Xiaojun Chen

Pregnancy complications and outcomes in patients with early endometrial cancer or atypical hyperplasia after fertility-sparing treatment

To explore the characteristics of pregnancy outcomes in patients with early-stage endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH) after successful fertility-sparing treatment. This was a retrospective, single-center analysis of 481 patients with EEC/EAH who desired to conceive after successful fertility-sparing treatment from January 2015 to June 2023. Pregnancy outcomes across reproductive methods were compared. The pregnancy rate was 58.24% and the live birth rate was 48.65% in patients with EAH/EEC after successful fertility-preserving treatment. An age ≥35 years, BMI ≥25 kg/m², and hypertension were independent risk factors for failure of pregnancy. Higher pregnancy (65.77% and 63.64%) and live birth (53.08% and 48.86%) rates were achieved in the in vitro fertilization and embryo transfer (IVF-ET) and ovulation induction group than in the natural conception group (47.68% and 35.10%, respectively). The incidence of threatened abortion (56.52%), cervical insufficiency (5.58%), and placenta accrete/increta (11.15%) appeared to be numerically higher in patients with EAH/EEC than in epidemiological data. More than 5 times of hysteroscopic evaluation was an independent risk factor for placenta accreta/increta. Assisted reproductive technology including IVF-ET and ovulation induction might be preferred for patients with EEC/EAH after successful fertility-sparing treatment to achieve a relatively better pregnancy outcome, though IVF-ET has a higher incidence risk of threatened abortion, preterm birth and placenta accreta/increta. Obstetricians should be prepared for the treatment of threatened abortion, cervical insufficiency, and placenta accreta/increta in patients with EEC/EAH once they become pregnant, especially in those receiving more than 5 times of hysteroscopic evaluation.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10

Exploration of eMSCs with HA-GEL system in repairing damaged endometrium after endometrial cancer with fertility-sparing treatment

Despite the high complete response rate of fertility-sparing treatment in early-stage endometrial cancer (EC), the low pregnancy rate is a clinical challenge. Whether endometrium-derived mesenchymal stem cells (eMSCs) can repair damaged endometrium after EC reversal remains unclear. This study explored the potential therapeutic effects of eMSCs with suitable scaffold materials on endometrial damage caused by EC. Here, appropriate engineering scaffold materials were compared to identify the most suitable materials to carry eMSCs. Then, safety and efficacy evaluations of eMSCs with a suitable hyaluronic acid hydrogel (eMSCs/HA-GEL) were investigated in in vivo experiments with subcutaneous xenotransplantation in Balb/C nude mice and a model of endometrial mechanical injury in rats. HA-GEL has minimal cytotoxicity to eMSCs compared to other materials. Then, in vitro experiments demonstrate that eMSCs/HA-GEL enhance the inhibitory effects of progestins on EC cell biological behaviors. eMSCs/HA-GEL significantly inhibit EC cell growth and have no potential safety hazards of spontaneous tumorigenesis in Balb/C nude mouse subcutaneous xenotransplantation assays. eMSCs/HA-GEL intrauterine transplantation effectively increases endometrial thickness and glandular number, improves endometrial blood supply, reduces fibrotic areas, and improves pregnancy rates in a rat endometrial mechanical injury model. GFP-eMSCs/HA-GEL intrauterine transplantation in rats shows more GFP-eMSCs in the endometrium than GFP-eMSCs transplantation alone, and no tumor formation or suspicious cell nodules are found in the liver, kidney, or lung tissues. Our results reveal the safety and efficacy of eMSCs/HA-GEL in animal models and provide preliminary evidence for the use of eMSCs/HA-GEL as a treatment for EC-related endometrial damage.

Fertility-sparing treatment outcomes using immune checkpoint inhibitors in endometrial cancer patients with Lynch syndrome

To evaluate the efficacy of immune checkpoint inhibitors (ICIs) for fertility-sparing treatment in Lynch syndrome-associated endometrial cancer (LS-EC). Four LS-EC cases received programmed cell death protein 1 (PD-1) inhibitors for fertility preservation at the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2023. The clinical data and long-term outcomes were retrospectively reviewed. Case 1, carrying germline ICIs might be an effective choice for LS-EC patients desiring fertility preservation.

Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/β-catenin signaling pathway

AbstractBackgroundMesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.MethodsThe effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.ResultsOur results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.ConclusionsThe eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.

MRI-based radiomics model for distinguishing Stage I endometrial carcinoma from endometrial polyp: a multicenter study

Background Patients with early endometrial carcinoma (EC) have a good prognosis, but it is difficult to distinguish from endometrial polyps (EPs). Purpose To develop and assess magnetic resonance imaging (MRI)-based radiomics models for discriminating Stage I EC from EP in a multicenter setting. Material and Methods Patients with Stage I EC (n = 202) and EP (n = 99) who underwent preoperative MRI scans were collected in three centers (seven devices). The images from devices 1–3 were utilized for training and validation, and the images from devices 4–7 were utilized for testing, leading to three models. They were evaluated by the area under the receiver operating characteristic curve (AUC) and metrics including accuracy, sensitivity, and specificity. Two radiologists evaluated the endometrial lesions and compared them with the three models. Results The AUCs of device 1, 2_ada, device 1, 3_ada, and device 2, 3_ada for discriminating Stage I EC from EP were 0.951, 0.912, and 0.896 for the training set, 0.755, 0.928, and 1.000 for the validation set, and 0.883, 0.956, and 0.878 for the external validation set, respectively. The specificity of the three models was higher, but the accuracy and sensitivity were lower than those of radiologists. Conclusion Our MRI-based models showed good potential in differentiating Stage I EC from EP and had been validated in multiple centers. Their specificity was higher than that of radiologists and may be used for computer-aided diagnosis in the future to assist clinical diagnosis.

PTEN mutation predicts unfavorable fertility preserving treatment outcome in the young patients with endometrioid endometrial cancer and atypical hyperplasia

This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.

Comparison of the effect of oral megestrol acetate with or without levonorgestrel-intrauterine system on fertility-preserving treatment in patients with early-stage endometrial cancer: a prospective, open-label, randomized controlled phase II trial (ClinicalTrials.gov NCT03241914)

To evaluate the effect of levonorgestrel-releasing intrauterine system (LNG-IUS) plus oral megestrol acetate (MA) as fertility-preserving treatment in patients with early-stage endometrial cancer (EEC). In this single-center, phase II study with open-label, randomized and controlled design, young patients (18-45 years) diagnosed with primary EEC were screened, who strongly required fertility-preserving treatment. Patients were randomly assigned (1:1) into MA group (160 mg oral daily) or MA (160 mg oral daily) plus LNG-IUS group. Pathologic evaluation on endometrium retrieved by hysteroscopy was performed every 3 months. The primary endpoint was complete response (CR) rate within 16 weeks of treatment. The secondary endpoints were CR rate within 32 weeks of treatment, adverse events, recurrent and pregnancy rate. Between July 2017 and June 2020, 63 patients were enrolled and randomly assigned. Totally 56 patients (26 in MA group; 28 in MA + LNG-IUS group) were included into primary-endpoint analyses. The median follow-up was 31.6 months (range, 3.1-94.0). No significant difference in 16-week CR rate were found between MA and MA + LNG-IUS groups (19.2% vs. 25.0%, p=0.610; odds ratio=1.40; 95% confidence interval=0.38-5.12), while the 32-week CR rates were also similar (57.1% and 61.5%, p=0.743), accordingly. More women in MA + LNG-IUS group experienced vaginal hemorrhage (46.4% vs. 16.1%; p=0.012) compared with MA group. No intergroup difference was found regarding recurrence or pregnancy rate. Compared with MA alone, the addition of LNG-IUS may not improve the early CR rate for EEC, and may produce more adverse events instead. ClinicalTrials.gov Identifier: NCT03241914.

Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma

AbstractEndometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis.

