and Recurrence in Fertility-Sparing Therapy Based on Progesterone for Endometrial Carcinoma

Background Endometrial carcinoma (EC) represents a unique clinical challenge. Fertility-sparing treatments rely on achieving complete response (CR) through progesterone-based therapy. We sought to investigate the prognostic value of molecular subtyping and immunohistochemical (IHC) markers in predicting three-month treatment outcomes and recurrence in EC patients undergoing fertility-sparing therapy. Methods A retrospective cohort of 68 patients diagnosed with early-stage EC received hysteroscopic surgery and conservative treatment whose paraffin-embedded tissue blocks preserved in our hospital between Jan. 2010 and Oct. 2022 was evaluated. Molecular subtyping based on TCGA classification identified low copy-number (CNL), microsatellite instability-high (MSI-H), and copy-number high (CNH) subtypes. IHC markers, including PTEN, PIK3CA, β-catenin, ARID1A, estrogen receptor (ER), and progesterone receptor (PR) were analyzed for their association with CR and recurrence. Transcriptome sequencing gene chips were used to study patients who achieved or did not achieve CR after three months, those who experienced recurrence within one year, and those who did not recur within two years. Differential genes were then mapped to KEGG pathways to explore the underlying mechanisms of progesterone therapy efficacy. Results Among the 68 patients classified through TCGA molecular typing, 65 cases (95.6%) were CNL subtype, two (2.9%) were MSI-H subtype, and one (1.5%) was CNH subtype. Following a three-month treatment, the CR rate for the CNL subtype was 75.4% (49/65), the MSI-H subtype was 50.0% (1/2), and the CNH subtype was 0% (0/1). In CNL subtype endometrial carcinoma, individuals with high PTEN and PR expression were more likely to achieve CR after three months ( P  < .05). Conversely, those with elevated CA199 levels and increased PIK3CA expression were more prone to recurrence after CR. Conclusion MSI-H and p53-mutant subtypes of endometrial carcinoma are not suitable for fertility preservation therapy. PTEN/PI3K-AKT-mTOR pathway activation contributes to reduced progesterone sensitivity, underscoring the need for targeted therapeutic strategies to improve patient outcomes.

Effects of Adjuvant Radiation Plus Chemotherapy on Survival Outcomes in Stage III C Endometrial Cancer According to Histology: Analysis of Data from the Surveillance, Epidemiology, and End Results Database

Purpose: To evaluate the survival benefit of radiation plus chemotherapy in adult females with stage IIIC endometrial cancer and to investigate whether the benefit varies according to histology. Methods: Data from adult females with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrial cancer, who underwent at least total hysterectomy between 2010 and 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Adjuvant treatments were categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariate Cox regression models, Kaplan–Meier curves, and log-rank tests were used to assess the association between treatment modality and overall survival (OS). Results: In total, 2138 cases were identified: stage IIIC1 (n = 1299 [60.8%]) and stage IIIC2 (n = 839 [39.2%]). Median OS for all patients was 48 (interquartile range [IQR] 28-70) months. Regarding adjuvant treatment, 40.5% of patients underwent chemotherapy only, followed by chemotherapy with EBRT (35.5%). Stage IIIC patients treated with chemotherapy plus radiation exhibited a significantly reduced risk for death from endometrial cancer in both univariate and multivariate analyses ( P < 0.001). However, when stratified according to histology, OS also differed according to treatment modality when analyzing each histological type; combination therapy was no longer significantly different from chemotherapy alone for any histology (clear cell and carcinosarcoma). Combination therapy was associated with improved OS in patients with IIIC1 and IIIC2 disease. Similar associations were observed in patients with high-grade stage IIIC endometrioids. However, for low-grade tumors, combination therapy was no longer associated with reduced risk for death compared with chemotherapy alone. Conclusion: For patients with stage IIIC endometrial cancer, combined treatment with radiation and chemotherapy was associated with improved OS compared with chemotherapy alone. However, no survival benefit was found, and radiotherapy may be unnecessary in patients with low-grade endometrioids.

Hsa_circ_0075960 Serves as a Sponge for miR-361-3p/SH2B1 in Endometrial Carcinoma

Although the cases of endometrial carcinoma (EC) is gradually increasing across the world, its etiology and pathogenesis remain unknown. The present study is the first to define the role and biological function of circRNA hsa_circ_0075960 in the development and progression of EC. We first determined that hsa_circ_0075960 is aberrantly expressed in EC cells. Then, we uncovered that the downregulation of hsa_circ_0075960 suppressed cell proliferation and promoted cell apoptosis of EC cells, suggesting that hsa_circ_0075960 could inhibit the progression of EC in vitro. In addition, we identified that miR-361-3p was the direct target of hsa_circ_0075960. Further analysis revealed that hsa_circ_0075960 affected the development of EC via sponging miR-361-3p. Interestingly, we verified that the level of SH2B1 was controlled by the downregulation of hsa_circ_0075960 and that the negative effect caused by hsa_circ_0075960 could be reversed via miR-361-3p inhibition. Our cumulative results revealed that the novel tumor regulator hsa_circ_0075960 functioned as a sponge for miR-361-3p/SH2B1 in EC cells and regulated the progression of EC through the modulation of miR-361-3p.

Sirtuin 2 in Endometrial Cancer: A Potential Regulator for Cell Proliferation, Apoptosis and RAS/ERK Pathway

Objective: The present study aimed to explore the function of sirtuin 2 (SIRT2) on cell proliferation, apoptosis, rat sarcoma virus (RAS)/ extracellular signal-regulated kinase (ERK) pathway in endometrial cancer (EC). Methods: SIRT2 expression in human EC cell lines and human endometrial (uterine) epithelial cell (HEEC) line was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. SIRT2 knock-down and control knock-down plasmids were transfected into HEC1A cells, respectively; SIRT2 overexpression and control overexpression plasmids were transfected into Ishikawa cells, respectively. After transfection, SIRT2, HRas proto-oncogene, GTPase (HRAS) expressions were evaluated by RT-qPCR and western blot. ERK and phosphorylated ERK (pERK) expressions were evaluated by western blot. Meanwhile, cell proliferation and cell apoptosis were measured. Results: Compared to normal HEEC cell line, SIRT2 mRNA and protein expressions were increased in most human EC cell lines (including HEC1A, RL952 and AN3CA), while were similar in Ishikawa cell line. In HEC1A cells, SIRT2 knock-down decreased cell proliferation but increased apoptosis. In Ishikawa cells, SIRT2 overexpression induced cell proliferation but inhibited apoptosis. For RAS/ERK pathway, SIRT2 knock-down reduced HRAS and inactivated pERK in HEC1A cells, whereas SIRT2 overexpression increased HRAS and activated pERK in Ishikawa cells, suggesting that SIRT2 was implicated in the regulation of RAS/ERK pathway in EC cells. Conclusion: SIRT2 contributes to the EC tumorigenesis, which appears as a potential therapeutic target.

Role of Human Epididymis Protein 4 (HE4) in Determining Survival of Patients With Endometrial Cancer: A Meta-Analysis

Background: Human epididymis protein 4 (HE4) is a novel cancer biomarker. This study evaluates the prognostic role of HE4 in determining the survival of endometrial cancer patients. Methods: Literature search was conducted in electronic databases (Embase, Ovid, PubMed, Scopus, and Web of Science). Studies were selected if they reported the relationship between HE4 and the survival of endometrial cancer patients. Random-effects meta-analyses were performed to achieve estimates of baseline serum HE4 levels, the 5-year survival with high and low serum HE4 levels/expression, and the hazard ratios (HRs) of the survival between patients with high and low serum HE4 levels. Results: 9 studies (1404 patients; age 63.1 years [95% confidence interval (CI): 61.2, 64.9]; follow-up 35.9 months [95% CI: 32.2, 39.6]) were included. In these patients, serum HE4 levels were 83.36 picomole/liter (pM) [95% CI: 70.15, 96.56] overall but these were higher in patients with recurrence (108.13 pM [95% CI: 63.09, 153.18] and lower in patients with no recurrence (67.88 pM [95% CI: 65.09, 70.67]). The 5-year overall survival rate was higher in patients with low HE4 levels/expression (86% [95% CI: 79, 92] but lower in patients with high HE4 levels/expression (63% [95% CI: 58, 68]. A pooled HR of survival between patients with high and low serum HE4 levels of 2.25 [95% CI: 1.56, 2.94] indicated shorter survival in patients with high serum HE4 levels. Conclusion: High HE4 concentrations in patients with endometrial cancer are found to be associated with shorter survival.

The Prognostic Value of Circulating Tumor DNA in Ovarian Cancer: A Meta-Analysis

Background: Studies have shown that circulating tumor DNA (ctDNA) indicates a poor prognosis in ovarian cancer. In this study, meta-analysis was used to assess the relationship between ctDNA and the prognosis of patients with epithelial ovarian cancer. Methods: The clinical trials included in this study were obtained via a search of PubMed, the Cochrane Library, the Web of Science and Embase between the period of establishment and March 2020. We selected clinical studies using qualitative or quantitative ctDNA methods to analyse the prognosis of ovarian epithelial cancer, screened the studies according to the determined inclusion and exclusion criteria, and used the modified JADAD score scale and NOS scale for evaluation, with OS (overall survival) and PFS (progression-free survival) as end events. The Cochrane Evaluation Tool was used to evaluate the quality of the randomized controlled trials. Stata 15.0 software was used to combine the effect ratio (hazard ratio, HR) and its 95% confidence interval (CI). In addition, a source analysis of ctDNA specimens, an analysis of ctDNA detection methods and a subgroup and sensitivity analysis of FIGO staging were performed. Results: A total of 8 studies were included in this meta-analysis, and ctDNA was found to be an independent risk factor for patients with epithelial ovarian cancer (OS: HR = 2.36, 95% CI [1.76,3.17], P < .001; PFS: HR = 2.51, 95% CI [1.83,3.45]). Conclusions: The results of our analysis suggested that ctDNA is a potential biomarker that can be used to evaluate the prognosis of patients with ovarian cancer.

Kinesin Family Member C1 (KIFC1) Accelerates Proliferation and Invasion of Endometrial Cancer Cells Through Modulating the PI3K/AKT Signaling Pathway

Endometrial cancer (EC) is one of the most common cancers among women worldwide. Kinesin family member C1 (KIFC1) has been demonstrated to play crucial roles in various tumors. However, the function of KIFC1 in EC remains to be revealed. In this study, upregulation of KIFC1 expression in human EC tissues was found from analysis on data from The Cancer Genome Atlas (TCGA), and positively correlated with short survival outcome of EC patients. In addition, the mRNA and protein levels of KIFC1 were confirmed to be up-regulated in EC cells (Ishikawa, HEC-1B, HEC-1A and KLE) compared to human normal endometrial stromal cells (hESCs) by quantitative real time PCR and western blot. In vitro functional experiments showed that overexpression of KIFC1 promoted proliferation, migration and invasion of EC cells, while KIFC1 depletion showed the opposite results. Moreover, KIFC1 knockdown suppressed tumor growth in mice. Further mechanism analysis showed that KIFC1 participated in the regulation of EC progression through regulating the PI3K/AKT signaling pathway. Collectively, KIFC1 promoted proliferation and invasion through modulating PI3K/AKT signaling pathway in EC, implying that KIFC1 might provide a promising therapeutic target for the therapy of EC.

The Clinical Characteristics of Endometrial Cancer With Extraperitoneal Metastasis and the Value of Surgery in Treatment

Objective: To describe the clinical and pathological features of endometrial carcinoma with extraperitoneal metastasis and examine whether surgery could improve the prognosis. Methods: The Surveillance, Epidemiology, and End Results database was used to analyze 730 patients who were diagnosed with extraperitoneal metastasis of endometrial cancer from 2010 to 2015, including metastasis to the lung, bone, or brain. Results: Of the 730 patients, 372 (50.96%) patients had single lung metastases, and 196(26.85%) patients had multiple organ metastases that included pulmonary invasion. Therefore, the lung was the most common target organ for extraperitoneal metastasis of endometrial cancer. In multivariate risk factor analysis, grade 3 tumor (odds ratio = 3.39, P < .001), positive peritoneal cytology (odds ratio = 2.02, P < .001), and cervical stromal invasion (odds ratio = 1.42, P = .030) were independent risk factors for extraperitoneal metastasis. Once metastasis occurred in the brain or multiple organs, the prognosis was often poor. Of the patients, 362 underwent surgery, and surgery was performed only for primary tumors of the reproductive organs in almost all patients (97.23%) with extraperitoneal metastasis. The median cancer-specific survival periods of patients with solitary pulmonary metastasis undergoing surgery and those without surgery were 23 (16.43-29.57) months and 9 (6.21-11.79) months, respectively ( P < .001), and survival superiority also existed in patients with bone metastasis (19 vs 8 months, P = .015) and multiple organs metastases (15 vs 4 months, P < .001). However, patients with brain metastasis had the same median survival period in the 2 groups (6 months, P = .146). Conclusions: The lung was the most common target organ for extraperitoneal metastasis in patients with endometrial cancer. Surgery was associated with improved survival in women with extraperitoneal metastasis, except for patients with brain metastasis.

Region-specific Multi-Omics Modeling for Predicting Acute Radiation-Induced Proctitis in Cervical Cancer Radiotherapy: A Retrospective Analysis

Introduction To develop and evaluate a multi-omics machine-learning model that integrates clinical variables, dose-volume histogram (DVH) metrics, radiomics, and dosiomics from both the rectum and rectal wall regions of interest (ROIs) to improve prediction of acute radiation proctitis (ARP) in cervical cancer patients receiving radiotherapy. Methods In this single-center retrospective cohort, 107 cervical cancer patients were randomly split into a training set (n = 85) and a testing set (n = 22) in an 8:2 ratio. Radiomic were extracted from planning CT, and dosiomic features from 3-D RT-dose distributions, for both rectum and rectal wall ROIs. Features were z-score standardized; redundant features were filtered by Pearson correlation, followed by least absolute shrinkage and selection operator (LASSO) for selection. Support Vector Machine (SVM) and Multilayer Perceptron (MLP) classifiers were trained using stratified five-fold cross-validation within the training set. Model performance was assessed on the held-out test set using receiver operating characteristic (ROC) analysis; clinical utility was evaluated with decision-curve analysis (DCA). The primary endpoint was Common Terminology Criteria for Adverse Events (CTCAE,version 5.0) grade ≥2 ARP. Results Multi-omics fusion outperformed single-modality models across ROIs and classifiers. The rectal-wall multi-omics SVM achieved the best discrimination with AUC 0.867 (95% Confidence Interval [CI]:0.709-1.000) in the test set; performance for the whole-rectum region of interest (ROI) was lower (AUC 0.714). DVH-only models showed limited discrimination, and no DVH feature was retained after penalized selection in the multi-omics pipeline. DCA demonstrated the greatest net clinical benefit for the rectal-wall multi-omics model across threshold probabilities 0.20–0.50. Conclusion A rectal-wall, region-specific multi-omics approach integrating clinical, radiomic, and dose-based descriptors improves prediction of radiotherapy-induced ARP compared with single-modality and whole-rectum analyses. These findings highlight the importance of ROI selection and multi-omics integration for precision toxicity assessment and support future external validation and prospective evaluation.

