Jianliu Wang

Analysis of fertility-preserving treatment outcomes in patients with POLE-mutated endometrioid carcinoma

To explore the clinical outcomes of fertility-sparing treatment (FST) in patients with POLE-mutated endometrioid carcinoma (EEC). A total of 9 EEC patients who received FST and were classified to the POLE-mutated subtype in Peking University People's Hospital from April 2020 to October 2023, were retrospectively collected. Clinical and pathological data were analyzed to describe the outcomes of FST in patients with POLE-mutated EEC. A total of 9 patients with EEC including 6 cases with well-differentiated (G1) and 3 cases with moderately-differentiated (G2). The average age was 34.8±2.1 years. POLE mutation sites were P286R (5 cases), V411L (2 cases), L424I (1 cases), and S459F (1 cases), respectively. The median follow-up time was 16 months (9-41 months). The complete response (CR) rate was 88.9% (8/9), with a median time to CR of 5.5 months (3-18 months). The partial response (PR) rate was 11.1% (1/9). The relapse rate was 50.0% (4/8), with a median recurrence time of 9.5 months (5-25 months). Of these, 75% (3/4) underwent secondary FST, with all achieving CR again (3/3). Three of 5 who were out-of-indication patients achieved CR by individual therapy. FST in patients with POLE-mutated EEC achieve a CR rate of 88.9% in this study, the largest number of retrievable reports. In certain patients who are out-of-indication, individualized treatment may also result in remission. However, unlike surgical patients, some patients experience disease recurrence and whether POLE-mutated EEC is sensitive to conventional therapy in FST is controversial given its pathogenesis.

Diagnostic significance and predictive efficiency of metabolic risk score for fertility-sparing treatment in patients with atypical endometrial hyperplasia and early endometrial carcinoma

This study aims to assess the impact of the metabolic risk score (MRS) on time to achieve complete remission (CR) of fertility-sparing treatments for atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) patients. Univariate and multivariate cox analyses were employed to identify independent risk factors affecting the time to CR with patients at our center. These factors were subsequently incorporated into receiver operator characteristic curve analysis and decision curve analysis to assess the predictive accuracy of time to CR. Additionally, Kaplan-Meier analysis was utilized to determine the cumulative CR rate for patients. The 173 patients who achieved CR following fertility preservation treatment (FPT) were categorized into three subgroups based on their time to CR (9 months). Body mass index (hazard ratio [HR]=0.20; 95% confidence interval [CI]=0.03, 0.38; p=0.026), MRS (HR=0.31; 95% CI=0.09, 0.52; p=0.005), insulin resistance (HR=1.83; 95% CI=0.05, 3.60; p=0.045), menstruation regularity (HR=3.77; 95% CI=1.91, 5.64; p=0.001), polycystic ovary syndrome (HR=-2.16; 95% CI=-4.03, -0.28; p=0.025), and histological type (HR=0.36; 95% CI=0.10, 0.62; p=0.005) were identified as risk factors for time to CR, with MRS being the independent risk factor (HR=0.29; 95% CI=0.02, 0.56; p=0.021). The inclusion of MRS significantly enhanced the predictive accuracy of time to CR (area under the curve [AUC]=0.789 for Model 1, AUC=0.862 for Model 2, p=0.032). Kaplan-Meier survival curves revealed significant differences in the cumulative CR rate among different risk groups. MRS emerges as a novel evaluation system that substantially enhances the predictive accuracy for the time to achieve CR in AEH and early EC patients seeking fertility preservation.

Identification of an immune-related risk signature and nomogram predicting the overall survival in patients with endometrial cancer

Aimed to construct an immune-related risk signature and nomogram predicting endometrial cancer (EC) prognosis. An immune-related risk signature in EC was constructed using the least absolute shrinkage and selection operator regression analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A nomogram integrating the immune-related genes and the clinicopathological characteristics was established and validated using the Kaplan-Meier survival curve and receiver operating characteristic (ROC) curve to predict the overall survival (OS) of EC patients. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) R tool was used to explore the immune and stromal scores. CCL17, CTLA4, GPI, HDGF, HFE2, ICOS, IFNG, IL21R, KAL1, NR3C1, S100A2, and S100A9 were used in developing an immune-related risk signature evaluation model. The Kaplan-Meier curve indicated that patients in the low-risk group had better OS (p<0.001). The area under the ROC curve (AUC) values of this model were 0.737, 0.764, and 0.782 for the 3-, 5-, and 7-year OS, respectively. A nomogram integrating the immune-related risk model and clinical features could accurately predict the OS (AUC=0.772, 0.786, and 0.817 at 3-, 5-, and 7-year OS, respectively). The 4 immune cell scores were lower in the high-risk group. Forkhead box P3 (FOXP3) and basic leucine zipper ATF-like transcription factor (BATF) showed a potential significant role in the immune-related risk signature. Twelve immune-related genes signature and nomogram for assessing the OS of patients with EC had a good practical value.

