Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis.

INTRODUCTION: The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). METHODS: A retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. RESULTS: The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. CONCLUSIONS: FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

Genomic and expressional dynamics of ovarian cancer cell lines in PARPi treatment revealed mechanisms of acquired resistance.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Survival Analysis of Lymph Node Resection in Ovarian Cancer: A Population-Based Study.

Objective: This study aimed at comprehensively investigating the survival impact of lymphadenectomy during primary surgery in ovarian cancer. Methods: Based on the surveillance, epidemiology, and end results registry (SEER) database, we included ovarian cancer patients with detailed information between 2010 and 2016. Cox regression was performed to select prognostic factors. We conducted propensity score-weighted survival analysis to balance baseline variables, and series of stratified analyses to control main confounding factors. Results: A total of 8,652 patients were ultimately identified. Among 4,360 patients with advanced disease, lymphadenectomy did not show significant survival benefit in general (median overall survival 44 months in non-lymphadenectomy vs. 49 months in lymphadenectomy group, P = 0.055). In subgroup analysis on patients received optimal debulking, lymphadenectomy did not significantly benefit the survival outcome (median overall survival 51, 47, 60, and 58 months in the non-lymphadenectomy, 1-9 lymph nodes, 10-19 lymph nodes, ≥20 lymph nodes groups, respectively, P = 0.287). Consistent results were observed in further stratification analyses. In optimal debulking subgroup, lymph node metastasis indicated worse survival. However, when limited the number of removed lymph nodes to more than 15, there was a marginal statistical difference in overall survival (P = 0.0498) while no significant difference presented in cause-specific survival (P = 0.129) between non-lymphadenectomy, pathological negative lymph node group and positive lymph node group. And the regions of lymph metastasis were also not significantly associate with survival (P = 0.123). Among 3,266 (75%) patients with apparent early-stage disease received lymphadenectomy, 7.75% of whom were reported isolated lymph nodes metastasis and have a poorer survival (P < 0.05). Conclusions: In primary debulking for patients with advanced ovarian cancer, lymphadenectomy was not associated with more favorable outcomes when compared to no lymphadenectomy. The value of lymphadenectomy lies more in staging for apparent early disease rather than therapeutic benefit.

Central Sensitization-Related Changes in Brain Function Activity in a Rat Endometriosis-Associated Pain Model.

BACKGROUND: Pain sensitization processing in the central nervous system may be related to endometriosis-associated pain in patients. The purpose of this study was to understand the alterations in the abnormal pain response in central brain areas and explore the central sensitization mechanism of endometriosis-associated pain. METHODS: An endometriosis model was established in 40 Sprague-Dawley rats, and the rats underwent pain model assessment through behavioral tests. Twenty Sprague-Dawley rats underwent a sham operation as the control group. Thirteen pain rats and 8 control rats received Rs-fMRI examination to explore the brain functional activity areas, and the regional homogeneity (ReHo) method was used to analyze relevant functional signals among the whole brain. The states of neurons and expression of TRPV1 and NMDRA located in the abnormal ReHo signal brain regions were observed using Nissl staining, qRT-PCR and immunohistochemistry. RESULTS: The rats were divided into a pain group and a control group based on the different syndromes and behavioral assessments. We detected significant enhancement of ReHo signals in the anterior cingulate cortex, hippocampus, and thalamus and a reduction in the ReHo values in the basomedial amygdaloid nucleus (BM) and primary motor cortex (M1) in the pain rat group via Rs-fMRI examination. The number of Nissl bodies and apoptotic neurons was increased; moreover, the volume of neurons increased compensatorily in the cingulate cortex, thalamus and hippocampus in the pain group. TRPV1 and NMDRA were overexpressed in apoptotic neurons in the higher ReHo value brain regions in the endometriosis pain group. CONCLUSION: These findings suggest that in rats with endometriosis-associated pain, ReHo signal enhancement was observed in the cingulate cortex, thalamus and hippocampus, which may be due to the increase in the number of apoptotic neurons or the compensatory increase in the volume of overactive neurons.

Pathological findings following risk-reducing salpingo-oophorectomy in BRCA mutation carriers: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the benefit of risk-reducing salpingo-oophorectomy (RRSO) by estimating the pathological positive rate of occult lesions, including serous tubal intraepithelial carcinoma (STIC) and occult cancers (OCCs). METHODS: BRCA1/2 mutation carriers who underwent RRSO in a Chinese study center between 2014 and 2018 were included. A literature review was performed, followed by a meta-analysis of the literature to further validate the findings. RESULTS: Twenty-four BRCA1/2 mutation carriers who underwent RRSO were identified; one patient (4.2%) had STIC, and one patient (4.2%) had occult fallopian tube cancer complicated by STIC. Thirty-four articles were ultimately included in the meta-analysis. Of the reported cases of OCC, 61.3% occurred in the fallopian tubes and 32.3% in the ovaries, and 81.5% were in the early stages. The estimated rate of overall pathological positive events was 5%. The estimated rates of overall STIC events and OCC were 1% and 3%, respectively. The rates of STIC and OCC were 1% and 3%, respectively, for BRCA1 mutation carriers and 1% and 1%, respectively, for BRCA2 mutation carriers. No significant difference was observed between the results of a routine examination of pathological sections and those of the Sectioning and Extensively Examining the Fimbriae (SEE-FIM) protocol. CONCLUSIONS: This study is the first report of RRSO results in China. In this systematic review, the positive rates of STIC or OCC after RRSO were no more than 3%, which are 200-fold higher than the risk of the general population. The use of a strict SEE-FIM protocol would likely increase positive results.