Constructing a Classification Model for Cervical Cancer Tumor Tissue and Normal Tissue Based on CT Radiomics

This study aimed to develop an automated classification framework for distinguishing between cervical cancer tumor and normal uterine tissue, leveraging CT images for radiomics feature extraction. We retrospectively analyzed CT images from 117 cervical cancer patients. To distinguish between cancerous and healthy tissue, we segmented gross tumor volume and normal uterine tissue as distinct regions of interest (ROIs) using manual segmentation techniques. Key radiomic parameters were extracted from these ROIs. To bolster model's predictive capability, the data was stratified into train data (70%) and validation data (30%). During feature selection phase, we applied Least Absolute Shrinkage and Selection Operator regression algorithm to identify most relevant features. Subsequently, we built classification models using five state-of-the-art machine learning algorithms: Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbors (KNN), Extreme Gradient Boosting (XGBoost), and Decision Tree (DT). Ultimately, the performance of each model was evaluated. Through stringent feature selection process, we identified 18 pivotal radiomic features for classification of cervical cancer and normal uterine tissue. When applied to test data, all five models achieved excellent performance, with area under the curve (AUC) values ranging from 0.8866 to 0.9190 (SVM: 0.9144, RF: 0.9078, KNN: 0.9051, DT: 0.8866, XGBoost: 0.9190), all surpassing threshold of 0.8. In terms of test data, all five models had high sensitivity; accuracy of SVM, RF, and XGBoost models was comparable; and specificity of five models was similar. XGBoost model outperformed the others in terms of diagnostic accuracy, achieving an AUC of 0.8737 (95% CI: 0.8198-0.9277) for train data and 0.9190 (95% CI: 0.8525-0.9854) for test data. Our findings underscore the potential of CT radiomics combined with machine learning algorithms for accurately classifying cervical cancer tumors and normal uterine tissue with high recognition capabilities. This approach holds significant promise for clinical diagnostics.

A Novel Network-Level Fused Self-Attention Deep Neural Network for Cervical Cancer Classification from Cervicography Images

Introduction cervical cancer ranks as the fourth most common cancer among females worldwide. Approximately 528,000 new cases of cervical cancer are reported annually, and about 85% of them occur in less-developed countries. The lack of skilled medical staff and pre-screening procedures is the main cause of the high fatality rate in these countries. Cervicography images are the gold standard procedure for the evaluation of cervical cancer; however, the high intra-class inconsistency makes the diagnosis process more challenging for skilled medical specialists. Method In this work, we propose a fully automated computer-aided diagnosis (CAD) system for classifying cervical cancer using Cervicography images. Data augmentation is performed in the initial phase to address dataset imbalance. Subsequently, we proposed two novel deep learning modules: the 11-Parallel Inverted Residual Bottleneck Blocks (11-PIRBnet) architecture and the 9-Parallel Inverted Residual blocks with Self-Attention Mechanism (9-PIRSANet). Both modules are fused at the network level via a depth concatenation layer to form a new network, 375NFNet. The proposed network is trained on the selected dataset, whereas the hyperparameters are initialized through Bayesian Optimization (BO). For feature extraction, a depth concatenation layer is used during testing to combine information from both deep learning modules. Finally, the extracted features are classified using a shallow neural network (SNN) to produce the final classification. Result To evaluate the model, experiments were conducted on a publicly available cervical screening dataset of Cervicography images, and results demonstrate an accuracy of 95.5%, a precision of 95.4%, and an area under the curve of 0.97. When compared with several pre-trained techniques, the proposed architecture achieved significant improvement in accuracy, precision, and number of trainable parameters. Conclusion The proposed 375NFNet architecture demonstrates remarkable accuracy and efficiency in classifying cervical cancer through cervicography images, which shows its potential as a valuable tool in resource-constrained environments.

MDA-TransUNet: A Deep Learning-Based Automatic Segmentation Method for Cervical Cancer Brachytherapy

Introduction Accurate delineation of the high-risk clinical target volume (HR-CTV) and organs at risk (OARs) is critical for cervical cancer brachytherapy. However, treatment planning is time-consuming, and prolonged waiting can lead to organ displacement and patient discomfort. Additionally, the steep dose gradients around HR-CTV amplify segmentation errors in HR-CTV and OARs. Therefore, achieving rapid and precise delineation of HR-CTV and OARs remains challenging. This study proposes a novel network model, MDA-TransUNet, for fast segmentation of HR-CTV and OARs in cervical cancer. Methods We applied MDA-TransUnet, a CNN-Transformer hybrid model, to segment the bladder, colon, rectum, small bowel, and HR-CTV on cervical cancer CT images. 122 cervical cancer brachytherapy patients’ CT images from three clinical centers were utilized for training and testing, with 80 cases allocated to training, 22 to testing, and 20 to external validation. Segmentation accuracy was quantified using the Dice Similarity Coefficient (DSC), Hausdorff Distance (HD95), and Average Surface Distance (ASD). Dosimetric differences were analyzed via paired t-tests. Results Compared to other methods, MDA-TransUnet achieved superior segmentation performance on the test dataset. The DSCs for the bladder, colon, rectum, small bowel, and HR-CTV were 94.54%, 79.27%, 79.27%, 88.90%, and 82.35%, respectively. Paired t-tests on five dosimetric metrics (D5cc, D2cc, D0.1cc, D90%, and Dmean) showed no significant differences. For OARs, the average difference in D2cc was less than 12%. For HR-CTV, the average difference in Dmean was less than 8%, and D90% was less than 11%. Conclusion This work demonstrates the superiority of MDA-TransUnet in segmenting OARs and HR-CTV for cervical cancer brachytherapy, with robust performance across multi-center datasets.

Cervical Cancer in Pregnancy: A 10-Year Retrospective Analysis of Clinical Management and Future Perspectives

Introduction This study aims to evaluate diagnosis, treatment and clinical outcomes for patients with cervical cancer in pregnancy (CCIP) and their fetuses over a 10-year period, providing clinical evidence for the management of CCIP. Methods Clinical data of 28 patients diagnosed with CCIP at our center between January 1st, 2013 and June 30th, 2023 were retrospectively analyzed, focusing on gestational age at diagnosis, treatment, and maternal-fetal outcomes. Results A total of 28 patients with CCIP were identified, accounting for 0.42% (28/6678) of patients with cervical cancer during the study period. The majority of patients (86%, 24/28) had squamous cell carcinoma diagnosed by colposcopic biopsy, and 21 patients presented with recurrent vaginal bleeding. Cervical cancer was diagnosed during pregnancy in 19 cases and in the postpartum period in 9 cases. The mean tumor diameter was 5.4 (2-12) cm. Among 19 patients diagnosed during pregnancy, 13 patients chose pregnancy preservation, resulting in an average delay of treatment by 16.4 (0-33) weeks without observed disease progression. Fetuses were delivered via cesarean section at an average gestational age of 36.3 weeks; eight of these patients received neoadjuvant chemotherapy. At a median follow-up duration of 40.1 (12-103) months, 25 patients survived. Disease-free survival was observed in 20 patients, whereas two patients experienced local progression, and six developed distant metastases. Conclusion Clinical outcomes for patients with CCIP appear comparable to those observed in non-pregnant patients in the general population. Pregnant patients presenting with abnormal vaginal bleeding should undergo prompt cervical cancer screening to enable early diagnosis and tailored management strategies. For patients with a strong desire to maintain their pregnancy, careful consideration should be given to postponing delivery until fetal maturity, thereby minimizing maternal and fetal complications and improving maternal and fetal outcomes.

Elevated INHBA Promotes Tumor Progression of Cervical Cancer

Objectives: This study aimed to explore the role of inhibin subunit beta A (INHBA) in the progression of cervical cancer (CCa) and investigate its potential as a therapeutic target. Specifically, the objectives were to assess the expression levels of INHBA in CCa, examine its correlation with patient survival, and elucidate its impact on CCa cell proliferation, cell cycle regulation, migration, invasion, and in vivo tumor growth and metastasis. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. INHBA expression in CCa was analyzed, and its association with patient survival was assessed using clinical data. In vitro experiments involved the investigation of INHBA's effects on CCa cell proliferation, cell cycle dynamics, migration, and invasion through the epithelial–mesenchymal transition (EMT) process. Additionally, in vivo experiments were performed to evaluate the influence of INHBA on CCa growth and lung metastasis. Results: The results of this study revealed upregulated expression of INHBA in CCa, with a significant association between high INHBA expression and poor patient survival. Functionally, INHBA was found to promote the proliferation of CCa cells, regulate the cell cycle, and enhance migration and invasion through the EMT process in vitro. Moreover, in vivo experiments demonstrated that INHBA facilitated the growth and lung metastasis of CCa. Conclusion: In conclusion, our findings suggest that INHBA plays a crucial role in the progression of cervical cancer. The upregulation of INHBA is associated with poor patient survival, and its involvement in promoting key aspects of cancer progression makes it a potential therapeutic target for CCa treatment. These results provide valuable insights into the molecular mechanisms underlying CCa and offer a foundation for further exploration of targeted therapeutic interventions.

β-catenin is a Potential Prognostic Biomarker in Uterine Sarcoma

Introduction Uterine sarcoma (US) is an extremely rare and aggressive gynecologic malignancy with a poor overall survival (OS). The efficient prognostic biomarker is currently lacking. Methods Utilizing a Sweden microarray dataset from the Gene Expression Omnibus (GEO) (GSE119043, n = 50) and a clinical cohort (n = 31) retrospectively collected from Suining Central Hospital, we analyzed β-catenin expression profiles and corresponding clinicopathological characteristics. Immunohistochemistry (IHC) was used to assess β-catenin expression level. Survival analysis was used to assess the relationship between β-catenin expression and prognosis. Gene set enrichment analysis (GSEA) was performed to characterize the specific pathways involved in β-catenin expression. Results Immunohistochemistry indicated that β-catenin expression was significantly upregulated in US group compared to both the normal uterine smooth muscle (UNSM) and uterine leiomyoma (ULM) groups ( P  < .01). IHC also exhibited a significant difference in β-catenin expression levels in four pathological subtypes. Leiomyosarcoma (LMS) and high-grade endometrial stromal sarcoma (HG-ESS) suggested higher levels of β-catenin expression compared with adenosarcoma (AS) or low-grade endometrial stromal sarcoma (LG-ESS), but no statistically significant difference was found in box plot ( P  > .05). GSEA indicated that transcriptional dysregulation in cancer, Wnt, AMPK, MAPK, PI3K, p53, Ras, and TNF signaling pathway were positively enriched in β-catenin high-expression group. Though survival analysis showed that β-catenin expression level was not associated with survival, low-β-catenin expression group showed a longer median OS compared to high expression group (56.17 months VS 9.60 months) in Sweden microarray dataset. Similar results were also observed for progression-free survival (PFS) in clinical cohort (not reached VS 45.97 months in high-expression group). Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor type, stage and tumor recurrence had prognostic significance for PFS. Age, tumor size, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, were not associated with survival ( P  > .05). Conclusion β-catenin was highly expressed in uterine sarcoma and may be promising as a novel potential biomarker for diagnosis and prognosis.

Orosomucoid 1 is a Potential Prognostic Biomarker for Uterine Sarcoma

Introduction Uterine sarcoma (US) is a rare tumor characterized by high aggressiveness, a tendency for recurrence and distant metastasis, and an extremely poor prognosis. In this study, we evaluated the expression of Orosomucoid 1 (ORM1) in different subtypes of US and the relationship between survival rates and clinicopathological features. Method A retrospective study was conducted on 50 cases diagnosed with US in our hospital from 2011 to 2023. Immunohistochemistry (IHC) was used to detect the expression levels of ORM1 in different subtypes of US.The chi-square test and Kaplan-Meier survival analysis were used to analyze the relationship between ORM1 expression and clinical parameters as well as prognosis. Cox analysis was employed to evaluate the relationships between prognosis and clinical parameters in US. Result Compared to normal proliferative endometrial tissue (NPE), the expression of ORM1 was downregulated in low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS) (P < .001,P < .001,and P < .001, respectively). Compared to normal uterine smooth muscle tissue (UNSM), the expression of ORM1 was upregulated in leiomyosarcoma (LMS) (P = .006). High ORM1 expression levels in US patients were associated with poor overall survival (OS) and progression-free survival (PFS) (P = .027 and P = .005, respectively). Multivariate COX analysis revealed that tumor stage and ORM1 expression are independent prognostic factors for US patients. Conclusion ORM1 is expressed at low levels in ESS and at high levels in LMS. ORM1 potentially serve as a novel biomarker for the diagnosis, classification, and prognosis of US.

Risk Factors of Positive Endocervical Curettage and Predictive Model Construction Based on Primary Human Papillomavirus Screening

Introduction The utility and application of endocervical curettage (ECC) during colposcopy remain controversial. This study optimized ECC application for primary human papillomavirus (HPV) screening in patients with high-risk (HR)-HPV. Methods This retrospective study included patients with HR-HPV, who underwent subsequent cervical biopsy and ECC from January 1, 2014, to December 31, 2020. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). The prediction model was presented as a nomogram and evaluated for discrimination and calibration. Results The additional detection rate of cervical intraepithelial neoplasia 2 + lesions with ECC was 2.0% (77/3887) in patients with HR-HPV. In multivariate risk factor analysis, HPV 16 infection presented a high risk of positive ECC, followed by HPV 33, HPV 58, and HPV 31. Irrespective of the abnormal cytopathological results, positive ECC was significantly increased (all P  < .001). Females with acetowhite changes on colposcopy, transformation zone (TZ) type II, TZ type III, colposcopic impression of high-grade squamous intraepithelial lesion, or cancer were at a high risk of positive ECC. The final prediction model included significant variables from risk factor analysis, and had excellent calibration and classification capabilities, with an area under the receiver operating curve of 0.902 (95% CI, 0.881-0.922). Additionally, calibration analysis suggested consistency. Conclusion As the additional detection value of ECC is limited. A satisfactory prediction model was designed to optimize ECC application in patients with HR-HPV infection.

Radiomics Harmonization in Ultrasound Images for Cervical Cancer Lymph Node Metastasis Prediction Using Cycle-GAN

Background: Ultrasound (US) based radiomics is susceptible to variations in scanners, sonographers. Objective: To retrospectively investigate the feasibility of an adapted cycle generative adversarial networks (CycleGAN) in the style transfer to improve US based radiomics in the prediction of lymph node metastasis (LNM) with images from multiple scanners for patients with early cervical cancer (ECC). Methods: The CycleGAN was firstly trained to transfer paired US phantom images from one US device to another one; the model was then further trained and tested with clinical US images of ECC by transferring images from four US devices to one specific device; finally, the adapted model was tested with its effects on the radiomics feature harmonization and accuracy of LNM prediction in US based radiomics for ECC patients. Results: Phantom study demonstrated an increased radiomics harmonization using CycleGAN with an average Pearson correlation coefficient of 0.60 and 0.81 for radiomics features extracted from original and generated images in correlation with the target phantom images, respectively. Additionally, the image quality metric Peak Signal-to-Noise Ratio (PSNR) was increased from 11.18 for the original images to 15.45 for the generated image. Clinical US images of 169 ECC patients were enrolled for style transfer model training and validation. The area under curve (AUC) of LNM prediction radiomics models with features extracted from generated images of different style transfer models ranged from 0.73 to 0.85. The AUC was improved from 0.78 with features extracted from original images to 0.85 with style transferred images. Conclusions: The adapted CycleGAN network is able to increase the radiomics feature harmonization for images from different ultrasound equipment based on image domain and improve the LNM prediction accuracy for ECC.