Developing a Complex Intervention Plan for Physical Activity in Overweight and Obese Endometrial Cancer Patients: A Multimethod Study

Aims and Objectives This study aims to develop a comprehensive physical activity (PA) intervention tailored for overweight and obese patients with endometrial cancer (EC). It integrates theoretical frameworks, empirical evidence, expert opinions, and stakeholder perspectives to assist clinical providers in implementing standardized PA guidelines. Background Obesity is a significant risk factor for EC and is closely linked to treatment outcomes. Although previous studies have focused on the role of PA in weight loss and survival, they lack detailed, evidence‐based guidance specifically tailored for EC patients. Design and Methods We developed a PA instruction program using the Evidence‐Based Nursing Practice Pathway and the Medical Research Council’s Framework for Complex Interventions. The development process consisted of three phases: a preparatory phase, the development and implementation of evidence‐based interventions, and the refinement of the program through Delphi consultation. Results The program framework was developed using multiple methods, including evidence searches (guidelines and expert consensus), semistructured interviews, and expert consultations. It encompasses preinstruction, implementation methods, and strategies for maintaining PA. Instructional materials such as posters, brochures, videos, and checklists were created to facilitate clinical integration. Conclusions This study is the first to develop a tailored PA program for overweight EC patients. The rigorous design, based on complex intervention frameworks and expert input, has the potential to improve clinical practice, enhance tumor remission rates, and improve fertility outcomes. Relevance to Clinical Practice Utilizing the MRC framework, this study integrated evidence and stakeholder feedback to develop a tailored intervention program. It aims to increase PA among overweight and obese EC patients by providing educational materials for clinicians and patients, thereby promoting its adoption in clinical practice. Trial Registration: ClinicalTrials.gov_identifier: NCT06312917

Lipid‐Driven OLR1/FOXM1/FGF19 Axis Orchestrates Crosstalk in an Epithelial‐Fibroblast Positive Feedback Promoting Progesterone Resistance in Endometrial Cancer

Abstract Progesterone resistance (ProR) remains a major obstacle in the conservative management of endometrial cancer (EC). Here, a metabolic‐stromal signaling loop centered on the OLR1/FOXM1/FGF19 axis is identified that drives progesterone resistance in EC. Single‐cell transcriptomic profiling first revealed a striking correlation between epithelial cells and fibroblasts in EC tissues with ProR. Tumor epithelial cells display profound alterations in lipid metabolism, whereas fibroblasts exhibited enhanced oxidative stress signatures. Clinical samples analyses indicated that oxidized low density lipoprotein (oxLDL), a product of LDL oxidation, is associated with adverse outcomes. The binding of oxLDL to its receptor OLR1 promoted the expression of FOXM1, a transcription factor that directly upregulates fibroblast growth factor 19 (FGF19). Immunofluorescence confirmed not only the spatial co‐localization of epithelial cells and fibroblasts but also the enrichment of OLR1 within epithelial compartments. Furthermore, treatment with the antioxidant resveratrol (RSV) and its nanoformulation (RSV‐NPs) markedly inhibited tumor growth in mice with lipid metabolic disorders, highlighting their potential to counteract progesterone resistance by disrupting this OLR1/FOXM1/FGF19 axis. This work highlights the therapeutic potential of targeting the tumor–stroma metabolic axis to increase progesterone sensitivity and improve outcomes in EC patients with fertility‐preserving demands.

Comparison of sentinel lymph node distribution and lymphatic drainage pathway between high- and low-risk endometrial cancers