Efficacy of different surgical approaches in the clinical and survival outcomes of patients with early-stage cervical cancer: protocol of a phase III multicentre randomised controlled trial in China.

INTRODUCTION: In the last three decades, minimally invasive surgery (MIS) for radical hysterectomy (RH) has become a popular treatment option for early-stage cervical cancer. However, a recently published randomised controlled trial (LACC trial) and an epidemiological study in the USA revealed strong evidence against the survival advantage of MIS for RH. However, the influencing factors of research centres and the learning curves of surgeons in these studies lacked sufficient evaluation. The efficacy of different surgical approaches for early-stage cervical cancer in the clinical and survival outcomes remains to be validated. METHODS AND ANALYSIS: Patients diagnosed with FIGO (2009) stage IA1 (with lymphovascular space invasion), IA2 or IB1 cervical cancer with histological subtype of squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma will be recruited in this multicentre randomised controlled study. Patients will be randomly assigned to undergo MIS (robot-assisted or laparoscopic RH) or abdominal RH. Within 2 years, 1448 patients in 28 centres in China will be recruited to meet the criteria of a non-inferiority threshold of HR of 1.6 with bilateral nominal α <0.05 and power of 0.8. All surgeries will be performed by the indicated experienced surgeons. At least 100 RH cases in the individual past one decade of practice will be analysed as proof of learning curves. The primary objective of this study is 5-year disease-free survival. The secondary objectives include the overall survival rate, progression-free survival rate, disease-free survival rate, cost-effectiveness and quality of life. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of Peking Union Medical College Hospital and is filed on record by all other centres. Written informed consent will be obtained from all eligible participants before enrolment. The results will be disseminated through community events, academic conferences, student theses and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03739944.

Evaluation of the brain functional activities in rats various location-endometriosis pain model.

BACKGROUND: Endometriosis (EM) is a common gynecological disease in women of reproductive age. These patients in approximately 80% suffer the various degree pain. This study will investigate synergistically the mechanism of the higher-position central sensitization and offer a pre-clinical experiment evidence for treatment of various location-EM patients with pain. METHODS: Twenty Sprague-Dawley rats were induced three types EM including abdominal EM (n=5), gastrocnemius EM (n=5) and ovary EM group (n=5) and one sham control group (n=5). All groups were measured the pain sensitization by hotplate test, then scanned by the functional magnetic resonance imaging (fMRI). The resting-state fMRI (rs-fMRI) date was analyzed using regional homogeneity (ReHo) approach to find out the abnormal functional activity brain regions. Nissl staining method observed the state of neurons in aberrant ReHo signal brain regions. RESULTS: Rats with EM pain sensitization were increased in abdominal EM and gastrocnemius EM than ovary EM group and sham control. The ReHo value is decreased in gastrocnemius EM in right thalamus and left olfactory tubercle compared with other three groups. The number of neurons was decreased; cavitation around nucleus, and pyknotic homogenous nuclei. Nissl bodies were stained deeply, and the shape was irregular in gastrocnemius EM by Nissl staining in right thalamus. In left olfactory tubercle, there was no significant difference in 4 groups. CONCLUSIONS: The thalamus may be the potential key brain region for the central sensitization mechanism of various location-EM pain. The oxidative activation may be weakened in thalamus in gastrocnemius EM group with more severe pain. This finding could lend support for future research on the imageology and pathology of various location-EM pain.

Is it necessary to perform routine appendectomy for mucinous ovarian neoplasms? A retrospective study and meta-analysis.

OBJECTIVES: To evaluate whether routine appendectomy is necessary in all patients with mucinous borderline ovarian tumor (mBOT) or mucinous ovarian cancer (MOC) who undergo gynecologic surgery. METHODS: The database of Qilu Hospital was searched for women who underwent appendectomy in a primary surgery for an ovarian tumor between June 2005 and June 2015 and whose final diagnosis was mBOT, MOC or primary appendiceal tumor. A retrospective review was performed, as well as a meta-analysis of the literature to further validate the findings. RESULTS: Seventy-one patients, 29 with mBOT and 42 with malignant mucinous tumors (including 40 with primary MOC and 2 with appendiceal mucinous adenocarcinoma), underwent appendectomy at the time of primary surgery. Among those with mBOT, two (6.9%) appendices were grossly abnormal and pathologically diagnosed with appendiceal implantation by mBOT. In the 42 patients with malignant disease, five (12%) appendices had a grossly abnormal appearance, one (2.4%) was diagnosed with an appendiceal metastasis from MOC and two (4.7%) were primary appendiceal adenocarcinoma. For grossly normal appendices, only one (2.4%) was confirmed to have microscopic metastasis from MOC. The meta-analysis included a total of 914 mBOT and MOC cases with appendectomies, including our current cases. The estimated rate of overall appendiceal pathology is 4.97%, and the pooled odds ratio (OR) showed statistical differences between MOC and mBOT (MOC vs. mBOT, OR=2.15, P<0.05). The estimated malignant pathology rate in macroscopically normal vs. abnormal appendices is 1.4% and 59%, respectively, with an estimated OR up to 97.5 (95% CI 28.1-338.5, P<0.05). CONCLUSION: There is not sufficient evidence to support a routine appendectomy for patients with a grossly normal appendix in mBOT and MOC. A careful intra-operative exploration of the appendix is crucial, but appendectomy is only warranted when the appendix is abnormal.