Mechanism of MicroRNA-375 Promoter Methylation in Promoting Ovarian Cancer Cell Malignancy

Objective: Ovarian cancer (OC) ranks one of the most prevalent fatal tumors of female genital organs. Aberrant promoter methylation triggers changes of microRNA (miR)-375 in OC. Our study aimed to evaluate the mechanism of methylated miR-375 promoter region in OC cell malignancy and to seek the possible treatment for OC. Methods: miR-375 promoter methylation level in OC tissues and cells was detected. miR-375 expression in OC tissues and cell lines was compared with that in demethylated cells. Role of miR-375 in OC progression was measured. Dual-luciferase reporter gene assay was utilized to verify the targeting relationship between miR-375 and Yes-associated protein 1 (YAP1). Then, Wnt/β-catenin pathway-related protein expression was tested. Moreover, xenograft transplantation was applied to confirm the in vitro experiments. Results: Highly methylated miR-375 was seen in OC tissues and cell lines, while its expression was decreased as the promoter methylation increased. Demethylation in OC cells brought miR-375 back to normal level, with obviously declined cell invasion, migration and viability and improved apoptosis. Additionally, miR-375 targeted YAP1 to regulate the Wnt/β-catenin pathway protein expression. Overexpressed YAP1 reversed the protein expression, promoted cell invasion, migration and viability while reduced cell apoptosis. Overexpressed miR-375 in vivo inhibited OC progression. Conclusion: Our study demonstrated that demethylated miR-375 inhibited OC growth by targeting YAP1 and downregulating the Wnt/β-catenin pathway. This investigation may offer novel insight for OC treatment.

The Progress of the Specific and Rapid Genetic Detection Methods for Ovarian Cancer Diagnosis and Treatment

Cancer is a public health problem that threatens human health. Due to the lack of specific and rapid diagnosis and treatment methods, the 5-year survival rate of patients has not been effectively improved in the past 10 years. Abnormal gene expression is closely related to the occurrence and development of cancer. Cancer diagnosis and treatment methods based on genetic testing have received extensive attention in recent years. It is essential to explore specific and rapid cancer genetic testing methods. Taking ovarian cancer as an example, we reviewed the progress of specific and rapid nucleic acid detection methods related to cancer risk assessment, low-abundance mutation detection, and methylation detection, to provide new strategies and ideas for related research.

Downregulation of DNMT3A Attenuates the Warburg Effect, Proliferation, and Invasion via Promoting the Inhibition of miR-603 on HK2 in Ovarian Cancer

Background: Ovarian cancer is a highly malignant gynecological cancer. Aerobic glycolysis is one of the features of cancer cell metabolism. Studying the molecular modulation of the Warburg effect in ovarian cancer is significantly valuable for understanding the progression mechanism of ovarian cancer. Materials and Methods: The expression level and prognostic significance of DNMT3A were analyzed using public databases. DNMT3A was overexpressed by plasmid transfection, and DNMT3A was interfered with specific siRNAs transfection. miR-603 was overexpressed by mimic transfection or inhibited by inhibitor transfection. The expression of the molecules was detected by qPCR or western blotting. CCK-8 and transwell assays were used to determine the cell proliferation, migration, and invasion abilities of ovarian cancer. Results: We found that the DNMT3A protein level was higher in ovarian cancer tissues than in normal ovary tissues, but the mRNA level had no significant difference in ovarian cancer tissues and normal ovary tissues. The higher the RNA level of DNMT3A, the poorer prognosis of patients. DNMT3A knocking down impeded the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer cells. Further investigations discovered that DNMT3A promoted ovarian cancer cell malignancy via silencing miR-603. Conclusion: We found that patients who overexpressed DNMT3A showed a poor prognosis. DNMT3A was found to promote the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer by inhibiting the expression of miR-603. As a result, the research revealed that DNMT3A/miR-603/HK2 axis contributed to the Warburg effect of ovarian cancer and DNMT3A may be a potential therapeutic target for ovarian cancer.

DARS-AS1 Knockdown Inhibits the Growth of Cervical Cancer Cells via Downregulating HMGB1 via Sponging miR-188-5p

Background: Evidence has been shown that long noncoding RNAs (lncRNAs) play an important role in the development of cervical cancer. Recently, lncRNA DARS-AS1 was shown to be dysregulated in several cancer types, but the role of DARS-AS1 in cervical cancer remains unclear. Methods: Immunofluorescence staining, flow cytometry and transwell invasion assays were used to determine proliferation, apoptosis and invasion in cervical cancer cells, respectively. The dual luciferase reporter system assay was performed to assess the interaction between DARS-AS1, miR-188-5p, and high mobility group box 1 (HMGB1) in cervical cancer cells. Results: Downregulation of DARS-AS1 markedly inhibited the proliferation and invasion of cervical cancer cells. Moreover, DARS-AS1 knockdown obviously induced the apoptosis of SiHa and HeLa cells. Meanwhile, luciferase reporter assay identified that miR-188-5p was the potential miRNA binding of DARS-AS1, and HMGB1 was the potential binding target of miR-188-5p. Mechanistic analysis indicated that downregulation of DARS-AS1 decreased the expression of HMGB1 by acting as a competitive “sponge” of miR-188-5p. Conclusion: In this study, we found that DARS-AS1 knockdown suppressed the growth of cervical cancer cells via downregulating HMGB1 via sponging miR-188-5p. Therefore, DARS-AS1 might serve as a potential target for the treatment of cervical cancer.

Circulating Tumor Cells Counting Act as a Potential Prognostic Factor in Cervical Cancer

Background: Circulating tumor cells (CTCs) hold huge potential for both clinical applications and basic research into the management of cancer, but the relationship between CTC count and cervical cancer prognosis remains unclear. Therefore, research on this topic is urgently required. Objective: This study investigated whether CTCs were detectable in patients with cervical cancer and whether CTC count was an indicator of prognosis. Methods: We enrolled 107 patients with pathologically confirmed cervical cancer. CTCs were detected after radiotherapy or concurrent cisplatin-containing chemotherapy in all patients. We evaluated all medical records and imaging data as well as follow-up information to calculate progression-free survival (PFS). PFS was defined as the time until first diagnosis of tumor progression or death. We also analyzed the relationship between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. Results: CTCs were identified in 86 of 107 patients (80%), and the CTC count ranged from 0 to 27 cells in 3.2 mL blood. The median progression-free survival (PFS) was 43.1 months. Patients in which CTCs were detected had a significantly shorter PFS than CTC-negative patients (P = 0.018). Multivariate analysis indicated that CTC count was an independent negative prognostic factor for survival. However, no correlation was observed between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. Conclusion: CTC count is an independent negative prognostic factor for cervical cancer.

Automated Intensity Modulated Radiation Therapy Treatment Planning for Cervical Cancer Based on Convolution Neural Network

Purpose: To develop and evaluate an automatic intensity-modulated radiation therapy (IMRT) program for cervical cancer, including a Convolution Neural Network (CNN)-based prediction model and an automated optimization strategy. Methods: A CNN deep learning model was trained to predict a patient-specify set of IMRT objectives based on overlap volume histograms (OVH) and high-quality plan of previous patients. A total of 140 cervical cancer patients were enrolled in this study, including 100 patients in the training set, 20 patients in the validation set and 20 patients in the testing set. The input of this model was OVH data and the output were values of IMRT plan objectives. For patients in the testing set, the set of planning objectives were predicted by the CNN model and used to automatically generate IMRT plans. Meanwhile, manual plans of these patients were generated by 1 beginner planner and 1 senior planner respectively. Finally, dose distribution, dosimetric parameters and planning time were analyzed. In addition, the 3 types of plans were blinded compared and ranked by an experienced oncologist. Results: There were almost no statistically differences among these 3 types of plans in target coverage and dose conformity. Dose homogeneity were slightly decreased while the average dose and parameters for most organs-at-risk (OARs) were decreased in automatic plans. Especially in comparison with manual plans by the beginner planner, V40 of bladder and rectum decreased 6.3% and 12.3%, while mean dose of rectum and marrow were 1.1 Gy and 1.8 Gy lower with automatic plans (either P < 0.017). In the blinded comparison, automatic plans were chosen as best plan in 14 cases. Conclusions: For cervical cancer, automatic IMRT plans optimized from the CNN generated objectives have superior dose sparing without compromising of target dose. It significantly reduced the planning time.

MiR-101-3p Suppresses Progression of Cervical Squamous Cell Carcinoma by Targeting and Down-Regulating KPNA2

Objective We explored mechanism of microRNA-101-3p/Karyopherin α2 (KPNA2) axis in cervical squamous cell carcinoma. Methods: Bioinformatics methods were applied to identify genes for the study. Cell functional assays were implemented to examine the role of the genes in malignant progression of cervical squamous cell carcinoma. Targeting relationship between genes was verified by dual-luciferase assay. Results: MicroRNA-101-3p was lowly expressed in cervical squamous cell carcinoma, while KPNA2 was highly expressed. Dual-luciferase assay identified direct targeting relationship between microRNA-101-3p and KPNA2. Functional assays manifested that highly expressed microRNA-101-3p suppressed cervical squamous cell carcinoma cell growth by targeting KPNA2. Conclusion: Overall, microRNA-101-3p/KPNA2 axis can play an important part in progression of cervical squamous cell carcinoma.

Ovarian Function Preservation in Patients With Cervical Cancer Undergoing Hysterectomy and Ovarian Transposition Before Pelvic Radiotherapy

To examine the factors associated with ovarian failure (OF) and assess the effectiveness of ovarian transposition (OT) before pelvic irradiation for preserving ovarian function in patients with cervical cancer (CC) undergoing hysterectomy. During 2003 to 2017, patients who underwent hysterectomy with preservation of one or both ovaries were retrospectively enrolled. Patients were divided into 4 groups, depending on whether radiotherapy (RT) and OT were performed: group 1, RT(+) and OT(+); group 2, RT(+) and OT(−); group 3, RT(−) and OT(+); group 4, RT(−) and OT(−). OF was defined as serum follicle-stimulating hormone levels of ≥30 mIU/mL. Sixty-six patients (59 [89.4%] invasive CC and 7 [10.6%] cervical intraepithelial neoplasia) were included. The 2-year OF-free survival rate was 61.4% (95% confidence interval [CI] 37.8-86.0), 0%, 91.7% (95% CI 76.0-100), and 75.8% (95% CI 58.2-93.4) for groups 1, 2, 3, and 4, respectively. In groups 1 and 2 receiving RT, OT, and combination of external beam radiotherapy and vaginal brachytherapy were associated with OF on multivariate analysis (MVA) ( P-value  =  .002 and .046, respectively). In groups 3 and 4 without RT, older age (40 years old) and OT did not affect OF; however, the number of remaining ovaries was independently associated with OF in MVA ( P  =  .035). OT could effectively preserve ovarian function in patients treated with adjuvant RT, while OT procedure itself did not affect ovarian failure. OT should be considered in the management of premenopausal cervical cancer patients.

Pretreatment Squamous Cell Carcinoma Antigen (SCC-Ag) as a Predictive Factor for the Use of Consolidation Chemotherapy in Cervical Cancer Patients After Postoperative Extended-Field Concurrent Chemoradiotherapy

Objective: The goal of this study was to confirm the clinical value of pretreatment serum squamous cell carcinoma antigen (SCC-Ag) in the administration of consolidation chemotherapy in patients with cervical cancers undergoing postoperative extended-field radiotherapy (EFRT) and concurrent chemotherapy (CCRT). Methods: Between 2007 and 2018, a total of 113 patients were treated with postoperative extended-field intensity-modulated radiotherapy (EF-IMRT) and CCRT. There were 63 patients receiving extended-field concurrent chemoradiotherapy (EF-CCRT) and consolidation chemotherapy, while another 50 patients underwent EF-CCRT alone. For the planning target volume, the prescribed dose was 45 to 50.4Gy/25 to 28 fractions. The consolidation chemotherapy regimen contained docetaxel and cisplatin. Results: For the patients with high pretreatment SCC-Ag, the addition of consolidation chemotherapy significantly improved their treatment outcomes and they had better 5-year overall survival (OS) (81.02% vs 63.44%, P = .018) and disease-free survival (DFS) (76.95% vs 61.12%, P = .007) than those without it. Meanwhile, the patients with consolidation chemotherapy had a lower rate of distant metastasis (8.8% vs 34.8%, P = .001). For the patients with low pretreatment SCC-Ag, there was no difference in prognosis between patients receiving consolidation chemotherapy and those not receiving consolidation. In multivariate analysis, consolidation chemotherapy was found to be a factor significantly associated with DFS ( P = .035, 95% confidence interval (CI): 0.304-0.977) and distant metastasis ( P = .009, 95% CI: 0.125-0.841). Conclusion: The patients who received consolidation chemotherapy showed significantly better DFS. Furthermore, pretreatment serum SCC-Ag > 6.5 ng/mL may be a predictive factor for the use of consolidation chemotherapy in cervical cancer patients treated with postoperative EF-CCRT.

The Influence of Different Ultrasonic Machines on Radiomics Models in Prediction Lymph Node Metastasis for Patients with Cervical Cancer

Objective To investigate the effects of different ultrasonic machines on the performance of radiomics models using ultrasound (US) images in the prediction of lymph node metastasis (LNM) for patients with cervical cancer (CC) preoperatively. Methods A total of 536 CC patients with confirmed histological characteristics and lymph node status after radical hysterectomy and pelvic lymphadenectomy were enrolled. Radiomics features were extracted and selected with US images acquired with ATL HDI5000, Voluson E8, MyLab classC, ACUSON S2000, and HI VISION Preirus to build radiomics models for LNM prediction using support vector machine (SVM) and logistic regression, respectively. Results There were 148 patients (training vs validation: 102:46) scanned in machine HDI5000, 75 patients (53:22) in machine Voluson E8, 100 patients (69:31) in machine MyLab classC, 110 patients (76:34) in machine ACUSON S2000, and 103 patients (73:30) in machine HI VISION Preirus, respectively. Few radiomics features were reproducible among different machines. The area under the curves (AUCs) ranged from 0.75 to 0.86, 0.73 to 0.86 in the training cohorts, and from 0.71 to 0.82, 0.70 to 0.80 in the validation cohorts for SVM and logistic regression models, respectively. The highest difference in AUCs for different machines reaches 17.8% and 15.5% in the training and validation cohorts, respectively. Conclusions The performance of radiomics model is dependent on the type of scanner. The problem of scanner dependency on radiomics features should be considered, and their effects should be minimized in future studies for US images.

Bispecific c-Met/PD-1 CAR-T Cells Have Enhanced Therapeutic Effects on Solid Tumor

Objective To evaluate the killing effect of c-Met CAR-T on tumor cells with different degrees of c-Met expression. It was demonstrated that CAR-T autocrine PD-1 antibody could alleviate immune checkpoint inhibition and enhance the anti-tumor effect of T cells. Methods The specificity and clinical significance of c-Met and PD-L1 expression in various solid tumors were verified by bioinformatics analysis. c-Met specific CAR-T and c-Met specific CAR-T secreted by PD-L1 were synthesized, and c-Met CAR-T and c-Met/PD-1 CAR-T were prepared by constructing lentivirus. Flow cytometry was used to verify the positive rate and cell population of CAR-T, western blot was used to verify the secretion of PD-1 antibody, and cck-8 was used to detect the proliferation of CAR-T in tumor cells with different c-Met expression. LDH and ELISA further evaluated the antitumor effects of c-Met CAR-T and c-Met/PD-1 CAR-T in vitro. Results c-Met and PD-L1 were expressed in pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, glioma and other tumors, and were associated with a variety of immune cell infiltration. Tumor cells with high expression of c-Met can strongly stimulate the proliferation of c-Met CAR-T, and c-Met CAR-T has strong cell lysis ability on tumor cells with high expression of c-Met. Autocrine PD-1 antibody can significantly improve the activity of c-Met CAR T cells, tumor lysis ability and cytokine secretion level. Conclusion The antitumor activity of c-Met CAR-T is positively correlated with the expression of c-Met. c-Met CAR-T secreted by PD-1 showed enhanced antitumor function in solid tumor treatment.