NrCAM secreted by endometrial stromal cells enhances the progestin sensitivity of endometrial cancer cells through epigenetic modulation of PRB

AbstractProgestin is one of the main hormone treatment regimens for early-stage estrogen receptor- and progesterone receptor (PR)-positive endometrial cancer (EC). However, the response rate of EC to progestins is unsatisfactory. Investigating the mechanisms related to progestin treatment could help improve treatment efficacy. Studies have demonstrated that normal endometrial stromal cells (ESCs) increase the inhibitory effect of progestin on EC cell proliferation via paracrine signaling, but the mechanisms involved remain unclear. In this study, we found that ESCs had different morphological features between progestin-sensitive and -insensitive EC tissues. ESCs presented typical decidualization changes in progestin-sensitive cases, while they remained slim in progestin-insensitive EC lesions, indicating no response. Furthermore, ESCs enhanced the inhibitory effect of medroxyprogesterone acetate (MPA) on EC cell proliferation by secreting neuron cell adhesion molecule (NrCAM). MPA treatment enhanced NrCAM secretion by ESCs. EC xenografts in BALB/C nude mice demonstrated that MPA combined with NrCAM had an increased tumor inhibitory effect compared with MPA or NrCAM alone. Mechanistically, MPA upregulated NrCAM expression in ESCs through PR. Specifically, NrCAM increased PR expression in EC cells through TET1-induced hydroxymethylation of the PRB gene promoter region. These findings indicate that NrCAM or NrCAM combined with progestins could be a new EC treatment.

Clinical implications of morular metaplasia in fertility-preserving treatment for atypical endometrial hyperplasia and early endometrial carcinoma patients

Abstract Objective Morular metaplasia (MM) is a benign epithelial metaplasia that sometimes appears in atypical endometrial hyperplasia (AEH) and endometrioid endometrial carcinoma (EEC). However, the clinical implications of MM for fertility-preserving treatment in AEH and EEC patients are unclear. This study investigated the clinical features and impact of MM on the efficacy of fertility-preserving treatment. Methods We retrospectively studied 427 AEH and EEC patients who received fertility-preserving treatment. Clinical features, treatment efficacy, and onco-fertility results were compared between patients with and without MM. Results MM appeared in 147 of 427 (34.4%) patients. Among them, 49 (33.3%) had MM only before treatment (BEF group), 32 (21.8%) had sustained MM before and during treatment (SUS group), and 66 (44.9%) had MM only during treatment (DUR group). The BEF group had a higher 12-month CR rate (98.0% vs 85.7%, p = 0.017) and shorter therapeutic duration to achieve CR (4.0 vs 5.7 months, p = 0.013) than the non-MM group had. In comparison with the non-MM group, the SUS and DUR groups had a lower CR rate after 7 months of treatment (SUS vs non-MM, 37.5% vs 61.1%, p = 0.010; DUR vs non-MM 33.3% vs. 61.1%, p < 0.001), and a longer median therapeutic duration to achieve CR (SUS vs non-MM, 7.6 vs. 4.0 months, p = 0.037; DUR vs non-MM, 7.9 vs. 4.0 months, p < 0.001). Conclusion Appearance of MM only before treatment was positively correlated with outcome of fertility-preserving treatment, while sustained MM or appearance of MM only during treatment implied poorer outcome of fertility-preserving treatment in AEH and EEC patients.

Efficacy of sentinel lymph node mapping in endometrial cancer with low‐ or high‐intermediate risk

