Zhumei Cui

Prognostic evaluation of lymph-vascular space invasion in patients with endometrioid and non-endometrioid endometrial cancer: A multicenter study

The prognostic value of lymph-vascular space invasion (LVSI) on endometrial cancer (EC) remains controversial. This study aimed to explore the impact of LVSI on patients with endometrioid and non-endometrioid EC in China. We analyzed EC patients who underwent surgery from 2010 to 2019 in seven Chinese hospitals retrospectively and stratified patients based on histopathologic types and LVSI status. Endpoints were disease-free survival (DFS) and overall survival (OS). Propensity score matching (PSM) algorithm was used to balance the confounding factors. The survival was examined using Kaplan-Meier analysis. Cox proportional hazards regression analyses were used to find prognostic independent risk factors. Among 3715 EC patients, LVSI positive rate was 9.31% (346/3715). After matching, LVSI present group had shorter DFS (P = 0.005), and similar OS (P = 0.656) than LVSI absent group for endometrioid EC patients. For non-endometrioid EC patients, there was no statistical difference in either DFS (P = 0.536) or OS (P = 0.512) after matching. The multivariate Cox analysis showed that LVSI was an independent risk factor of DFS [hazard ratio (HR) 2.62, 95% confidence intervals (CI) 1.35-5.10, P = 0.005] and not OS (HR 1.24, 95%CI 0.49-3.13, P = 0.656) for endometrioid EC patients. It was not a prognostic factor of either DFS (HR 1.28, 95%CI 0.58-2.81, P = 0.539) or OS (HR 1.33, 95%CI 0.55-3.13, P = 0.515) for non-endometrioid EC patients. LVSI is an adverse prognostic factor for endometrioid EC patients and has no impact on non-endometrioid EC patients. Necessity of postoperative adjuvant therapy based on LVSI needs to be carefully considered for non-endometrioid EC patients.

RUNX1-IT1 acts as a scaffold of STAT1 and NuRD complex to promote ROS-mediated NF-κB activation and ovarian cancer progression

Dysregulated expression of long-stranded non-coding RNAs is strongly associated with carcinogenesis. However, the precise mechanisms underlying their involvement in ovarian cancer pathogenesis remain poorly defined. Here, we found that lncRNA RUNX1-IT1 plays a crucial role in the progression of ovarian cancer. Patients with high RUNX1-IT1 expression had shorter survival and poorer outcomes. Notably, knockdown of RUNX1-IT1 suppressed the proliferation, migration and invasion of ovarian cancer cells in vitro, and reduced the formation of peritoneum metastasis in vivo. Mechanistically, RUNX1-IT1 bound to HDAC1, the core component of the NuRD complex, and STAT1, acting as a molecular scaffold of the STAT1 and NuRD complex to regulate intracellular reactive oxygen homeostasis by altering the histone modification status of downstream targets including GPX1. Consequently, RUNX1-IT1 activated NF-κB signaling and altered the biology of ovarian cancer cells. In conclusion, our findings demonstrate that RUNX1-IT1 promotes ovarian malignancy and suggest that targeting RUNX1-IT1 represents a promising therapeutic strategy for ovarian cancer treatment.

BCHE as a Prognostic Biomarker in Endometrial Cancer and Its Correlation with Immunity

Background. In developed countries, the most common gynecologic malignancy is endometrial carcinoma (EC), making the identification of EC biomarkers extremely essential. As a natural enzyme, butyrylcholinesterase (BCHE) is found in hepatocytes and plasma. There is a strong correlation between BCHE gene mutations and cancers and other diseases. The aim of this study was to analyze the role of BCHE in patients with EC. Methods. A variety of analyses were conducted on The Cancer Genome Atlas (TCGA) data, including differential expression analysis, enrichment analysis, immunity, clinicopathology, and survival analysis. The Gene Expression Omnibus (GEO) database was used to validate outcomes. Using R tools, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) analyses revealed the potential mechanisms of BCHE in EC. Sangerbox tools were used to delve into the relations between BCHE expression and tumor microenvironment, including microsatellite instability (MSI), tumor neoantigen count (TNC), and tumor mutation burden (TMB). BCHE’s genetic alteration analysis was conducted by cBioPortal. In addition, the Human Protein Atlas (HPA) was used to validate the outcomes by immunohistochemistry, and an analysis of the protein-protein interaction network (PPI) was performed with the help of the STRING database. Results. Based on our results, BCHE was a significant independent prognostic factor for patients with EC. The prognosis with EC was affected by age, stage, grade, histological type, and BCHE. GSEA showed that BCHE was closely related to pathways regulating immune response, including transforming growth factor-β (TGF-β) signaling pathways and cancer immunotherapy through PD1 blockade pathways. The immune analysis revealed that CD4+ regulatory T cells (Tregs) were negatively correlated with BCHE expression and the immune checkpoint molecules CD28, ADORA2A, BTNL2, and TNFRSF18 were all significantly related to BCHE. BCHE expression was also associated with TMB by genetic alteration analysis. Conclusions. Identifying BCHE as a biomarker for EC might help predict its prognosis and could have important implications for immunotherapy.