Small Nucleolar RNAs as Diagnostic and Prognostic Biomarkers in Cancer: A Systematic Review and Meta-Analysis

Objectives Small nucleolar RNAs (snoRNAs) form clusters within the genome, representing a mysterious category of small non-coding RNAs. Research has demonstrated that aberrant snoRNAs can contribute to the development of various types of cancers. Recent studies have identified snoRNAs as potentially valuable biomarkers for the diagnosis or/and prognosis of cancers. However, there has been a lack of comprehensive reviews on prognostic and diagnostic snoRNAs across different types of cancers. Methods We conducted a systematic search of various databases including Google Scholar, Medline, Cochrane, Scopus, PubMed, Embase, ScienceDirect, Ovid-Medline, Chinese National Knowledge Infrastructure, WanFang, and SinoMed with a time frame reception to December 30, 2022. A total of 49 relevant articles were included in our analysis, consisting of 21 articles focusing on diagnostic aspects and 41 articles focusing on prognostic aspects. Pooled odds ratio, 95% confidence intervals (CIs), and hazard ratio (HR) were utilized to evaluate clinical parameters and overall survival (OS), respectively. Result The findings indicated that area under the curve, sensitivity, and specificity were 0.85, 75%, and 80% in cancer, respectively. There was a possibility that snoRNAs had a positive impact on the diagnosis (risk ratio, RR = 2.95, 95% CI: 2.75-3.16, P = 0.000) and OS (HR = 1) in cancer. Additionally, abnormally expressed snoRNAs were associated with a positive impact on OS time for chronic lymphocytic leukemia (HR: 0.88, 95%Cl: 0.69-1.11, P < 0.00001), colon adenocarcinoma (HR: 0.97, 95%Cl: 0.91-1.03, P < 0.0001), and ovarian cancer (HR: 0.98, 95%Cl: 0.98-0.99, P < 0.00001). However, dysregulated snoRNAs of colon cancer and colorectal cancer had a negative impact on OS time (HR = 3.01 and 1.01 respectively, P < 0.0001). Conclusion The results strongly suggested that snoRNAs could serve as potential novel indicators for prognosis and diagnosis in cancers. This systematic review followed the guidelines of the Transparent Reporting of Systematic Review and Meta-Analyses (PROSPERO register: CRD42020209096).

Endometrial Cancer Detection by DNA Methylation Analysis in Cervical Papanicolaou Brush Samples

Background: Endometrial cancer (EC) is the leading gynecological cancer worldwide, yet current EC screening approaches are not satisfying. The purpose of this retrospective study was to evaluate the feasibility and capability of DNA methylation analysis in cervical Papanicolaou (Pap) brush samples for EC detection. Methods: We used quantitative methylation-sensitive PCR (qMS-PCR) to determine the methylation status of candidate genes in EC tissue samples, as well as cervical Pap brushes. The ability of RASSF1A and HIST1H4F to serve as diagnostic markers for EC was then examined in cervical Pap brush samples from women with endometrial lesions of varying degrees of severity. Results: Methylated RASSF1A and HIST1H4F were found in EC tissues. Further, methylation of the two genes was also observed in cervical Pap smear samples from EC patients. Methylation levels of RASSF1A and HIST1H4F increased as endometrial lesions progressed, and cervical Pap brush samples from women affected by EC exhibited significantly higher levels of methylated RASSF1A and HIST1H4F compared to noncancerous controls ( P < .001). Receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses revealed RASSF1A and HIST1H4F methylation with a combined AUC of 0.938 and 0.951 for EC/pre-EC detection in cervical Pap brush samples, respectively. Conclusion: These findings demonstrate that DNA methylation analysis in cervical Pap brush samples may be helpful for EC detection, broadening the scope of the commonly used cytological screening. Our proof-of-concept study provides new insights into the field of clinical EC diagnosis.

Efficacy and Safety Analysis of Recombinant Human Endostatin (Endostar) Combined With Chemoradiotherapy for Locally Advanced Cervical Cancer: A 2-Center Retrospective Study

Background This study aims to assess the efficacy and safety of Endostar in the management of locally advanced cervical cancer. Methods This retrospective, 2-center study enrolled 41 patients with locally advanced cervical cancer between June 2017 and December 2020. The patients were subjected to a combination of Endostar and chemoradiotherapy until they experienced disease progression or an unacceptable level of toxicity. The patients in the Endostar combined chemoradiotherapy (E + CRT) and CRT groups were matched 1:1 based on clinical features, including age, disease stage, and pathological type. The therapeutic efficacy and safety outcomes were compared between the 2 groups. Results Early treatment response: the CR rates in E + CRT and CRT groups were 48.8% and 26.8%, respectively ( χ2 = 4.20, P < .05). The ORR and DCR were not significantly different between the 2 groups. Long-term efficacy: there was no significant difference in the 1-year and 2-year PFS rates and OS rates between 2 groups. However, in patients with stage IIB, subgroup analyses revealed a significant difference in PFS between the 2 groups ( P < .05). Prognostic factors: stage, Eastern Cooperative Oncology Group (ECOG) score, and tumor size were independent predictive factors for PFS, while ECOG score and tumor size were those of OS in patients with locally advanced cervical cancer. Safety: The incidence of grade III-IV myelosuppression was significantly lower in E + CRT group than in CRT group ( P < .05). Conclusions The combination of Endostar and concurrent CRT exhibited greater efficacy in treating locally advanced cervical cancer with no severe adverse reactions, when compared to simple CRT. It is expected that this approach will evolve into a new treatment alternative for patients with locally advanced cervical cancer.

Comprehensive Analysis of ESRRA in Endometrial Cancer

Background: Estrogen-related receptor alpha (ESRRA) was reported to play an important role in multiple biological processes of neoplastic diseases. The roles of ESRRA in endometrial cancer have not been fully investigated yet. Methods: Expression data and clinicopathological data of patients with uteri corpus endometrial carcinoma (UCEC) were obtained from The Cancer Genome Atlas (TCGA). Comprehensive bioinformatics analysis was performed, including receiver operating characteristics (ROC) curve analysis, Kaplan-Meier survival analysis, gene ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Immunohistochemistry was used to detect the protein expression level of ESRRA and CCK-8 assay was performed to evaluate the effect of ESRRA on the proliferation ability. Results: A total of 552 UCEC tissues and 35 normal tissues were obtained from the TCGA database. The mRNA and protein expression level of ESRRA was highly elevated in UCEC compared with normal tissues, and was closely associated with poor prognosis. ROC analysis indicated a very high diagnostic value of ESRRA for patients with UCEC. GO and GSEA functional analysis showed that ESRRA might be mainly involved in cellular metabolism processes, in turn, tumorigenesis and progression of UCEC. Knockdown of ESRRA inhibited the proliferation of UCEC cells in vitro. Further immune cell infiltration demonstrated that ESRRA enhanced the infiltration level of neutrophil cell and reduced that of T cell (CD4+ naïve), NK cell, and cancer associated fibroblast (CAF). The alteration of immune microenvironment will greatly help in developing immune checkpoint therapy for UCEC. Conclusions: Our study comprehensively analyzed the expression level, clinical value, and possible mechanisms of action of ESRRA in UCEC. These findings showed that ESRRA might be a potential diagnostic and therapeutic target.

Literature Review and Our Experience With Bleomycin-Based Electrochemotherapy for Cutaneous Vulvar Metastases From Endometrial Cancer

Endometrial carcinoma is the most common gynecological malignancy and the fifth most common malignancy in women. The worldwide incidence is 15.9 new cases per 100,000 women per year, and the incidence in Europe is 22.7 new cases. Minority of cases are diagnosed at an advanced stage of the disease. Cutaneous metastases are very rare with a prevalence of 0.8%. If cutaneous metastases are present, the prognosis is poor with an overall survival of up to 12 months. In this review, we presented clinical data on treatment of gynecological cancers with electrochemotherapy, with focus on treatment of cutaneous vulvar metastases from endometrial cancer. Further, we present our data on the case of a 64-year-old woman with recurrent endometrial adenocarcinoma with vulvar skin metastases. Treatment of endometrial carcinoma metastases is multimodal with surgery, chemotherapy, radiotherapy and hormone treatment. There is still no consensus about the specific treatment of cutaneous metastases from endometrial cancer, in particular in order to release symptoms. Electrochemotherapy may be a treatment option to reduce pain and bleeding and a safe option to treat multiple skin metastases.

NLRC5 Might Promote Endometrial Cancer Progression by Inducing PD-L1 Expression

Aims: The NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5 (NLRC5) was dysregulated in endometrial cancer (EC). However, the potential regulatory mechanisms of NLRC5 in EC remained unclear. We aimed to explore whether NLRC5 could regulate the programmed cell death protein ligand 1 (PD-L1) in EC. We also investigated the related molecular which led to the inactivation of NLRC5 in EC. Methods: The expressions of NLRC5 and PD-L1 in endometrium tissue microarray were detected by immunohistochemistry. Pearson’s correlation analysis was performed to detect the expression correlation between NLRC5 and PD-L1. Immunofluorescence staining, western blotting, and quantitative real-time PCR (qRT-PCR) were used to detect the role of NLRC5 in PD-L1 in EC cell lines. The somatic mutation in EC patients was detected by whole-exome sequencing (WGS). Results: NLRC5 was downregulated in the endometrium of EC patients when compared to those in the normal endometrium. The level of PD-L1 in the endometrium of EC patients was higher when compared to those in the normal endometrium. There was a negative expression correlation between NLRC5 and PD-L1. NLRC5 could promote the expression of PD-L1 in EC cell lines. The mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Conclusion: NLRC5 could inhibit the activation of PD-L1 in EC. Mutations of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK may lead to the downregulation of NLRC5 in EC patients. Future study should investigate the mechanism of NLRC5 in PD-L1, as well as the mechanism of ANKRD20A2, C2orf42, ADGRB3, AVPR2, GOLGA6C, and IPPK in NLRC5.

MicroRNA-133b Inhibits nTumor Cell Proliferation, Migration and Invasion by Targeting SUMO1 in Endometrial Carcinoma

Objectives: An increasing number of studies have confirmed that microRNAs (miRNAs/miRs), as oncogenes or tumor suppressor genes, play an important regulatory role in the occurrence and development of numerous types of cancer. The aim of the present study was to investigate the potential role and mechanism of miR-133b and small ubiquitin like modifier 1 (SUMO1) in the development of endometrial carcinoma (EC). Methods: First, Venn diagrams are used to identify the differential expressions of miRNAs in EC from GSE35794 and GSE25405 datasets. Next, we conduct a series of functional tests, including Cell Counting Kit-8, wound healing, and transwell and matrigel assays. Then, a bioinformatics tool, is used to identify downstream target genes of miR-133b and to verify the predicted results by RT-qPCR, Western blotting and double luciferase reporter gene analysis. Finally, in order to further study whether the cellular function of miR-133b is mediated by the expression of SUMO1, rescue experiments were carried out. Results: The results of bioinformatics studies showed that the expression of miR-133b was down-regulated in EC tissues, and the expression level of miR-133b was lower in patients with high grade, different histology or menopausal status. The results of functional assay showed that overexpression of miR-133b reduced cell proliferation, migration and invasion. On the contrary, miR-133b silence has the opposite effect. SUMO1 was the direct target of miR-133b and was negatively regulated by miR-133b. The decrease of SUMO1mRNA expression inhibited the proliferation, migration and invasion of EC cells, and reversed the effect of miR-133b on EC cells. Conclusion: The findings from the present study suggested that miR-133b may be a tumor suppressor gene and a potential therapeutic target for the treatment of EC.

RETRACTED: Long Noncoding RNA HOXB-AS1 Is Upregulated in Endometrial Carcinoma and Sponged miR-149-3p to Upregulate Wnt10b

The functions of Long noncoding RNA (lncRNA) HOXB-AS1 have been investigated in glioblastoma and multiple myeloma. However, the role of lncRNA HOXB-AS1 in endometrial carcinoma (EC) remains largely unknown. This study investigated the underlying mechanisms of the lncRNA HOXB-AS1 on the progression of EC. In this study, We found that HOXB-AS1 expression was significantly upregulated in EC tissue samples and was associated with shorter survival time. Furthermore, upregulation of HOXB-AS1 promoted proliferation, invasion, and migration of EC cell. HOXB-AS1 and Wnt10b directly bound to miR-149-3p. HOXB-AS1 increased the expression of Wnt10b by binding to miR-149-3p. We further verified the upregulation of β-catenin, cyclin D1, and c-myc induced by HOXB-AS1. In conclusion, our results indicated that HOXB-AS1 exerted oncogenic function as competing endogenous RNA (ceRNA) of miR-149-3p to release Wnt10b and activated Wnt/β-catenin pathway.

Clinical Outcomes and Prognostic Factors in Stage III C Cervical Cancer Patients Treated with Radical Radiotherapy or Radiochemotherapy

Objective: Since the update of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging criteria, there have been few reports on the prognosis of stage III C cervical cancer. Moreover, some studies have drawn controversial conclusions, necessitating further verification. This study aims to evaluate the clinical outcomes and determine the prognostic factors for stage III C cervical cancer patients treated with radical radiotherapy or radiochemotherapy. Methods: The data of 117 stage III C cervical cancer patients (98 III C1 and 19 III C2) who underwent radical radiotherapy or radiochemotherapy were retrospectively analyzed. We evaluated 3-year overall survival (OS) and disease-free survival (DFS) using the Kaplan–Meier method. Prognostic factors were analyzed using the Log-rank test and Cox proportional hazard regression model. The risk of para-aortic lymph node metastasis (LNM) in all patients was assessed through Chi-squared test and logistic regression analysis. Results: For stage III C1 and III C2 patients, the 3-year OS rates were 77.6% and 63.2% ( P = .042), and the 3-year DFS rates were 70.4% and 47.4% ( P = .003), respectively. The pretreatment location of pelvic LNM, histological type, and FIGO stage was associated with OS ( P = .033, .003, .042, respectively); the number of pelvic LNM and FIGO stage were associated with DFS ( P = .015, .003, respectively). The histological type was an independent prognostic indicator for OS, and the numbers of pelvic LNM and FIGO stage were independent prognostic indicators for DFS. Furthermore, a pelvic LNM largest short-axis diameter ≥ 1.5 cm and the presence of common iliac LNM were identified as high-risk factors influencing para-aortic LNM in stage III C patients ( P = .046, .006, respectively). Conclusions: The results of this study validated the 2018 FIGO staging criteria for stage III C cervical cancer patients undergoing concurrent chemoradiotherapy. These findings may enhance our understanding of the updated staging criteria and contribute to better management of patients in stage III C.

