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Patients with epithelial ovarian cancer (EOC) can benefit from poly- (ADP ribose) polymerase inhibitors (PARPi) therapy. However, PARPi resistance has become a challenge in clinical practice, and its mechanism requires further exploration.We established three PARPi-resistant cell strains following olaparib exposure. CCK-8, clonogenic survival, transwell, wound healing, cell cycle, RT-qPCR and western blot assays were performed to explore the functional phenotype of the resistant cells. Whole-exome sequencing and RNA-sequencing were performed to identify the altered genes. Stable knockdown and overexpression were used to investigate the role of EP300, an upstream regulator of E-cadherin and epithelial-mesenchymal transition (EMT), in cell lines. We further validated the finding in clinical ovarian cancer samples by immunohistochemistry.We combined public datasets to obtain an integrated PARPi sensitivity profile in EOC cells, which indicated that primary PARPi resistance could not be fully explained by mutations in BRCA1/2 or homologous recombination deficiency related genes. Genomic and transcriptome analyses revealed distinct mechanisms between primary and acquired resistance. Long-term PARPi treatment induced accumulation of de novo single nucleotide variants (SNV), and the complete frame-shift deletion of PARP1 was detected in the A2780 resistant strain. Additionally, the depressed histone acetyltransferase of EP300 could cause resistant phenotype through activated EMT process in vitro, and associated with PARPi-resistance in EOC patients.Long-term PARPi treatment led to evolutionary genomic and transcriptional alterations that were associated with acquired resistance, among which depressed EP300 partly contributed to the resistant phenotype.

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

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

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

Background Ovarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC. Experimental design Plasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method. Results The DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples. Conclusions This study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.

Objective To determine the combination of fasting blood glucose (FBG) with squamous cell carcinoma antigen (SCCA) assessments in the prediction of tumor responses to chemotherapy and pretreatment prognostication among patients receiving neoadjuvant chemotherapy (NACT) for locally advanced cervical cancer (LACC). Methods Data of 347 LACC patients were retrospectively reviewed. Receiver operating characteristic (ROC) curves were constructed, and areas under the curves (AUCs) were compared to evaluate the ability to predict complete response (CR) following NACT. Patients were stratified into groups with low and high levels of SCCA and FBG and combined into low‐ or high‐SCCA and low‐ or high‐FBG groups. Cox regression analysis was performed to identify determinants of recurrence‐free survival (RFS) and overall survival (OS). Results The AUCs were 0.70, 0.68, and 0.66 for SCCA, FBG, and a combination of SCCA and FBG for predicting CR following NACT, respectively; however, the differences among AUCs were not significant (P = .496). Pretreatment SCCA and FBG levels were identified as independent predictors of RFS and OS. The high‐SCCA/high‐FBG group showed significantly worse prognosis than the low‐SCCA/low‐FBG group. After adjusting for other variables, high‐SCCA/high‐FBG remained independently associated with an increased risk of tumor recurrence and death. Conclusion SCCA, FBG, and a combination of SCCA and FBG could acceptably predict CR following NACT. Pretreatment SCCA and FBG levels were independent prognostic factors. The combination of SCCA and FBG levels refined the prognostic stratification of LACC patients, which allowed the group of patients with the highest risk of recurrence and death to be identified.

Background To investigate whether poor glycemic control status has a negative impact on survival outcomes and tumor response to chemotherapy in patients receiving neoadjuvant chemotherapy (NACT) for locally advanced cervical cancer (LACC). Methods A retrospective cohort study was conducted to examine LACC patients undergoing NACT and radical hysterectomy between 2002 and 2011. Patients were divided into three groups: patients without diabetes mellitus (DM), diabetic patients with good glycemic control, and diabetic patients with poor glycemic control. Hemoglobin A1c (HbA1c) levels were used to indicate glycemic control status. Recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed using log-rank tests and Cox proportional hazards models. Results In total, 388 patients were included and had a median follow-up time of 39 months (range: 4–67 months). Diabetes mellitus (DM) was diagnosed in 89 (22.9%) patients, only 35 (39.3%) of whom had good glycemic control prior to NACT (HbA1c