AbstractBackground and ObjectivesThis study was aimed to evaluate the efficacy of sentinel lymph node (SLN) mapping using indocyanine green (ICG) in Chinese women with endometrial cancer (EC).MethodsConsecutive EC patients undergoing SLN mapping at Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed. Overall and bilateral SLN detection rates and SLN locations were presented. Sensitivity, negative predictive value (NPV), and agreement rate were calculated and were compared between patients with low‐intermediate (LIR) or high‐intermediate risk (HIR).ResultsThere were 454 patients screened, with SLN mapping with ICG performed in 428 patients and systematic lymphadenectomy performed in 159 patients. Overall and bilateral SLN detection rates were 96.50% and 82.71%, respectively. The sensitivity of SLN mapping was 80.00%, and the NPV was 97.76%. SLNs were most commonly located in obturator and external iliac regions. Efficacy of SLN mapping was higher in LIR patients than in HIR patients, with sensitivities of 100.00% and 75.00% (p > 0.05), NPVs of 100.00% and 90.00% (p = 0.002), and agreement rates of 100.00% and 92.31% (p = 0.007), respectively.ConclusionSLN mapping with ICG had acceptable diagnostic efficacy in Chinese women with EC, but may cause more missed diagnoses in patients with HIR due to relatively low NPV and agreement rate.

The efficiency of a combined injection technique for sentinel lymph node mapping in intermediate‐high‐risk endometrial cancer

AbstractBackground and ObjectivesSentinel lymph node (SLN) mapping was considered for treating endometrial cancer (EC) which was apparent confined to the uterus. Nevertheless, intermediate‐high‐risk EC patients have super high risk to undergo isolated para‐aortic lymph node metastases comparing with low‐risk patients. Therefore, this investigation aimed to compare the efficacy of two SLN methods in detecting para‐aortic lymph node metastases.MethodsAccording to SLN mapping injection methods, intermediate‐high‐risk EC patients who received both SLN mapping and systematic lymphadenectomy were divided into the combined group (fundal and cervical injections) and the cervical group (cervical injection only).ResultsThe para‐aortic SLN detection rate in the combined group (40.4%) was higher than that in the cervical group (4.4%) with p < 0.001. While the differences concerning the sensitivity, false‐negative rate, and negative predictive value between the two groups were not significant. The survival outcomes of patients were comparable between the two groups.ConclusionOur data showcased that the combined (fundal and cervical) injection had a higher detection rate of para‐aortic SLNs than cervical injection only. The efficiency of SLN mapping and the survival outcomes were not significantly different between the two groups. Further investigations are warranted to assess the value of combined injection regarding SLN technique.

Fertility-preserving treatment outcome in endometrial cancer or atypical hyperplasia patients with polycystic ovary syndrome

This study aimed to investigate the impact of polycystic ovary syndrome (PCOS) on fertility-sparing treatment in young patients with atypical endometrial hyperplasia (AEH) or endometrioid endometrial cancer (EEC). A total of 285 patients with EEC (n=76, FIGO stage IA, without myometrium invasion) or AEH (n=209) who received progestin-based fertility-sparing treatment were evaluated retrospectively. Among the 285 patients, 103 (36.1%), including 70 AEH cases and 33 EEC cases, were diagnosed with PCOS. General characteristics, cumulative 16- and 32-week complete response (CR) rate, pregnancy outcome and recurrence were compared between patients with or without PCOS. The cumulative 16-week CR rate was lower in the PCOS group than in the non-PCOS group (18.4% vs. 33.8%, p=0.006). Patients with PCOS took longer treatment duration to achieve CR (7.0 months vs. 5.4 months, p=0.006) and shorter time to relapse after CR (9.6 months vs. 17.6 months, p=0.040) compared with non-PCOS group. After adjusting for patient age, body mass index, PCOS, homeostasis model assessment-insulin resistance index, and serum testosterone levels, we found that body mass index ≥25 kg/m² (HR=0.583; 95% CI=0.365-0.932; p=0.024) and PCOS (HR=0.545; 95% CI=0.324-0.917; p=0.022) were significantly correlated with lower 16-week CR rate. PCOS was associated with lower 16-week CR rate, longer treatment duration and shorter recurrence interval in patients with AEH or EEC receiving fertility-preserving treatment.