Knockdown of Ubiquitin-Specific Protease 53 Enhances the Radiosensitivity of Human Cervical Squamous Cell Carcinoma by Regulating DNA Damage-Binding Protein 2

Background: Cervical cancer ranks fourth in incidence and mortality among women. Ubiquitin-specific protein 53 binds to damage-specific DNA binding protein 2 and affects the biological properties of colon cancer. Damage-specific DNA binding protein is involved in nucleotide excision repair, which can repair DNA damage. However, the mechanism by which ubiquitin-specific protein 53 regulates the radiosensitivity of cervical cancer through damage-specific DNA binding protein remains unclear. Methods: Tissue samples from 40 patients with cervical squamous cell carcinoma who received radiotherapy were examined by immunohistochemistry to detect the expression of ubiquitin-specific protein 53, and clinical data were collected for statistical analysis. The cell cycle was detected by flow cytometry in Siha cells transfected with Si-USP53 and exposed to 8 Gy irradiation. Cell viability was determined by the CCK8 method in cells transfected with Si-USP53 and exposed to 0, 2, 4, 6, 8, or 10 Gy. The expression of damage-specific DNA binding protein, cyclin-dependent kinase 1, and cell cycle checkpoint kinase 2 was detected in cells transfected with Si-USP53. Results: The expression of ubiquitin-specific protein 53 in the tissues of patients with cervical squamous cell carcinoma was correlated with the sensitivity to radiotherapy. Knockdown of ubiquitin-specific protein 53 in Siha cells downregulated damage-specific DNA binding protein and caused G2/M cell cycle arrest and decreased the survival rate of cells in response to radiation. Conclusion: Ubiquitin-specific protein 53–induced cell cycle arrest and affected the radiotherapy sensitivity of tumors through damage-specific DNA binding protein.

MicroRNA-592 Inhibits the Growth of Ovarian Cancer Cells by Targeting ERBB3

Objectives: Ovarian cancer is the most lethal gynecologic malignancy, and targeted therapy for different pathological types and molecular phenotypes is urgent to be studied. Studies have shown that MicroRNA-592 (miR-592) plays an important negative regulatory role in the occurrence of gastrointestinal malignancies, breast cancer, non-small cell lung cancer, and glioma, but the expression of miR-592 in ovarian cancer and the mechanism of action are still unclear. Methods: The expressions of miR-592 were examined by RT-PCR and Western Blot. Cell viability and migratory capacity were detected by CCK-8 and transwell assay. TargetScan ( http://www.targetscan.org ) was analyzed to predict potential targets of miR-592. Then Dual-luciferase reporter gene assay was performed to verify the targeting relationship between miR-592 and ERBB3. A mouse xenograft model was applied to confirm the effect of miR-592. Results: In our study, we found that the expression of miR-592 is reduced in epithelial ovarian cancer tissues. The exogenous expression of miR-592 inhibits the proliferation, migration, and invasion in epithelial ovarian cancer tumor cells. Furthermore, the exogenous expression of miR-592 inhibits tumor growth in the nude mouse xenograft model. Therefore, miR-592 may play a role of tumor suppressor miRNA in the occurrence and development of ovarian cancer. Further experiments demonstrated that tumor-related ERBB3 is a target gene mediated by miRNA-592. The dual-luciferase reporter system was used to identify miRNA-592 target genes; qPCR and Western Blot were used to detect the expression of ERBB3. Mechanical experiments confirmed that miRNA-592 negatively regulated ERBB3.Conclusion: Together, these findings identify a heretofore unrecognized link between miR-592 and ERBB3 and suggest that targeting on miR-592 warrants attention as a novel and potential therapeutic strategy for ovarian cancer.

Screening and Discovery of New Potential Biomarkers and Small Molecule Drugs for Cervical Cancer: A Bioinformatics Analysis

Background: Cervical cancer (CC) is the second most common type of malignant tumor survival rate is low in advanced stage, metastatic, and recurrent CC patients. This study aimed at identifying potential genes and drugs for CC diagnosis and targeting therapies. Methods: Three GEO mRNA microarray datasets of CC tissues and non-cancerous tissues were analyzed for differentially expressed genes (DEGs) by limma package. GO (Gene Ontologies) and KEGG (Kyoto Encyclopedia of Genes and Genomes) were used to explore the relationships between the DEGs. Protein-protein interaction (PPI) of these genes was established by the STRING database. MCODE was used for screening significant modules in the PPI networks to select hub genes. Biochemical mechanisms of the hub genes were investigated with Metascape. GEPIA database was used for validating the core genes. According to these DEGs, molecular candidates for CC were recognized from the CMAP database. Results: We identified 309 overlapping DEGs in the 2 tissue-types. Pathway analysis revealed that the DEGs were involved in cell cycle, DNA replication, and p53 signaling. PPI networks between overlapping DEGs showed 68 high-connectivity DEGs that were chosen as hub genes. The GEPIA database showed that the expression levels of RRM2, CDC45, GINS2, HELLS, KNTC1, MCM2, MYBL2, PCNA, RAD54 L, RFC4, RFC5, TK1, TOP2A, and TYMS in CC tissues were significantly different from those in the healthy tissues and were significantly relevant to the OS of CC. We found 10 small molecules from the CMAP database that could change the trend of gene expression in CC tissues, including piperlongumine and chrysin. Conclusions: The 14 DEGs identified in this study could serve as novel prognosis biomarkers for the detection and forecasting of CC. Small molecule drugs like piperlongumine and chrysin could be potential therapeutic drugs for CC treatment.

Clinical Significance of Soluble LAG-3 (sLAG-3) in Patients With Cervical Cancer Determined via Enzyme-Linked Immunosorbent Assay With Monoclonal Antibodies

Background: The tumor microenvironment and tumor immunity have become the focus of research on tumor diagnosis and treatment. Lymphocyte activation gene-3 (LAG-3, CD223) is a newly discovered immunosuppressive receptor that is abnormally expressed in various tumor microenvironments and plays an important role as an immune checkpoint in the tumor immune response. Objective: We developed a novel enzyme-linked immunosorbent assay kit, examined the levels of soluble LAG-3 (sLAG-3) in the serum of patients with cervical cancer, and identified new biomarkers for cervical cancer development. Methods: To investigate the potential biological function of sLAG-3, we generated and characterized 2 novel anti-LAG-3 monoclonal antibodies, namely 4F4 and 4E12. We performed western blotting, immunofluorescence, and immunohistochemistry using hybridoma technology and an enzyme-linked immunosorbent assay kit for detecting human sLAG-3 based on an improved double-antibody sandwich enzyme-linked immunosorbent assay method. The stability and sensitivity of these kits were also assessed. Results: We screened and characterized 2 novel monoclonal antibodies against human LAG-3. The enzyme-linked immunosorbent assay kit also includes a wide range of tests. Using this enzyme-linked immunosorbent assay system, we found that the expression level of sLAG-3 in the peripheral blood of patients with cervical cancer significantly decreased as the disease progressed ( P < .0001). Multivariate logistic regression analysis revealed that low sLAG-3 expression was an independent predictor of cervical cancer and related diseases ( P < .05). Furthermore, receiver operating characteristic curve analysis showed that sLAG-3 had diagnostic value for cervical cancer metastasis ( P < .0001). Conclusion: These data suggest that sLAG-3 is a potential biomarker for cervical cancer development. Therefore, this kit has a certain application value in the diagnosis of cervical cancer.

Research Progress of Immuno-Inhibitory Receptors in Gynecological Cervical Cancer

The mortality rate of cervical cancer is the highest among female malignant tumors and seriously threatens women's lives and health. Persistent high-risk human papillomavirus (HPV) infection is the leading cause of cervical cancer, which provides the basis for immunotherapy. In recent years, owing to progress in targeted therapy and immunotherapy, the survival time of patients with cervical cancer has been significantly extended. However, effective treatments for advanced, recurrent, and metastatic cancers are lacking. “Tumor immunotherapy” has been described as a viable option for tumor therapy but the efficacy of immunotherapy for cervical cancer has only been demonstrated in phase I or II clinical trials. Immune checkpoint inhibitors (ICIs) have shown promising clinical results particularly for treating recurrent and advanced cervical cancer, however, they remain inadequate in some patients. Immune checkpoint is the target of immunotherapy. Therefore, the identification of novel therapeutic targets is essential. In this paper, the structure, expression, function, biological effect of immune inhibitory receptors (IRs) and related clinical studies were reviewed, in order to further explore the application potential of these immune checkpoints and apply them to the future clinical treatment of cervical cancer.

The Efficacy of Volumetric Modulated Arc Therapy Combined With Chemotherapy, Brachytherapy, and Local Hyperthermia on Patients with Locally Advanced Cervical Cancer: A Retrospective Study

Objective To evaluate the clinical outcomes of volumetric modulated arc therapy (VMAT) followed by brachytherapy (BT), combined with chemotherapy, and local hyperthermia (HT) on locally advanced cervical cancer (LACC). Methods In total, 40 patients with FIGO stage IB1-IVB cervical cancer from January 2016 to December 2018 were selectively enrolled in this study. All patients were treated with VMAT (50.4 Gy/1.8 Gy/28 f) concurrent with cisplatin-based chemotherapy (40 mg/m 2 , q1w, 6 cycles) and local HT (40.5-41°C for 60 min, BIW). BT (30-36 y/5-6 f, 2 f/w) was conducted after VMAT. Objective response rate (ORR), local control (LC) time, LC rate, progression-free survival (PFS) rate, cancer-specific survival (CSS) rate, overall survival (OS), median time to tumor progression and treatment-related toxicity were evaluated. Results The median follow-up time was 31 months (8-48). The ORR was 100% at 3 months after treatment and 92.1% at 6 months, respectively. The 1-year, 2-year, and 3-year LC rates were 87.4%, 81.9%, and 70.9%, respectively. The average LC time was 31.50 ± 1.89 months (95% CI 27.79-35.21). The 1-year, 2-year, and 3-year PFS rates were 75.85%, 61.2%, and 51.3%, respectively, while the median PFS was 27.07 months. The 1-year, 2-year, and 3-year OS rates were 95%, 84%, and 79.6%, respectively. In total, 12(30%) patients had grade 3/4 bone marrow suppression. One patient had grade 4 leukopenia. In total, 17 patients had grade 1/2 bone marrow suppression. Two patients had grade 3 nausea and grade 3 vomiting reaction, respectively. No grade 3/4 proctitis and bladder reaction were observed. In the late period of treatment, 1 patient had a rectal hemorrhage. In total, 13 patients had vaginal stenosis. Conclusion VMAT concurrent with chemotherapy, BT, and local HT had a favorable short-term efficacy and acceptable toxicity on cervical cancer, which was an alternative option for LACC.

The Prevalence, Associated Factors for Lung Metastases Development and Prognosis in Ovarian Serous Cancer Based on SEER Database

Ovarian carcinoma (OC) is one of the 3 most common gynecological malignancies, and the prognosis of patients with lung metastasis was the worst. SEER documented OC patients, diagnosed between 2010 and 2016, were included in the study. Univariable and multivariable logistic regression analyses were performed to identify associated factors for lung metastases (LM) development. Kaplan–Meier analysis was used to estimate the overall survival for OC patients with LM. A total of 10146 eligible serous ovarian cancer (SOC) patients were included, the prevalence of LM was 3.77% (N = 378). Patients with T4 stage (χ2 = 128.515; P = 0.000), N1 stage (χ2 = 49.536; P = 0.000), right laterality (χ2 = 18.756; P = 0.000) (compared with left side), undifferentiated grade (χ2 = 36.174; P = 0.000), bone metastasis (χ2 = 183.529); P = 0.000), brain metastasis (χ2 = 117.539; P = 0.000), liver metastasis (χ2 = 442.472; P = 0.000) had a larger probability of LM than other groups. Results showed that T3/N1 stage, bone metastases, liver metastases, chemotherapy, surgery were positively correlated with LM. Multivariable cox analysis showed that age, bone metastasis, no chemotherapy, no surgery were independent risk factors in SOC-LM patients. This study provided new research insights on the prevalent LM in patients with SOC. The factors associated with LM development and prognosis can be potentially used for LM early screening and professional care.

The BRCA2 p.N372 H i.a.1342A>C Could Regulate the Sensitivity of Ovarian Cancer Cells to Platinum-Based Drugs

Background and Objective: We have previously reported that BRCA2 N372 H i.a.1342A>C heterozygous variation presented in platinum-resistant patients. This study aimed to further investigate the mechanism of BRCA2 N372 H mutation in the development of platinum resistance in ovarian cancer. Methods: The BRCA2 N372 H i.a.1342A>C was synthesized and used to exchange 1 wildtype allele followed by sequencing to confirm the mutant allele sequence. Plasmids were constructed and transfected into the OVCAR-3 cells after lentiviral packaging. BRCA2 N372 H mRNA was detected by qPCR. BRCA2 protein was assessed by immunoblotting. Binding of the BRCA2 to Rad51 was detected by immunofluorescence staining. Sensitivity of the cells to cisplatin treatment was assessed with CCK-8 assay. Results: It was found that expression of BRCA2 protein in ovarian cancer cells transfected with BRCA2 N372 H i.a.1342A>C gene (2.177 ± 0.003) was significantly increased compared to that of the cells transfected with lenti-EGFP only (1.227 ± 0.003, P < 0.001). Binding of the BRCA2 and Rad51 proteins was significantly increased in the cells with BRCA2 N372 H i.a.1342A>C mutation (3.542 ± 0.24) than that in the cells transfected with lenti-EGFP (1.29 ± 0.32) or empty cells (1.363 ± 0.32, P < 0.001). Cell viability significantly increased in the cells transfected with BRCA2 N372 H mutant gene. The IC50 value was significantly higher in the cells transfected with BRCA2 N372 H mutant gene (1.963 ± 0.04) than that of the cells transfected with lenti-EGFP (0.955 ± 0.03, P < 0.01) or empty cells (1.043 ± 0.007, P < 0.01). Conclusion: Over expression of mRNA and protein of BRCA2 was detected in the cells with BRCA2 N372 H i.a.1342A>C mutation but not in the lentivirus negative control (lenti-EGFP) or the cells without transfection (empty cells), which may lead to resistance to platinum-based drugs in ovarian cancer cells through homologous recombination repair pathway.

Periostin Secreted by Carcinoma-Associated Fibroblasts Promotes Ovarian Cancer Cell Platinum Resistance Through the PI3K/Akt Signaling Pathway

Periostin (POSTN) is a protein secreted by mesenchymal cells. Periostin is upregulated in several cancer types and overexpression is associated with poor prognosis. However, the functional role and molecular underpinnings of periostin in epithelial ovarian cancer (EOC) is unknown. In the present study, periostin was found to be significantly upregulated in EOC stroma. Functional studies revealed that periostin could decrease cisplatin (DDP)-induced apoptosis in EOC. Periostin led to DDP resistance in EOC cells, potentially through the PI3K/Akt signaling pathway. We generated periostin-overexpressing fibroblasts and found that EOC cells were resistant to DDP when co-cultured with periostin-overexpressing fibroblasts. The findings of the present study indicated that periostin secreted by cancer-associated stromal cells may be a potential therapeutic target for EOC.