Objective To analyse the associations between aldehyde dehydrogenase 1 (ALDH1) tumour immunopositivity and disease-free survival in cervical carcinoma. Methods ALDH1 immunohistochemistry was performed on formalin-fixed, paraffin wax-embedded cervical tumour tissue samples obtained from hospital archives. Data regarding disease-free survival were obtained. Kaplan–Meier survival analyses and Cox proportional hazards regression models were performed. Results Patients with ALDH1-positive tumours ( n = 31) had significantly shorter disease-free survival than those with ALDH1-negative tumours ( n = 167; 41.99 ± 0.90 vs 53.64 ± 2.67 months). ALDH1 positivity was associated with poor prognosis (relative risk 2.727; 95% confidence intervals 1.253, 5.914). Conclusions ALDH1 positivity is associated with poor prognosis of cervical carcinoma, and may be an independent predictor of prognosis.

Objective Women with locally advanced vulvar carcinoma have an excellent chance of a cure by undergoing a radical vulvectomy with an “en bloc” inguinofemoral lymphadenectomy, but the morbidity associated this surgical approach is substantial. To achieve an outcome comparable with the traditional radical method in terms of oncologic safety, and an improved post-operative quality of life, we modified the classic triple-incision technique and suggested it as an alternative for these patients. The aim of this study was to report this new technique. Study design Between January 2004 and November 2009, 24 patients with clinical stage T2 (≥4 cm) or T3 invasive vulvar cancer underwent surgical treatment with our modified triple incision technique. Their clinical and surgical complications and follow-up data were retrospectively reviewed. Results The post-surgical complications were as follows: lymphoedema in 45.8%, wound breakdown in 20.8% and cellulitis in 8.3%. After a median follow-up of 35.5 months, three (12.5%) patients developed a recurrence in the skin bridge (2/24, 8.3%) or lungs (1/24, 4.2%). All patients suffering from skin bridge recurrences were salvaged by local re-resection. Four (16.7%) cases of death were noted: three (12.5%) patients died of non-cancer-related diseases and one (4.2%) died from a multifocal pulmonary metastasis; no evidence of vulvar or groin disease was observed at these patients’ last follow-up. Conclusion The modified triple-incision technique described in this preliminary study appears to be safe, feasible and tolerable for patients with a locally advanced vulvar cancer, and offers an acceptable morbidity.

Because altered microRNAs (miRNAs) expression patterns have been observed in a variety of diseased tissues, miRNA expression was compared in human cervical cancer tissues relative to adjacent normal cervical tissues in the present study. Microarray chips with 924 probes were used to detect the expression of miRNAs in cervical cancer tissue and adjacent normal cervical tissue of 13 patients with cervical cancer (11 squamous cervical cancers, one cervical adenocarcinoma, and one cervical sarcoma), all of whom were infected with human papilloma virus (HPV) 16 and/or HPV18. Compared to the expression levels in normal cervical tissues, 18 miRNAs (1.9%) were significantly upregulated (increase of ≥2×), and 19 miRNAs (2.1%) were significantly downregulated (decrease of ≤0.5×) in cervical cancer tissues. miRNA expression was independent of lymph node involvement, vascular invasion, and pathological differentiation. Taken together, cervical cancer tissues have altered expression of miRNAs relative to adjacent normal tissues. Further studies are necessary to determine whether aberrant miRNA expression is related to the pathogenesis of cervical cancer.

Background Multiple studies proved that miRNAs have a causal role in tumorigenesis. Some miRNAs are regulated by epigenetic alterations in their promoter regions and can be activated by chromatin- modifying drugs. Methods We treated cervical cancer cells with 5-aza-2’-deoxycytidine and get a microarray analysis. Dysregulation of miRNAs was measured by qPCR in cervical cell lines and methylation status of them in cervical cancer tissue were performed with MeDIP-qPCR assay. Results We found hypermethylation of miR-432, miR-1286, miR-641, miR-1290, miR-1287 and miR-95 may have some relationship with HPV infection in cervical cell lines. In primary tumors of cervix with paired normal tissue, expression levels of miRNAs were inversely correlated with their DNA methylation status in the cervical cancer cell lines treated with 5-AZA. Conclusions Our results indicate that miRNAs might play a role in the pathogenesis of human cervical cancer with HPV and identify altered miRNA methylation as a possible epigenetic mechanism involved in their aberrant expression.