Characteristics of progestin-insensitive early stage endometrial cancer and atypical hyperplasia patients receiving second-line fertility-sparing treatment

This study investigated the characteristics of progestin-insensitive endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients receiving fertility-sparing treatments and assessed the therapeutic effects of second-line fertility-preserving treatments. Three hundred and thirty-eight patients with EEC (n=75) or AEH (n=263) receiving fertility-preserving treatment were retrospectively analyzed. 'Progestin-insensitive' was defined as meeting one of the following criteria: 1) presented with progressed disease at any time during conservative treatment, 2) remained with stable disease after 7 months of treatment, and/or 3) did not achieve complete response (CR) after 10 months of treatment. Clinical characteristics and treatment results of progestin-insensitive patients receiving second-line treatment and those of progestin-sensitive patients were compared. Eight-two patients (59 AEH and 23 EEC) were defined as progestin-insensitive and 256 as progestin-sensitive. In multivariate analysis, body mass index ≥28.0 kg/m² (odds ratio [OR]=1.898) and lesion size >2 cm (OR=2.077) were independent predictors of progestin-insensitive status. Compared to AEH patients, progestin-insensitive EEC patients had poorer second-line treatment responses (28-week cumulative CR rate after changing second-line treatment, 56.3% vs. 85.4%, p=0.011). No statistical difference was found in CR rate among different second-line treatments. Obesity and larger lesion size were independent risk factors associated with progestin-insensitive status. In progestin-insensitive patients receiving second-line treatment, EEC patients had lower CR rate comparing with AEH patients. Further study with larger sample size is needed to evaluate efficacy of different second-line treatments for progestin insensitive patients.

Sentinel lymph Node mapping versus systematic pelvic lymphadenectomy on the prognosis for patients with intermediate-high-risk Endometrial Cancer confined to the uterus before surgery: trial protocol for a non-inferiority randomized controlled trial (SNEC trial)

Sentinel lymph node (SLN) mapping has been recommended as an alternative staging approach to lymphadenectomy for apparent uterine-confined endometrial cancer (EC). However, the prognostic value of SLN mapping alone instead of systematic lymphadenectomy on EC patients remains unclear. A multi-center, open label, non-inferiority randomized controlled trial has been designed to identify if SLN mapping alone is not inferior to pelvic lymphadenectomy on prognosis of patients with intermediate-high-risk EC clinically confined to uterus. Eligible patients will be 1:1 randomly assigned to accept SLN mapping or pelvic lymphadenectomy. The primary endpoint is the 2-year progression-free survival (PFS). The second points are the 5-year PFS, 5-year overall survival, surgery-related adverse events and life quality. A total of 780 patients will be enrolled from 6 hospitals in China within 3-year period and followed up for 5 years. ClinicalTrials.gov Identifier: NCT04276532.

Correlation analysis and clinical significance of CA125, HE4, DDI, and FDP in type II epithelial ovarian cancer

Abstract Ovarian cancer is one of the common female malignant tumors. The early diagnosis and treatment of ovarian cancer has been a research hotspot. Therefore, we aimed to investigate the correlations between the levels of carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4), D-dimer (DDI), and fibrinogen degradation product (FDP) in patients with type II epithelial ovarian cancer. From January 2018 to January 2019, a total of 952 patients who underwent initial surgery for epithelial ovarian cancer were enrolled in this study. Peripheral venous blood was taken before operation, and the levels of CA125, HE4, DDI, and FDP were tested. The correlations between the levels of CA125, HE4, DDI, and FDP and other clinical indicators (such as presence or absence of chemotherapy, surgical conditions) were analyzed. The level of DDI or FDP was statistically associated with age, chemotherapy, Figo staging, surgical procedure, HE4 level, and CA125 level, respectively. Moreover, the Figo staging was statistically correlated with the levels of HE4 and CA125. Besides, we found the levels of CA125 and HE4 were positively correlated with the levels of DDI and FDP. The levels of CA125 and HE4 are the traditional detection indexes for patients with type II epithelial ovarian cancer, and these 2 indicators reflected the degree of disease and prognosis. The levels of DDI and FDP were closely related to the levels of CA125 and HE4 in type II epithelial ovarian cancer, and they also helped to assess the prognosis of epithelial ovarian cancer. Further larger-scale prospective cohort studies are warranted to determine these associations in the future.

