Prognostic Role of Matrix Metalloproteinases in Cervical Cancer: A Meta-Analysis.

OBJECTIVE: Studies have published the association between the expression of matrix metalloproteinases (MMPs) and the outcome of cervical cancer. However, the prognostic value in cervical cancer remains controversial. This meta-analysis was conducted to evaluate the prognostic functions of MMP expression in cervical cancer. METHODS: A comprehensive search of PubMed, Embase, and Web of Science databases was conducted to identify the eligible studies according to defined selection and excluding criteria and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Fixed and random effects models were evaluated through the hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the overall survival (OS), recurrence-free survival (RFS), and progress-free survival (PFS). RESULTS: A total of 18 eligible studies including 1967 patients were analyzed for prognostic value. Totally 16 selected studies including 21 tests were relevant to the cervical cancer OS, 4 studies focused on RFS, and 1 study on PFS. The combined pooled HRs and 95% CIs of OS were calculated with random-effects models (HR = 1.64, 95% CI = 1.01-2.65, P = .000). In the subgroup analysis for OS, there was no heterogeneity in MMP-2 (I2 = .0%, P = .880), MMP-1 (I2 = .0%, P = .587), and MMP-14 (I2 = 28.3%, P = .248). In MMP-7 and MMP-9, the heterogeneities were obvious (I2 = 99.2% (P = .000) and I2 = 77.9% (P = .000), respectively). The pooled HRs and 95% CIs of RFS were calculated with fixed-effects models (HR = 2.22, 95% CI = 1.38-3.58, P = .001) and PFS (HR = 2.29, 95% CI = 1.14-4.58, P = .035). CONCLUSIONS: The results indicated that MMP overexpression was associated with shorter OS and RFS in cervical cancer patients. It suggested that MMP overexpression might be a poor prognostic marker in cervical cancer. Research Registry Registration Number: reviewregistry 1159.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

SVM classifier of cervical histopathology images based on texture and morphological features.

BACKGROUND: Cervical histopathology image classification is a crucial indicator in cervical biopsy results. OBJECTIVE: The objective of this study is to identify histopathology images of cervical cancer at an early stage by extracting texture and morphological features for the Support Vector Machine (SVM) classifier. METHODS: We extract three different texture features and one morphological feature of cervical histopathology images: first-order histogram, K-means clustering, Gray Level Co-occurrence Matrix (GLCM) and nucleus feature. The original dataset used in our experiment is obtained from 20 patients diagnosed with cervical cancer, including 135 whole slide images (WSIs). Given an entire WSI, the patches on its tissue region are extracted randomly. RESULTS: We finally obtain 3,000 patches, including 1,000 normal, 1,000 hysteromyoma and 1,000 cancer images. Among them, 80% of the entire data set is randomly selected as training set and the remaining 20% as test set. The accuracy of SVM classification using first-order histogram, K-means clustering, GLAM and nucleus feature for extracting features are respectively 87.4%, 90.6%, 91.6% and 93.5%. CONCLUSIONS: The classification accuracy of the SVM combining the four features is 96.8%, and the proposed nucleus feature plays a key role in the SVM classification of cervical histopathology images.

Efficacy and safety of sintilimab plus albumin-bound-paclitaxel in recurrent or metastatic cervical cancer: a multicenter, open-label, single-arm, phase II trial.

Background: Sintilimab is an antibody against programmed cell death protein 1. We assessed the efficacy and safety of sintilimab plus albumin-bound (nab)-paclitaxel for the treatment of recurrent or metastatic cervical cancer. Methods: This multicenter, open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT04341883) enrolled patients with recurrent or metastatic cervical cancer who progressed after at least one line of systemic therapy. The patients received sintilimab 200 mg and nab-paclitaxel 260 mg/m2 body surface area every 3 weeks. The primary endpoint was objective response rate (ORR) assessed by investigators per Response Evaluation Criteria in Solid Tumors version 1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Findings: From January 13, 2020 to February 21, 2022, 27 patients were enrolled and received treatment. Median patient age was 50 years (range, 34-68 years). By data cut-off (May 22, 2022), in intention-to-treat population, ORR was 44.4% (95% CI, 24.4%-64.5%). The disease control rate was 88.9% (95% CI, 70.8%-97.6%). Median PFS was 5.2 months (95% CI, 2.7-7.7 months). Median DoR was 3.8 months (95% CI, 0.7-6.9 months), and median OS was 13.1 months (95% CI, 5.8-20.4 months). Treatment-related grade 3 or 4 adverse events (AEs) occurred in 44.4% of the patients, and the most common AEs were decreased neutrophil count (22.2%), decreased white blood cell count (14.8%), and anemia (7.4%). The most common potential immune-related AEs were grade 1-2 hypothyroidism (18.5%), neutropenia (11.1%), and rash (7.4%). Interpretation: Sintilimab plus nab-paclitaxel treatment shows promising antitumor activity and manageable toxicity in patients with advanced cervical cancer. Larger randomized controlled trials are required for validation. Funding: Innovent Biologics Co., Ltd.; Csps Holdings Co., Ltd.