Retrospective Study of the Epidemiology, Pathology, and Therapeutic Management in Patients With Mucinous Ovarian Tumors

Aim: We sought to determine the epidemiology of mucinous ovarian tumors, the correlation between serum biomarkers and tumor status, and the outcomes of the management in different subtypes of mucinous ovarian tumors in a Chinese surgical cohort. Methods: A total of 513 patients were enrolled from January 2009 to May 2017. The number of patients who had benign mucinous ovarian tumor, borderline mucinous ovarian tumor, or malignant mucinous ovarian tumor was pathologically quantified. All patients underwent surgery with or without postoperative adjuvant therapy. Prognosis was analyzed based on clinicopathological characteristics and the type of treatment received. Hyperthermic intraperitoneal chemotherapy efficacy and adverse effects in patients were also explored. Results: In all, 383 (75%) patients were diagnosed as having benign mucinous ovarian tumor, 76 (14%) patients with borderline mucinous ovarian tumor, and 54 (5%) patients with malignant mucinous ovarian tumor. Levels of serum biomarkers increased as the tumors became more malignant. Patients with stage IA and IC (unilateral) malignant mucinous ovarian tumor who underwent fertility conserving surgery did not experience poorer prognoses when compared to those who received non-fertility conserving surgery. Hyperthermic intraperitoneal chemotherapy followed by chemotherapy significantly influenced survival rates in patients with a ruptured malignant mucinous ovarian tumor. Conclusions: Levels of serum tumor markers, carbohydrate antigen 125, carbohydrate antigen 199, carbohydrate antigen 242, and carcinoembryonic antigen may be useful in monitoring for malignant transformation. Fertility conserving surgery might be a preferable surgical procedure for patients with malignant mucinous ovarian tumor at early stage (IA and IC [unilateral]). Hyperthermic intraperitoneal chemotherapy appears to be a well-tolerated and promising postoperative adjuvant.

RETRACTED: MicroRNA-199a Inhibits Cell Proliferation, Migration, and Invasion and Activates AKT/mTOR Signaling Pathway by Targeting B7-H3 in Cervical Cancer

Cervical cancer is a deadly disease. Some microRNAs are involved in tumor invasion and metastasis. Decreased expression of microRNA-199a has been correlated with tumorigenesis. In our study, the quantitative real-time polymerase chain reaction results indicated that microRNA-199a was expressed at lower levels in cervical cancer tissues, and the expression level of B7-H3 was significantly increased compared with that in the adjacent normal tissues, and the expression levels of B7-H3 and microRNA-199a in cervical cancer tissues and in adjacent normal tissues were inversely correlated. We also found that the expression of microRNA-199a was downregulated in cervical cancer cell lines when compared to immortalized cells. In this study, B7-H3 was identified as a novel target of microRNA-199a in cervical cancer. TargetScan (http://www.targetscan.org/) bioinformatics analysis was used to predict that the 3'-untranslated region of B7-H3 is a direct target of microRNA-199a. The result was also verified by the luciferase reporter assay. MicroRNA-199a could directly target the 3'-untranslated region of B7-H3, but the specific signaling pathways that were involved in regulating B7-H3 expression remained unclear. To clarify whether the suppressive effect of microRNA-199a was mediated through B7-H3, a series of experiments were performed. We found that the overexpression of microRNA-199a inhibited cell proliferation, migration, and invasion via direct binding to B7-H3. Epithelial-mesenchymal transition is a major factor involved in cervical cancer metastasis. Quantitative real-time polymerase chain reaction and western blot results indicated that microRNA-199a inhibits tumor progression in cervical cancer by targeting B7-H3. The microRNAs regulatory network is quite complex. We further examined the effect of microRNA-199a on the AKT/mTOR signaling pathway. We explored the regulatory role of microRNA-199a and first demonstrated that highly expressed microRNA-199a inhibits tumor growth and activates the AKT/mTOR signaling pathway by targeting B7-H3

Treatment Strategies and Prognostic Factors of 2018 FIGO Stage IIIC Cervical Cancer: A Review

Cervical cancer is the fourth most common malignant tumor globally in terms of morbidity and mortality. The presence of lymph node metastasis (LNM) is an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in cervical cancer patients. The International Federation of Gynecology and Obstetrics (FIGO) staging system was revised in 2018. An important revision designates patients with regional LNM as stage IIIC, pelvic LNM only as stage IIIC1, and para-aortic LNM as stage IIIC2. However, the current staging system is only based on the anatomical location of metastatic lymph nodes (LNs). It does not consider other LN status parameters, which may limit its prognostic significance to a certain extent and needs further exploration and confirmation in the future. The purpose of this review is to summarize the choice of treatment for stage IIIC cervical cancer and the effect of different LN status parameters on prognosis.

Examining the Association Between the COVID-19 Pandemic and the Rate of Diagnostic Tests for Breast, Cervical, and Colorectal Cancer in Manitoba, Canada

Background: Strategies to minimize the impact of the COVID-19 pandemic led to a reduction in diagnostic testing. It is important to assess the magnitude and duration of this impact to plan ongoing care and avoid long-lasting impacts of the pandemic. Objective: We examined the association between the COVID-19 pandemic and the rate of diagnostic tests for breast, cervical, and colorectal cancer in Manitoba, Canada. Design and Participants: A population-based, cross-sectional study design with an interrupted time series analysis was used that included diagnostic tests from January 1, 2015 until August 31, 2022. Setting: Manitoba, Canada. Main Outcomes: Outcomes included mammogram, breast ultrasound, colposcopy, and colonoscopy rates per 100,000. Cumulative and percent cumulative differences between the fitted and counterfactual number of tests were estimated. Mean, median, and 90th percentile number of days from referral to colonoscopy date by referral type (elective, semiurgent, urgent) were determined. Results: In April 2020, following the declaration of the COVID-19 public health emergency, bilateral mammograms decreased by 77%, unilateral mammograms by 70%, breast ultrasounds by 53%, colposcopies by 63%, and colonoscopies by 75%. In Winnipeg (the largest urban center in the province), elective and semiurgent colonoscopies decreased by 76% and 39%, respectively. There was no decrease in urgent colonoscopies. As of August 2022, there were an estimated 7270 (10.7%) fewer bilateral mammograms, 2722 (14.8%) fewer breast ultrasounds, 836 (3.3%) fewer colposcopies, and 11 600 (13.8%) fewer colonoscopies than expected in the absence of COVID-19. As of December 2022, in Winnipeg, there were an estimated 6030 (23.9%) fewer elective colonoscopies, 313 (2.6%) fewer semiurgent colonoscopies, and 438 (27.3%) more urgent colonoscopies. Conclusions: In Manitoba, the COVID-19 pandemic was associated with sizable decreases in diagnostic tests for breast, colorectal, and cervical cancer. Two and a half years later, there remained large cumulative deficits in bilateral mammograms, breast ultrasounds, and colonoscopies.

A Comparative Study of Deep Learning Dose Prediction Models for Cervical Cancer Volumetric Modulated Arc Therapy

Purpose: Deep learning (DL) is widely used in dose prediction for radiation oncology, multiple DL techniques comparison is often lacking in the literature. To compare the performance of 4 state-of-the-art DL models in predicting the voxel-level dose distribution for cervical cancer volumetric modulated arc therapy (VMAT). Methods and Materials: A total of 261 patients’ plans for cervical cancer were retrieved in this retrospective study. A three-channel feature map, consisting of a planning target volume (PTV) mask, organs at risk (OARs) mask, and CT image was fed into the three-dimensional (3D) U-Net and its 3 variants models. The data set was randomly divided into 80% as training-validation and 20% as testing set, respectively. The model performance was evaluated on the 52 testing patients by comparing the generated dose distributions against the clinical approved ground truth (GT) using mean absolute error (MAE), dose map difference (GT-predicted), clinical dosimetric indices, and dice similarity coefficients (DSC). Results: The 3D U-Net and its 3 variants DL models exhibited promising performance with a maximum MAE within the PTV 0.83% ± 0.67% in the UNETR model. The maximum MAE among the OARs is the left femoral head, which reached 6.95% ± 6.55%. For the body, the maximum MAE was observed in UNETR, which is 1.19 ± 0.86%, and the minimum MAE was 0.94 ± 0.85% for 3D U-Net. The average error of the Dmean difference for different OARs is within 2.5 Gy. The average error of V40 difference for the bladder and rectum is about 5%. The mean DSC under different isodose volumes was above 90%. Conclusions: DL models can predict the voxel-level dose distribution accurately for cervical cancer VMAT treatment plans. All models demonstrated almost analogous performance for voxel-wise dose prediction maps. Considering all voxels within the body, 3D U-Net showed the best performance. The state-of-the-art DL models are of great significance for further clinical applications of cervical cancer VMAT.

Comparison of the Dosimetric Influence of Applicator Displacement on 2D and 3D Brachytherapy for Cervical Cancer Treatment

To compare the dosimetric influence of applicator displacement on two-dimensional brachytherapy (2D-BT) and three-dimensional brachytherapy (3D-BT) for cervical cancer. Nineteen patients who received computed tomography-guided tandem-and-ovoid (T&O) brachytherapy were retrospectively selected. Both 2D (point-based) and 3D (volume-based) plans with and without virtual applicator displacement in the 3 axes were created for each patient. Dose changes at point A, D90 of the high-risk clinical target volume (HR-CTV) and intermediate-risk CTV (IR-CTV), and the D0.1cc, D1cc, D2cc, and D5cc of organs-at-risk (OARs) caused by applicator displacement were evaluated. Both 2D-BT and 3D-BT plans were sensitive to T&O applicator displacement. The D90 of the CTV and the dose at point A were very sensitive to applicator displacement in the right–left direction ( X-axis). An applicator shift of >2 mm in the X-axis resulted in a change of >5% in the dose at point A and D90 of HR-CTV and IR-CTV. In addition, the doses to the OARs were mostly affected by applicator displacement in the anterior–posterior direction ( Z-axis). A displacement of <1.5 mm in the Z-axis was required to avoid a dose change of >10% for OARs. For both 2D-BT and 3D-BT plans, T&O displacement greater than  ± 2 mm in the X-axis or T&O applicator displacement  ± 1.5 mm in the Z-axis resulted in significant dose changes to the tumor and OARs. In comparison with 3D-BT plans, 2D-BT plans delivered a higher dose to the tumor, and the OARs received more undesirable doses when applicator displacement occurred. The influence of applicator displacement on the doses to the tumor and OARs differed between 2D-BT and 3D-BT. Physicians should take individual patient differences into account when selecting a brachytherapy plan to mitigate the influence of applicator displacement.

A New Risk Index Combining d-Dimer, Fibrinogen, HE4, and CA199 Differentiates Suspecting Endometrial Cancer From Patients With Abnormal Vaginal Bleeding or Discharge

Purpose: To establish an efficient new risk index for screening patients with endometrial cancer from patients with abnormal vaginal bleeding or discharge. Method: A total of 254 patients with abnormal vaginal bleeding or discharge were included in this study. Several candidate markers, including HE4, CA125, CA199, CA153, AFP, CEA, d-dimer, and fibrinogen, were employed. A new risk index for endometrial cancer screening was established by binary logistic regression. The diagnostic value of the candidate markers and the new risk index were assessed by a receiver operating characteristic curve, sensitivity, and specificity. Results: The most valuable diagnostic indicator for endometrial cancer was HE4, followed by d-dimer and then fibrinogen (area under the receiver operating characteristic curve: HE4 = 0.794, d-dimer = 0.717, fibrinogen = 0.690). The new risk index was superior to a single application of markers and a widely used combination (HE4 and CA125). At the ideal cutoff level, the sensitivity and specificity were 91.34% and 70.08%, respectively. In addition, only patients without organic disease served as controls, which further increase its performance (area under the receiver operating characteristic curve = 0.932, sensitivity = 94.49%, and specificity = 77.42%). Conclusions: The new risk index combining HE4, d-dimer, fibrinogen, and CA199 was the ideal combination for the screening of endometrial cancer. As a simple, rapid, nondestructive detection method, the new risk index is worth promotion in clinical practice, especially in primary medical institutions.

Quantitative PET Imaging and Clinical Parameters as Predictive Factors for Patients With Cervical Carcinoma: Implications of a Prediction Model Generated Using Multi-Objective Support Vector Machine Learning

Purpose: Quantitative features from pre-treatment positron emission tomography (PET) have been used to predict treatment outcomes for patients with cervical carcinoma. The purpose of this study is to use quantitative PET imaging features and clinical parameters to construct a multi-objective machine learning predictive model. Materials/Methods: Seventy-five patients with stage IB2-IVA disease treated at our institution from 2009–2012 were analyzed. Models predicting locoregional and distant failure were generated using clinical parameters (age, race, stage, histology, tumor size, nodal status) and imaging features (12 textural, 9 intensity, 8 geometric features, 2 additional imaging features) from pre-treatment PET. Model features were selected based on a multi-objective evolutionary algorithm to maximize specificity given a fixed moderately high sensitivity using support vector machine learning methods. Model 1 used clinical parameters only (C), Model 2 used imaging features only (I), and Model 3 used clinical and imaging features (C+I). Sensitivity, specificity, area under a receiver-operating characteristic curve (AUC), and p-values were compared to assess ability to predict locoregional and distant failure. Results: C+I had the highest performance for both locoregional failure (AUC 0.84, p < 0.01; specificity: 0.86; sensitivity: 0.79) and distant failure (AUC 0.75, p < 0.01; specificity: 0.75; sensitivity: 0.75). Conclusions: Based on a moderately high fixed sensitivity and optimized for specificity, the model using both clinical parameters and imaging features (C+I) had the best performance in predicting both locoregional failure and distant failure.

Assessing Genetic Variants in Matched Biocompartments From Patients With Serous Ovarian Cancer

The clinical use of molecular tumor profiling (MTP) is expanding and there is an increasing use of MTP data to manage patient care. At the University of Colorado, 18 patients were diagnosed with primary serous ovarian cancer between 9/2015 and 6/2019 and consented for banking and analysis of tumor, ascites and plasma. All 18 patients had tumor and plasma samples that were sent for MTP, and 13 of 18 patients additionally had ascites collected and sent for MTP. 50-gene panel testing and BRCA testing were performed on primary tumor. BRCA genetic variants were more likely to be identified in plasma as compared to ascites or tumor, though not statistically significant ( P = 0.17). Co-occurring genetic variants between plasma and ascites were less common in comparison to co-occurring variants between tumor and plasma or tumor and ascites, though not statistically significant ( P = 0.68). Variants in KDR (VEGFR2) and TP53 were most likely to be conserved across all 3 biocompartments. Mutant allele frequencies (MAF) of individual genetic variants varied across biocompartments, though tended to be highest in the tumor, followed by ascites.

A Novel Circulating MiRNA-Based Signature for the Diagnosis and Prognosis Prediction of Early-Stage Cervical Cancer

Background: MicroRNAs (miRNAs) have been shown to play a key role in regulating the progression of cervical cancer (CC). This study aimed to develop a circulating miRNA-based molecular signature for the diagnosis and prognosis prediction of early-stage CC. Methods: This study included 112 patients diagnosed with early-stage CC, 45 patients confirmed with cervical intraepithelial neoplasia (CIN) and 90 healthy subjects. Compared to the normal controls, the expression level of miR-21 was increased, while the levels of miR-125b and miR-370 were decreased in CC in both GSE30656 and The Cancer Genome Atlas (TCGA) cohort. The expression levels and diagnostic value of these candidate miRNAs were then validated through qRT-PCR. Their diagnostic and prognostic values for early-stage CC were further explored. Results: Compared to the patients with CIN and healthy subjects, serum miR-21 was increased, while serum miR-125b and serum miR-370 were reduced in early-stage CC. In addition, combining these molecules yielded good performance for differentiating early-stage CC from CIN or healthy subjects. Moreover, strong association was found between serum miR-21 and lymph node metastasis (LNM) as well as recurrence-free survival of early-stage CC. Similar observations were found for serum miR-125b and serum miR-370. Patients with simultaneously high serum miR-21 + low serum miR-125b + low serum miR-370 suffered a high risk of LNM and recurrence, while those with low serum miR-21 + high serum miR-125b + high serum miR-370 had little risk for LNM and recurrence. Conclusions: Combining serum miR-21, miR-125b and miR-370 as a miRNA-based signature is promising for the detection and prognosis prediction of early-stage CC.