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study

In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. ClinicalTrials.gov Identifier: NCT03983226.

Time for enhancing government-led primary prevention of cervical cancer

Constructing a prediction model for lymph node metastasis in patients with incidental finding of endometrial cancer based on Fully-Connected Network

Rare studies focused on patients with incidental diagnosis of endometrial cancer (EC) after hysterectomy. We intended to construct a prediction model of lymph node metastasis (LNM) based on Fully-Connected Network (FC Network) for these patients. A total of 3,920 cases of EC that met the criteria from Obstetrics & Gynecology Hospital of Fudan University between January 2016 and February 2023 and 1995 cases from Fudan University Shanghai Cancer Center between January 2013 and October 2020 were retrospectively included for the construction of a predicting model which was based on FC Network. At the same time, 572 cases were prospectively collected for external validation. The sensitivity of the model was 0.946. Lympho-vascular space invasion, myometrial invasion, tumor grade, microcystic elongated and fragmented invasion, progesterone receptor, and cancer antigen 125 were used to construct a simplified nomogram. The area under the curve of the nomogram was 0.890 and 0.885 in validation and prospective cohorts, respectively. The model we proposed has good sensitivity and can be used to predict the risk of LNM in patients with incidentally found EC. The simplified nomogram can be used as a substitute in certain situations. Based on another study, the threshold of 5% and 25% can be used for risk stratification.

Cholesterol desensitizes the response of endometrial cancer to progestin by attenuating progestin signaling.

Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine 887 with alanine 887 in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.

First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial

PURPOSE Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m 2 plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.

Clinical Studies of Endometrial Cytology and Cervical Methylation Assays in Endometrial Cancer Screening and Fertility-Preservation Evaluation

The current study aims to assess high-risk patients using both liquid-based cytology and cervical methylation testing. The results will be compared with the traditional hysteroscopic pathological findings to determine the sensitivity and specificity of these methods for early detection of endometrial cancer, thereby evaluating their potential application in early screening. Primary Objectives： 1. To evaluate the sensitivity, specificity, and accuracy of endometrial cytology for screening endometrial cancer. 2. To assess the sensitivity, specificity, and accuracy of methylation testing for screening endometrial cancer. 3. To perform further molecular testing on tissue samples obtained from endometrial cytology and cervical methylation tests, aiming to explore early screening-sensitive indicators. Secondary Objectives： 1. To determine the value of endometrial cytology in evaluating the efficacy of fertility-sparing treatments for endometrial cancer. 2. To assess the value of methylation testing in evaluating the efficacy of fertility-sparing treatments for endometrial cancer.

GnRHa + Letrozole in Obese Progestin-insensitive Endometrial Cancer Patients

To investigate the efficacy of GnRHa plus letrozole in obese progestin-insensitive EEC patients.

GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients

To investigate the efficacy of GnRHa plus letrozole vs Diane-35 plus metformin in non-obese progestin-insensitive early-stage endometrial cancer (EEC) and atypical hyperplasia(EAH) patients asking for conservative treatment.

Surgery and Niraparib in Secondary Recurrent Ovarian Cancer (SOC-3 Trial)

This is a Phase II, open-label, multicenter, randomized umbrella study to evaluate the efficacy of cytoreductive surgery and Niraparib maintenance in participants with platinum-sensitive secondary recurrent ovarian cancer. Cohort 1 will focus on participants without prior use of PARP inhibitor, and without prior secondary cytoreduction (SCR) when first recurrence. Cohort 2 will focus on participants with prior use of PARP inhibitor, but without prior SCR when first recurrence. Cohort 3 will focus on participants with SCR when first recurrence, but without prior use of PARP inhibitor.

Megestrol Acetate Plus LNG-IUS in Young Women With Early Endometrial Cancer

To see if megestrol acetate plus Levonorgestrel-releasing intrauterine system (LNG-IUS) will not be inferior to returning the endometrial tissue to a normal state than megestrol acetate alone in patients with early endometrial cancer.