Targeting ovarian cancer stem cells: a new way out

AbstractOvarian cancer (OC) is the most lethal gynecological malignancy due to tumor heterogeneity, the lack of reliable early diagnosis methods and the high incidence of chemoresistant recurrent disease. Although there are developments in chemotherapies and surgical techniques to improve the overall survival of OC patients, the 5-year survival of advanced OC patients is still low. To improve the prognosis of OC patients, it is important to search for novel therapeutic approaches. Cancer stem cells (CSCs) are a subpopulation of tumor cells that participate in tumor growth, metastasis and chemoresistance. It is important to study the role of CSCs in a highly heterogeneous disease such as OC, which may be significant to a better understanding of the oncogenetic and metastatic pathways of the disease and to develop novel strategies against its progression and platinum resistance. Here, we summarized the current findings about targeting methods against ovarian cancer stem cells, including related signaling pathways, markers and drugs, to better manage OC patients using CSC-based therapeutic strategies.

S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.

The prognosis of patients with locally advanced cervical cancer undergoing surgical versus non-surgical treatment: a retrospective cohort study based on SEER database and a single-center data

The aim of this study was to investigate the impact of surgical treatment on the survival prognosis of patients with locally advanced cervical cancer (LACC) and to identify factors that may influence the efficacy of surgery. Data from the SEER database (2000–2020) and a hospital (2013–2023) were collected for this investigation. Utilizing multivariable Cox regression analysis, Kaplan–Meier survival analysis, and log-rank tests, we assessed the effects of surgical intervention on overall survival (OS) and disease-specific survival (DSS) in LACC patients. Our results revealed that in the SEER database, the surgical group exhibited significantly better OS and DSS compared to the non-surgical group. Particularly noteworthy was the significantly higher survival rate in the surgical group for patients with tumor diameters less than 6 cm. Furthermore, both OS and DSS were improved in the surgical group regardless of whether the cancer was squamous cell carcinoma or adenocarcinoma. Additionally, patients who underwent surgery combined with radiotherapy had notably better OS and DSS compared to those who received chemoradiotherapy alone. Similarly, our hospital data showed that the surgical group demonstrated significantly better OS than the non-surgical group, especially for patients with tumors smaller than 6 cm in diameter. These findings suggest that surgery combined with radiotherapy may offer more favorable outcomes than chemoradiotherapy alone, particularly for LACC patients with smaller tumors.

Clinical analysis of 12 cases of ovarian cystic mature teratoma with malignant transformation into squamous cell carcinoma

Objective This study aimed to examine the clinicopathological characteristics, treatment, and prognostic factors in 12 cases of malignant transformation of mature cystic teratoma of the ovary (MCTO). Methods We performed a retrospective study of 12 patients with malignant transformation of MCTO who were admitted to the Affiliated Hospital of Qingdao University from 2003 to 2019. We examined case records, clinical parameters, and biological assessments. Results The median age of the patients was 56.5 years and seven of them were postmenopausal. The average tumor size was 18.5 cm. All patients had pelvic masses at their first hospital visit. Nine of the patients had discomfort in the lower abdomen, two presented with a lower abdominal palpable mass, and three were complicated by fever. The median follow-up time was 73 months (12‒193 months). Ten patients survived with a disease-free status and two died. Conclusions There is a low incidence of malignant transformation of MCTO, and its most common histological type is squamous cell carcinoma. Age and tumor size are important factors in malignant transformation of teratomas. While there is a lack of treatment guidelines for malignant transformation of MCTO, early diagnosis and treatment may be beneficial for these patients.

Laparoscopic versus open radical hysterectomy in FIGO 2018 early‐stage cervical adenocarcinoma: Long‐term survival outcomes after propensity score matching

AbstractObjectiveTo compare the long‐term survival outcomes of laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in International Federation of Gynecology and Obstetrics (FIGO) 2018 early‐stage cervical adenocarcinoma.MethodsBased on the clinical diagnosis and treatment for cervical cancer in mainland China (Four C) database, the medical records of 1098 patients with FIGO 2018 early‐stage cervical adenocarcinoma were retrospectively reviewed. Long‐term and short‐term survival outcomes of the two groups were compared using a multivariate Cox regression model and the log‐rank method in the whole study population and after propensity score matching.ResultsThere was no difference in disease‐free survival (hazard ratio [HR] 0.921, 95% confidence interval [CI]: 0.532–1.595, p = 0.770) and overall survival (HR 1.168, 95% CI: 0.526–2.592, p = 0.702) between LRH (n = 468) and ORH (n = 468) in the risk‐adjusted analysis. LRH resulted in significantly lower estimated blood loss (342.7 vs. 157.5 mL, p < 0.001) and shorter postoperative anal exhaust time (2.8 vs. 2.5 days, p < 0.001) in risk‐adjusted analysis. The overall rates of intraoperative complications (2.4% vs. 4.3%, p = 0.100) and postoperative complications (7.5% vs. 6.2%, p = 0.437) showed no significant difference between the two groups. However, the LRH group had a significantly higher incidence of ureter injury (0.4% vs. 2.4%, p = 0.012) and great vessel injury (0.0% vs. 0.9%, p = 0.045) compared to the other group. No statistical variation in the site of recurrence was observed between the two groups (p = 0.613).ConclusionsLRH has comparable survival outcomes with ORH and was associated with earlier recovery in FIGO 2018 early‐stage adenocarcinoma of the uterine cervix. However, the LRH group had higher risk of ureter injury and great vessel injury.

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.