Ropivacaine inhibits cervical cancer cell growth via suppression of the miR­96/MEG2/pSTAT3 axis.

Ropivacaine, one of the most commonly used local anesthetics in clinical practice, has shown potent antitumor activity in multiple types of cancer cells. However, its effect on cervical cancer cell growth remains unknown. In the present study, it was found that ropivacaine inhibited cervical cancer cell growth by suppressing cell cycle progression and promoting cell apoptosis, as determined by CCK­8 assay, cell cycle and apoptosis analyses. Western blot analysis and luciferase assay demonstrated that ropivacaine abrogated the phosphorylation and transcriptional activation of signal transducer and activator of transcription 3 (STAT3), and that STAT­3C overexpression reversed the inhibition of cervical cancer cell viability mediated by ropivacaine. Furthermore, our results revealed that the increased expression of maternally expressed gene 2 (MEG2) caused by ropivacaine led to STAT3 dephosphorylation. Finally, we found that ropivacaine upregulated MEG2 by decreasing the expression of microRNA­96 (miR­96). Taken together, our results describe a novel mechanism for the anticancer activity of ropivacaine and suggest ropivacaine as a potential therapeutic agent for cervical cancer patients.

Malignant Ovarian Tumors During Pregnancy: A Multicenter Retrospective Analysis.

PURPOSE: The aim of this study was to investigate the clinical characteristics and management of malignant ovarian tumors during pregnancy, as well as the feto-maternal outcomes and analyze the influential factors on the pregnancy outcomes. PATIENTS AND METHODS: Eighty-five patients with ovarian malignancies during pregnancy treated at 12 tertiary hospitals between 2009 and 2019 were analyzed in this study. The clinical features, histopathological characteristics, clinical management, and maternal and perinatal outcomes were retrospectively analyzed. The clinical features and managements were compared between abortion group and live birth group. RESULTS: The following diagnoses were made: 41 (48.24%) patients with borderline ovarian tumors, 18 (21.18%) patients with epithelial ovarian cancers, 17 (20.00%) patients with non-epithelial ovarian malignancies and 9 (10.59%) patients with metastatic ovarian tumors. Thirty-six (42.45%) patients underwent conservative surgical treatment. Thirty-four (40.00%) patients opted for fertility-sparing surgery, and fifteen (17.56%) patients received radical surgery. Chemotherapy was administered to 32.94% of the patients. The proportion of ovarian malignancies diagnosed in the first trimester in the abortion group was higher than that in the live birth group (P<0.05). However, tumor diameter, reproductive history, stage and surgical indications showed no significant differences between groups. A total of 67 live babies were recorded in this study, including 19 premature babies and 1 full-term newborn who died of respiratory distress. All of the BOTs were diagnosed with stage I, among whom 38 (92.68%) patients exhibited disease-free survival. Twenty-eight ovarian cancers were in stage I-II and 26 of them had disease-free survival with the longest follow-up time of 10 years. Five of the sixteen patients in advanced stage (stage III-IV) died, four of whom had metastatic tumors. CONCLUSION: Pregnant women with early-stage malignant ovarian tumors appear to have favorable outcomes. Conservative surgery is acceptable for early-stage borderline ovarian tumors during pregnancy. The gestational age of ovarian malignancy detection is key for pregnancy outcomes.

Icariin inhibits the growth of human cervical cancer cells by inducing apoptosis and autophagy by targeting mTOR/PI3K/AKT signalling pathway.

PURPOSE: Cervical cancer causes significant morbidity and mortality among women worldwide. The currently available treatment options are not efficacious and also create severe adverse effects. It is apparent that new therapeutic approaches are needed for this cancer. In this study, we examined the anticancer effects of a natural flavonoid, Icariin, against human cervical cancer cells. METHODS: The anti-proliferative effects of Icariin were evaluated on cervical cancer HeLa cell line and normal HCvEpC cells by cell counting assay. The effect of Icariin on colony production by HeLa cells was determined by colony formation assays. Apoptotic effects were determined by acridine orange/ethidium bromide (AO/EB) and DAPI staining. Autophagy was investigated by electron microscopy. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were estimated by flow cytometry. Protein expression was evaluated by western blotting. RESULTS: Icariin inhibited the growth of HeLa cervical cancer cells dose-dependently. IC50 of Icariin was 20 µM against the HeLa cells with comparatively negligible toxic effects on normal HCvEpC cells. The anticancer effects of Icariin were due to induction of apoptosis which was accompanied with cleavage of caspase 3 and 9, upregulation of Bax and downregulation of Bcl-2. Icariin also prompted autophagy in HeLa cells and enhanced the LC3 II expression concentration-dependently. Icariin also induced the generation of ROS and diminished the MMP levels in HeLa cells and blocked the mTOR/PI3K/AKT signalling cascade, suggestive of its potent anticancer activity. CONCLUSION: Taken together Icariin may prove potent and efficacious lead molecule for the development of therapy for cervical cancer.