RETRACTED: Inhibition of Microrna-766-5p Attenuates the Development of Cervical Cancer Through Regulating SCAI

MicroRNAs (miRNAs) are considered to play anti-tumor roles in cancers. This study is designed to illustrate the role and potential mechanism of miR-766-5p in cervical cancer (CC) progression. MiR-766-5p expression in tissues and serum of CC patients was detected by quantitative reverse-transcription PCR (qRT-PCR). Receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of serum miR-766-5p in CC. The 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound healing as well as transwell assay were utilized to detect the proliferation, apoptosis, migration and invasion of CC cells, respectively. The interaction between miR-766-5p and SCAI was confirmed by dual-luciferase reporter gene assay. Xenografted tumor model was established to measure the growth of tumor xenograft in vivo. MiR-766-5p was significantly increased in tissues and serum of CC patients. ROC curve suggested that serum miR-766-5p could serve as a biomarker for the diagnosis of CC. Inhibition of miR-766-5p suppressed the proliferation, migration and invasion, and promoted the apoptosis of CC cells. SCAI was proved to be a target of miR-766-5p. Silencing of SCAI eliminated the inhibiting effects of miR-766-5p inhibitor on the proliferation, migration and invasion of CC cells in vitro. Additionally, down-regulation of SCAI also reversed the inhibitory effect of miR-766-5p inhibitor on the growth of tumor xenograft in vivo. Inhibition of miR-766-5p restrains the cell proliferation, migration and invasion, and promotes the apoptosis in CC through negatively regulating SCAI.

Cytoreductive Surgery (CRS) Combined With Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Platinum-Sensitive Recurrence Epithelial Ovarian Cancer With HRR Mutation: A Phase III Randomized Clinical Trial

Background: Epithelial ovarian cancer (EOC) remains the leading cause of gynecologic cancer death worldwide due to the high recurrence rate. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative modality for platinum-sensitive recurrent EOC. The latest studies demonstrate homologous recombination-related (HRR) mutation status increases the sensitivity to platinum-based chemotherapy drugs in EOC. However, the molecular analysis of recurrent EOC patient benefits from HIPEC is unknown. Thus, we aimed to evaluate the efficacy and safety of CRS combined with HIPEC for platinum-sensitive in recurrent EOC with HRR mutation. Methods: This is a phase III randomized controlled clinical trial in patients with platinum-sensitive recurrent EOC. Participants were divided into 2 groups based on the HRR mutation status and randomized to receive CRS + HIPEC. The patients then received periodic chemotherapy and follow-up. Results: The primary objective of this study was to evaluate the effect of CRS + HIPEC compared to CRS alone in patients with a platinum-sensitive recurrent EOC stratified for HRD status. We hypothesize that the addition of HIPEC to CRS improves the progression-free survival (PFS) of platinum-sensitive recurrent EOC patients with HRR mutation compared with patients without HRR mutation. Conclusion: Recurrent EOC has a poor prognosis due to implantation and metastasis in the abdominal cavity. Intraperitoneal chemotherapy reduced seeding by removing free tumor cells. HIPEC utilizes physical and biological properties to significantly increase the clearance rate of tumors. Van Driel WJ et al proposed that HIPEC using platinum-based chemotherapy improves the survival of patients with ovarian cancer. HRR mutation, as a common pathogenic mutation in ovarian cancer, has a predictive effect on the platinum sensitivity of ovarian cancer patients. Whether lobaplatin-based HIPEC will play a greater role in ovarian cancer patients with HRR mutations is currently unknown.

Alternative Splicing: A New Therapeutic Target for Ovarian Cancer

Background: Increasing evidences have shown that abnormal alternative splicing (AS) events are closely related to the prognosis of various tumors. However, the role of AS in ovarian cancer (OV) is poorly understood. This study aims to explore the correlation between AS and the prognosis of OV and establish a prognostic model for OV. Methods: We downloaded the RNA-seq data of OV from The Cancer Genome Atlas databases and assessed cancer-specific AS through the SpliceSeq software. Then systemically investigated the overall survival (OS)-related AS and splicing factors (SFs) by bioinformatics analysis. The nomogram was established based on the clinical information, and the clinical practicability of the nomogram was verified through the calibration curve. Finally, a splicing correlation network was constructed to reveal the relationship between OS-related AS and SFs. Results: A total of 48,049 AS events were detected from 10,582 genes, of which 1523 were significantly associated with OS. The area under the curve of the final prediction model was 0.785, 0.681, and 0.781 in 1, 3, and 5 years, respectively. Moreover, the nomogram showed high calibration and discrimination in OV patients. Spearman correlation analysis was used to determine 8 SFs significantly related to survival, including major facilitator superfamily domain containing 11, synaptotagmin binding cytoplasmic RNA interacting protein, DEAH-box helicase 35, CWC15, integrator complex subunit 1, LUC7 like 2, cell cycle and apoptosis regulator 1, and heterogeneous nuclear ribonucleoprotein A2/B1. Conclusion: This study provides a prognostic model related to AS in OV, and constructs an AS-clinicopathological nomogram, which provides the possibility to predict the long-term prognosis of OV patients. We have explored the wealth of RNA splicing networks and regulation patterns related to the prognosis of OV, which provides a large number of biomarkers and potential targets for the treatment of OV. Put forward the potential possibility of interfering with the AS of OV in the comprehensive treatment of OV.

Elevated MYO10 Predicts Poor Prognosis and its Deletion Hampers Proliferation and Migration Potentials of Cells Through Rewiring PI3K/Akt Signaling in Cervical Cancer

MYO10, recognized as an important regulator of cytoskeleton remodeling, has been reported to be associated with tumorigenesis. However, its functional implication in cervical cancer and potential mechanism still remain to be undetermined currently. MYO10 level in cervical cancer tissues was analyzed by using data retrieved from The Cancer Genome Atlas and ONCOMINE databases. Messenger RNA and protein expression levels were determined by quantitative real-time polymerase chain reaction and Western blotting. Small-interfering RNA and overexpressing plasmid were used for MYO10 silencing and overexpression, and cell proliferation was analyzed by CCK-8. Transwell assays were performed to investigate the ability of cell migration and invasion. MYO10 was upregulated in cervical cancer tissues and cells when compared to normal controls, and survival analysis showed patients with high MYO10 expression had worse overall survival. Moreover, knockdown/overexpression of MYO10 significantly inhibited/enhanced the proliferation, invasion, and migration capabilities of cervical cells transfected with siRNAs/overexpressing plasmid. Additionally, MYO10 silencing inhibited PI3K/Akt signaling pathway by decreasing the phosphorylation status of PI3K and AKT. Data from the present study indicated that MYO10 were overexpressed in patients with cervical cancer and positively linked with poor prognosis. Experimental results suggested that MYO10 induced a significant encouraging effect in cervical cancer cell proliferation, invasion, and migration, linked with involvement of PI3K/Akt signaling. Collectively, these results emphasize a novel role for MYO10 overexpression in cervical cancer and provide a potent therapeutic strategy against cervical cancer.

RETRACTED: MicroRNA-96-5p Facilitates the Viability, Migration, and Invasion and Suppresses the Apoptosis of Cervical Cancer Cells by Negatively Modulating SFRP4

The current study was intended to research the functional role and regulatory mechanism of microRNA-96-5p in the progression of cervical cancer. MicroRNA-96-5p expression in cervical cancer tissues was assessed by quantitative real-time polymerase chain reaction. The association between microRNA-96-5p expression and clinicopathological features of patients with cervical cancer was analyzed. MTT, flow cytometry, wound healing, and transwell assay were performed to evaluate the viability, apoptosis, migration, and invasion of Hela and SiHa cells. Targetscan, dual-luciferase reporter gene assay, and RNA pull-down analysis were constructed to evaluate the target relationship between microRNA-96-5p and secreted frizzled-related protein 4. MicroRNA-96-5p was overexpressed in cervical cancer tissues, and microRNA-96-5p expression was markedly associated with the clinical stage and lymph node metastasis of patients with cervical cancer. Overexpressed microRNA-96-5p facilitated the viability, migration, invasion, and inhibited the apoptosis of Hela and SiHa cells, whereas suppression of microRNA-96-5p exerted the opposite trend. Secreted frizzled-related protein 4 was proved to be a target of microRNA-96-5p. Silencing of secreted frizzled-related protein 4 eliminated the anti-tumor effect of microRNA-96-5p on cervical cancer cells. MicroRNA-96-5p facilitated the viability, migration, and invasion and inhibited the apoptosis of cervical cancer cells via negatively regulating secreted frizzled-related protein 4.

Diagnostic Values of miR-21, miR-124, and M-CSF in Patients With Early Cervical Cancer

Objective: This study aimed to investigate the diagnostic values of microRNA-21, microRNA-124, and macrophage colony-stimulating factor in patients with cervical cancer. Methods: A total of 68 patients with cervical cancer admitted in our hospital (cervical cancer group) and 57 healthy individuals undergoing physical examinations (healthy group, also control group) were enrolled in this study. The expression of serum microRNA-21 and microRNA-124 was detected by quantitative reverse transcription polymerase chain reaction. The expression of serum macrophage colony-stimulating factor was detected by enzyme-linked immunosorbent assay. The diagnostic values of microRNA-21, microRNA-124, and macrophage colony-stimulating factor in cervical cancer were analyzed. The correlations between the expression of microRNA-21 and microRNA-124 with that of macrophage colony-stimulating factor were also analyzed. Results: Compared to those in the healthy group, patients in the cervical cancer group had a higher expression of microRNA-21 and macrophage colony-stimulating factor ( P < .05) but lower expression of microRNA-124 ( P < .05). The expression of microRNA-21, microRNA-124, and macrophage colony-stimulating factor in the patients correlated with the tumor size, tumor node metastasis (TNM) staging, tumor differentiation, and the presence or absence of lymph node metastasis and human papillomavirus infection ( P < .05). According to the receiver operating characteristic curves, the area under the curve of microRNA-21 for diagnosing cervical cancer was 0.723, the specificity was 58.82%, and the sensitivity was 91.23%. The area under the curve of microRNA-124 was 0.766, the specificity was 94.12%, and the sensitivity was 57.89%. The area under the curve of macrophage colony-stimulating factor was 0.754, the specificity was 64.71%, and the sensitivity was 87.72%. Pearson correlation analysis showed that the expression of microRNA-21 positively correlated with that of macrophage colony-stimulating factor ( r = 0.6825, P < .001), and the expression of microRNA-124 negatively correlated with that of macrophage colony-stimulating factor ( r = −0.6476, P < .001). Conclusion: MicroRNA-21, microRNA-124, and macrophage colony-stimulating factor may be involved in the development and progression of cervical cancer. The detection of serum microRNA-21, microRNA-124, and macrophage colony-stimulating factor has good sensitivity and specificity in the diagnosis of cervical cancer.

Electrochemotherapy as an Alternative Treatment Option to Pelvic Exenteration for Recurrent Vulvar Cancer of the Perineum Region

Objective: Pelvic exenteration in women with recurrent vulvar carcinoma is associated with high morbidity and mortality and substantial treatment costs. Because pelvic exenteration severely affects the quality of life and can lead to significant complications, other treatment modalities, such as electrochemotherapy, have been proposed. The aim of this study was to evaluate the feasibility and suitability of electrochemotherapy in the treatment of recurrent vulvar cancer. We aimed to analyze the treatment options, treatment outcomes, and complications in patients with recurrent vulvar cancer of the perineum. Methods: A retrospective analysis of patients who had undergone pelvic exenteration for vulvar cancer at the Institute of Oncology Ljubljana over a 16-year period was performed. As an experimental, less mutilating treatment, electrochemotherapy was performed on one patient with recurrent vulvar cancer involving the perineum. Comparative data analysis was performed between the group with pelvic exenteration and the patient with electrochemotherapy, comparing hospital stay, disease recurrence after treatment, survival after treatment in months, and quality of life after treatment. Results: We observed recurrence of disease in 2 patients with initial FIGO stage IIIC disease 3 months and 32 months after pelvic exenteration, and they died of the disease 15 and 38 months after pelvic exenteration. Two patients with FIGO stage IB were alive at 74 and 88 months after pelvic exenteration. One patient with initial FIGO stage IIIC was alive 12 months after treatment with electrochemotherapy with no visible signs of disease progression in the vulvar region, and the lesions had a complete response. The patient treated with electrochemotherapy was hospitalized for 4 days compared with the patients with pelvic exenteration, in whom the average hospital stay was 19.75 (± 1.68) days. Conclusion: Our experience has shown that electrochemotherapy might be a less radical alternative to pelvic exenteration, especially for patients with initially higher FIGO stages.

Expression Profiles Reveal Involvement of VEGF, IGF1, BIRC5, and MMP1 in Vulvar Carcinogenesis

Objective: The objective of this study was to identify key genes and shed light on the underlying molecular mechanisms of vulvar squamous cell carcinoma (VSCC). Methods: Bioinformatic software was utilized for the identification and characterization of key differentially expressed genes (DEGs) from microarrays GSE63678 and GSE38228, which contain VSCC and normal vulvar tissue data. These microarrays were obtained from Gene Expression Omnibus (GEO). Immunohistochemical assays (55 VSCC and 50 normal vulvar tissues) were utilized to validate the expression of VEGF, IGF1, BIRC5, and MMP1 screened from the identified DEGs. SPSS 18.0 software was used for statistical analyses of the relationships between IGF1, BIRC5, VEGF, MMP1 expression levels and patient clinicopathological characteristics. Results: A total of 141 DEGs were identified, among which 18 genes were closely correlated with the biological characteristics of VSCC. Four of the 18 genes ( VEGF, IGF1, BIRC5, and MMP1) screened from the GEO database were markedly enriched in pathways in cancer ( P < 0.05), and could be considered key genes in VSCC based on KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis in DAVID (Database for Annotation, Visualization and Integrated Discovery).The expression levels of these 4 hub genes, determined by immunohistochemical assays, were consistent with the bioinformatics results. Higher expression of IGF1 showed significant association with well-differentiated carcinomas ( P = 0.017). BIRC5 expression levels showed a positive correlation with clinical stage ( P = 0.039); compared with those in menopause for over 10 years, patients in menopause for less than 10 years at the time of diagnosis tended to have significantly higher expression of BIRC5 ( P = 0.003). VEGF and MMP1 expression levels were not correlated with any of the tested clinicopathological characteristics. Conclusion: VEGF, IGF1, BIRC5, and MMP1 were identified as being associated with VSCC using integrated bioinformatic methods, which may provide important insights into the pathogenesis of this disease and help to identify new biomarkers.

Diagnostic Value of Vaginal Microecology, Serum miR-18a, and PD-L1 for Identifying HPV-Positive Cervical Cancer

Objective: We aimed to investigate the diagnostic value of the vaginal microecology, serum miR-18a, and programmed death ligand-1 (PD-L1) for human papillomavirus (HPV)-positive cervical cancer. Methods: Eighty-four patients with HPV-positive cervical cancer were assigned to the observation group, 107 HPV-positive patients without cervical cancer were assigned to the positive group, and 191 healthy women were assigned to the control group. Vaginal microecology and serum levels of miR-18a and PD-L1 on the surface of CD4+ and CD8+ T cells were compared among the 3 groups. The observation group was further divided into subgroups according to patients’ characteristics for comparison. The diagnostic value of miR-18a and PD-L1 for HPV-positive cervical cancer was investigated. Results: Women in the control group had better vaginal microecology and lower levels of miR-18a and PD-L1 than those in the observation and the positive groups (all P < 0.05). Compared with the positive group, the observation group had similar vaginal microecology (all P > 0.05) but higher levels of miR-18a and PD-L1 (all P < 0.05). Moreover, the patients at stage III had higher levels of miR-18a and PD-L1 than those at stage I and II (all P < 0.05). The values of area under the curve for miR-18a and PD-L1 in the diagnosis of HPV-positive cervical cancer were over 0.8 (all P < 0.001). Conclusion: Patients with HPV-positive cervical cancer have vaginal microbial dysbiosis and high serum levels of miR-18a and PD-L1. miR-18a and PD-L1 have diagnostic value for identifying HPV-positive cervical cancer.

Label-Free Quantitative Comparison of Cervical Mucus Peptides in Subjects With Endocervical Adenocarcinoma and Adenocarcinoma in Situ

Purpose: To uncover potential diagnostic biomarkers for endocervical adenocarcinoma (EAC) and adenocarcinoma in situ (AIS). Experimental design: Quantitative label-free liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) peptidomics strategies were employed to profile 8 cervical mucus (CM) samples, including 3 EAC cases, 2 AIS cases and 3 normal controls (Ctrl). Results: Among the 3721 exclusive peptides identified, 12 (5 up-regulated and 7 down-regulated) endogenous peptides were significantly expressed in EAC compared to healthy controls (EAC/Ctrl); 10 (7 up-regulated and 3 down-regulated) endogenous peptides were significantly expressed in AIS compared to healthy controls (AIS/Ctrl); 11 (6 up-regulated and 5 down-regulated) endogenous peptides were significantly expressed in EAC compared to AIS (EAC/AIS) (absolute fold change ≥1.5, Benjamini-Hochberg adjusted p-value ≤0.05). Among these identifications, annexin A1 (ANXA1) was found to be down-regulated both in EAC and AIS, and its unique peptide (FIENEEQEYVQTVK) may be promising indicators for cervical glandular epithelial lesions. Conclusion: This is the first study to utilize CM peptidomics in cervical glandular malignancies, which may reveal the novel noninvasive biomarkers for EAC and AIS.

A Novel Risk Factor for Para-Aortic Lymph Node Recurrence After Definite Pelvic Radiotherapy in Stage IIIB Cervical Cancer

Background: Studies determining which patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB disease benefit from prophylactic extended-field irradiation (EFRT), which can reduce para-aortic lymph node (PALN) failure rates, are limited. The study was designed to evaluate the value of the controlling nutritional status (CONUT) score as a risk factor for predicting PALN recurrence and identifying potential indications of prophylactic EFRT. Methods: From 2010 to 2015, a retrospective review was conducted among patients with FIGO stage IIIB cervical cancer who were treated with definitive pelvic radiotherapy or concurrent chemoradiotherapy. We analyzed para-aortic lymph node metastasis-free survival (PALNMFS) using Kaplan-Meier curves. Multivariate analyses were performed using Cox regression models. Results: A total of 116 patients with FIGO stage IIIB cervical cancer were included in the study and the median follow-up was 42.2 months (range: 3.5-104.2 months). Multivariate analysis revealed that the CONUT score (HR: 3.141; 95% CI: 2.321-5.436; P < .001) and ≥3 pelvic lymph node metastases (HR: 2.235; 95% CI: 1.428-11.242; P < .001) were independent risk predictors of PALNMFS. Compared with the low CONUT group (score<3), the high CONUT group (score≥3) was associated with a significantly worse 3-year disease-free survival rate (46.9 vs 69.5%, P = .001), a significantly lower 3-year overall survival rate (68.5 vs 79.7%, P = .016) and a significantly lower PALNMFS rate (74.8 vs 96.4%, P < .001). Conclusions: A high CONUT score (score≥3) and ≥3 pelvic metastatic lymph nodes were significant predictors of PALNMFS after pelvic radiation in FIGO stage IIIB cervical cancer patients. Patients with these risk factors might benefit from prophylactic EFRT.

A Prognostic Nomogram for Predicting Overall Survival in Patients With Small-Cell Carcinoma of the Uterine Cervix: A SEER Population-Based Study

Background: This study aimed to develop a prognostic model based on the Surveillance, Epidemiology, and End Results (SEER) database to predict the overall survival (OS) of small cell carcinoma of the uterine cervix (SmCC). Methods: Between 1975 and 2016, a total of 401 patients were included, and their comprehensive sociodemographic and clinicopathological characteristics were collected. Univariate and multivariate Cox regression models were used to screen for independent prognostic factors. The identified factors were used to conduct a nomogram for predicting the OS of SmCC. The performance of the nomogram was determined using area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration curve, and decision curve analysis (DCA) metrics. Results: The median survival time of all patients was about 24 months (95% confidence interval [95% CI] [1.50-2.17]). Age (hazard ratio [HR] = 1.693 for 45-59 vs 21-34, 95% CI [1.140-2.513], P = .009; HR = 2.836 for 60-92 vs 21-34, 95% CI [1.851-4.345], P < .001), positive nodes (HR = 2.384, 95% CI [1.437-3.955], P < .001), regional nodes number ≥12 (HR = 0.500, 95% CI [0.282-0.886], P = .018), and treatment method (HR = 0.409 for surgery vs no, 95% CI [0.267-0.628], P < .001; HR = 0.649 for chemotherapy vs no, 95% CI [0.478-0.881)], P = .006) were independent factors of OS. Young patients who had surgical resection or chemotherapy, negative lymph nodes, and regional lymph nodes ≥12 had a longer survival time. These clinical factors were utilized to construct a nomogram for predicting OS. The AUC and C-index were higher than 0.7, indicating the good discriminating ability of the nomogram. The calibrations were all around the 45-degree line, indicating excellent consistency between the prediction of the model and actual observations. The DCA plots supported the clinical utility of the nomogram. Conclusion: The constructed nomogram is expected to help predict the prognosis of SmCC and guide patient treatment.

Age-Dependent Hematologic Toxicity Profiles and Prognostic Serologic Markers in Postoperative Radiochemotherapy Treatment for Uterine Cervical Cancer

Introduction: In the adjuvant setting for cervical cancer, classical risk factors for postoperative radiochemotherapy have been established. However, data on laboratory changes during therapy and the prognostic value of serological markers are limited and further knowledge is needed to optimize the toxic trimodal regimen. Methods: We retrospectively identified 69 women who underwent weekly postoperative radiochemotherapy with 40 mg/m2 of cisplatin for cervical cancer between 2010 and 2021 at a single center. Laboratory parameters were recorded before, at each cycle and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to calculate and compare survival, groups were compared using the Mann–Whitney U, χ2, and variance tests. Results: With a median follow-up of 17.7 months, the 1- and 5-year local control rates were 94.0% and 73.7%, respectively, with significantly better rates for more chemotherapy cycles and negative resection margins. Only 68.1% of patients completed all cycles. The most common reasons for early discontinuation were persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting infections in women aged > 50 years. Leukopenia was more likely to occur after the third cycle. Significantly worse survival was observed for post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase levels, low pre-radiochemotherapy nutritional index, and raised C-reactive-protein-levels; the latter were also predictable for local control. The Glasgow prognostic score did not reliably predict survival. Conclusion: Incomplete application of simultaneous chemotherapy leads to inferior local control, and age-dependent limiting factors should be identified at an early stage. In addition to classical risk factors, serological markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show prognostic significance.

The Effects of Automatic Segmentations on Preoperative Lymph Node Status Prediction Models With Ultrasound Radiomics for Patients With Early Stage Cervical Cancer

Introduction: The purpose of this study is to investigate the effects of automatic segmentation algorithms on the performance of ultrasound (US) radiomics models in predicting the status of lymph node metastasis (LNM) for patients with early stage cervical cancer preoperatively. Methods: US images of 148 cervical cancer patients were collected and manually contoured by two senior radiologists. The four deep learning-based automatic segmentation models, namely U-net, context encoder network (CE-net), Resnet, and attention U-net were constructed to segment the tumor volumes automatically. Radiomics features were extracted and selected from manual and automatically segmented regions of interest (ROIs) to predict the LNM of these cervical cancer patients preoperatively. The reliability and reproducibility of radiomics features and the performances of prediction models were evaluated. Results: A total of 449 radiomics features were extracted from manual and automatic segmented ROIs with Pyradiomics. Features with an intraclass coefficient (ICC) > 0.9 were all 257 (57.2%) from manual and automatic segmented contours. The area under the curve (AUCs) of validation models with radiomics features extracted from manual, attention U-net, CE-net, Resnet, and U-net were 0.692, 0.755, 0.696, 0.689, and 0.710, respectively. Attention U-net showed best performance in the LNM prediction model with a lowest discrepancy between training and validation. The AUCs of models with automatic segmentation features from attention U-net, CE-net, Resnet, and U-net were 9.11%, 0.58%, –0.44%, and 2.61% higher than AUC of model with manual contoured features, respectively. Conclusion: The reliability and reproducibility of radiomics features, as well as the performance of radiomics models, were affected by manual segmentation and automatic segmentations.

Genomic Justice as Reproductive Justice: Universal Coverage for Preimplantation Genetic Testing for Hereditary Breast and Ovarian Cancer Syndrome

With increasing limitations on reproductive choice in the past several years, reproductive rights—often relegated to abortion access and contraception—have become a critical consideration for American clinicians and patients. We implore the medical community to expand its understanding of reproductive autonomy by illuminating an overlooked community: those with hereditary breast and ovarian cancer syndrome. For those with pathogenic/likely pathogenic variants in cancer susceptibility genes that carry a 50% inheritance pattern, such as BRCA , preimplantation genetic testing for monogenic disorders offers a life-altering technology that provides the option to halt the generational legacy of cancer. This service, however, is cost-prohibitive. These financial barriers create disparities that not only directly impact the immediate offspring but also have the potential to form entire generational shifts in future gene pools based on socioeconomic status. This form of healthcare injustice is unacceptable, for which the medical community can and should advocate for urgent solutions. We posit that genomic justice, specifically within the framework of reproductive justice, demands that all communities have the ability to choose whether and how they will use genomic technologies to align with their reproductive goals and values.

The Gut Microbiota-Ovarian Cancer Axis: Mechanisms of Influence and Therapeutic Implications

Ovarian cancer (OC), one of the most lethal gynecological malignancies, urgently requires breakthrough diagnostic and therapeutic strategies due to its low survival rate and high recurrence rate. The gut microbiota (GM), which colonizes the human gastrointestinal tract, significantly influences human health. Recent technological advancements have enabled deeper investigation into tumor-bacteria interactions. The GM profoundly participates in OC initiation, progression, and treatment resistance by dynamically regulating the host's immune response, metabolism, and inflammatory microenvironment. This review focuses on three primary mechanisms by which the GM influences OC development and its impact on cancer therapies (chemotherapy, immunotherapy, and targeted therapy). At the mechanistic level, GM dysbiosis promotes OC through multiple pathways: (1) Modulating the tumor microenvironment (TME), including inducing immunosuppressive cell infiltration and impairing anti-tumor immunity; (2) Interfering with estrogen metabolism, thereby elevating bioactive estrogen levels; (3) Producing metabolites that mediate systemic inflammatory signaling and energy metabolism reprogramming. These alterations collectively drive tumor proliferation and metastasis. Although microbiota-based interventions offer novel opportunities for precision therapy in OC, clinical translation faces challenges such as mechanistic complexity and individual heterogeneity. Future research should integrate multi-omics technologies and large-scale clinical trials to advance microbiota modulation strategies from bench to bedside, thereby improving OC prognosis.

The Potential for Enhanced Ovarian Cancer Diagnostics Through Optimized Derivative Magnetic Resonance Spectroscopy

Introduction Ovarian cancer is a major global concern. Due to late detection, it is one of the few malignancies for which the five-year survival rate continues to be low without appreciable improvement in recent decades. Screening methods are needed that non-invasively, without ionizing radiation, detect early-stage ovarian cancer with clear distinction from benign lesions. Magnetic resonance spectroscopy (MRS) could be a key contributor to early ovarian cancer detection, insofar as data analysis and interpretation after appropriate signal processing are implemented. Methods The derivative non-parametric and parametric fast Padé transform (dFPT) and the derivative fast Fourier transform (dFFT: optimized, unoptimized) are applied to proton MRS time signals encoded from the ovary. These include in vivo MRS for a borderline cyst, and in vitro MRS for serous cystic adenoma and serous cystic adenocarcinoma. Results On a broad chemical shift axis (aliphatic and aromatic), over 300 thin, clearly-delineated peaks are baseline-resolved and displayed in a readily amenable form for clinical interpretation. This is from the in vivo encoding. Clearly quantifiable peaks include cancer biomarkers: total choline components (phosphocholine, glycerophosphocholine, free choline) and the lactate doublet, as well as other diagnostically-relevant metabolites in spectrally-crowded regions. Concordance among three algorithms (parametric and non-parametric dFPT as well as optimized dFFT) provides cross-validation, essential for clinical trustworthiness of derivative MRS. Conclusion With these results that help benchmark derivative MRS for clinical applications in oncology, the time is deemed ripe to implement the stated advances. More effective early detection of ovarian cancer should be among the most urgent priorities for this upgrade.

Comparison of Different Maintenance Treatment Options for Newly Diagnosed BRCA wt Advanced Ovarian Cancer: A Retrospective Cohort Analysis

Introduction Niraparib and bevacizumab are two principal maintenance therapies for newly diagnosed advanced ovarian cancer (AOC) patients with BRCA wild-type ( BRCA wt) status, regardless of homologous recombination deficiency (HRD). In China, however, a considerable proportion of BRCA wt patients have unknown or untested HRD status, complicating treatment selection. Methods To evaluate and compare the efficacy of niraparib and bevacizumab as maintenance therapy for BRCA wt AOC, we conducted a retrospective cohort study using real-world clinical data. Descriptive statistics were used to summarize clinical and demographic characteristics. Progression-free survival (PFS) was estimated using Kaplan–Meier analysis and compared using a stratified Cox proportional hazards model. A multivariable Cox regression was performed to adjust for potential confounding variables. Exploratory subgroup analyses were conducted, and propensity score matching (PSM) was applied as a sensitivity analysis. Results A total of 94 patients were included, with 51 receiving niraparib and 43 receiving bevacizumab. The median PFS was not reached in the niraparib group versus 13.77 months (95% CI, 4.12–23.41) in the bevacizumab group (HR = 0.240, 95% CI, 0.128–0.451; P  < .001). After covariate adjustment, the median PFS was 19.55 months (95% CI, 9.40–NA) with niraparib and 8.64 months (95% CI, 4.53–NA) with bevacizumab, with an adjusted HR of 0.282 (95% CI, 0.136–0.587; P  = .001). In the PSM sensitivity analysis, the median PFS was not reached (95% CI, 19.55–NR) in the niraparib group and was 18.33 months (95% CI, 8.90-25.26) in the bevacizumab group (HR = 0.360, 95% CI, 0.176–0.736; P  = .005). Conclusion This analysis suggests that niraparib may provide a progression-free survival advantage compared with bevacizumab in BRCA wt AOC patients, with both regimens appearing to be generally well tolerated in the real-world setting. These findings offer preliminary reference value for maintenance treatment selection in patients with newly diagnosed BRCA wt AOC.