This study aimed to compare the distribution and drainage pathway of sentinel lymph nodes between high- and low-risk endometrial cancers. In total, 429 patients with endometrial cancer who underwent sentinel lymph node biopsy in Peking University People's Hospital from July 2015 to April 2022 were retrospectively enrolled. There were 148 patients in the high-risk group and 281 patients in the low-risk group. The unilateral and bilateral detection rates of sentinel lymph nodes were 86.5% and 55.9%, respectively. The highest detection rate was achieved in the subgroup with a combined use of indocyanine green (ICG) and carbon nanoparticles (CNP) (94.4% for unilateral detection and 66.7% for bilateral detection). The upper paracervical pathway (UPP) was detected in 93.3% of cases in the high-risk group and 96.0% of cases in the low-risk group (p = 0.261). The lower paracervical pathway (LPP) was detected in 10.0% of cases in the high-risk group and 17.9% of cases in the low-risk group (p = 0.048). Remarkably increased detection rates of SLN in the common iliac (7.5%) and para-aortic or precaval areas (2.9%) were observed in the high-risk group. In contrast, a markedly decreased detection rate of SLN in the internal iliac area (1.9%) was observed in the high-risk group. The highest detection rate of SLN was observed in the subgroup with a combined use of ICG and CNP. The detection of UPP is important for both high-risk and low-risk cases, while LPP detection plays a more important role in the low-risk group. Lymphadenectomy in the common iliac and para-aortic or precaval areas is essential for patients with high-risk EC. Removal of internal iliac lymph nodes is essential for patients with low-risk EC, in case of ineffective SLN mapping.

Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer

AbstractIntroductionEndometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism‐related prognostic model for EC and explore potential targets for cancer treatment.MethodTranscriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model.ResultsFive glutamine metabolism‐related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan–Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high‐risk patients whereas immune relevance analysis revealed low immune scores in the high‐risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT‐503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002).ConclusionOur work established and validated a glutamine metabolism‐related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High‐risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.

Development and validation of a prognostic model based on metabolic risk score to predict overall survival of endometrial cancer in Chinese patients

Metabolic syndrome (MetS) is closely related to the increased risk and poor prognosis of endometrial cancer (EC). The purpose of this study was to analyze the relationship between metabolic risk score (MRS) and EC, and establish a predictive model to predict the prognosis of EC. A retrospective study was designed of 834 patients admitted between January 2004 to December 2019. Univariate and multivariate Cox analysis were performed to screen independent prognostic factors for overall survival (OS). A predictive nomogram is built based on independent risk factors for OS. Consistency index (C-index), calibration plots and receiver operating characteristic curve were used to evaluate the predictive accuracy of the nomogram. The patients were randomly divided into training cohort (n=556) and validation cohort (n=278). The MRS of EC patients, ranging from -8 to 15, was calculated. Univariate and multivariate Cox analysis indicated that age, MRS, FIGO stage, and tumor grade were independent risk factors for OS (p<0.05). The Kaplan-Meier analysis demonstrated that EC patients with low score showed a better prognosis in OS. Then, a nomogram was established and validated based on the above four variables. The C-index of nomogram were 0.819 and 0.829 in the training and validation cohorts, respectively. Patients with high-risk score had a worse OS according to the nomogram. We constructed and validated a prognostic model based on MRS and clinical prognostic factors to predict the OS of EC patients accurately, which may help clinicians personalize prognostic assessments and effective clinical decisions.

Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress

Abstract Background Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells. Methods A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage. Results We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression. Conclusions Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Adjuvant chemoradiotherapy versus chemotherapy alone in stage III endometrial cancer: A systematic review and meta‐analysis

AbstractObjectiveTo discuss the impact of chemoradiotherapy (CRT) on the survival of patients with stage III endometrial cancer (EC) compared with chemotherapy (CT) alone.MethodsArticles involving adjuvant CRT versus CT on survival in stage III EC were retrieved from PubMed and EMBASE. Hazard ratios (HRs) of overall survival (OS) and relapse‐free survival (RFS) were collected and pooled, and publication bias was measured by Begg's and Egger's test. Quality of researches was measured by the Newcastle–Ottawa scale and the modified Jadad scale.ResultsEleven were included in the statistical analysis. A significant advantage of CRT over CT on OS was shown (HR 0.59, 95% CI 0.49–0.70). Further subgroup analysis suggested the advantage was mostly associated with stage IIIC (HR 0.63, 95% CI 0.52, 0.76]). A similar result favoring CRT was also reached on RFS (HR 0.66, 95% CI 0.47–0.93). No significant publication bias was observed.ConclusionCRT was associated with a better OS and RFS than CT alone in stage III EC patients.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes

AbstractDiabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG) mimicking hyperglycemia in patientEC+/dia+. Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction‐sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06‐NPs) for drug delivery. It is found that in vitro JX06‐NPs have better inhibitory effect on the growth of IshikawaHG as well as patient‐derived EC cells (PDC) than JX06. Additionally, it is found that JX06‐NPs can accumulate to the tumor of EC‐bearing mouse with diabetes (miceEC+/dia+) after intravenous injection, and JX06‐NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+. Taken together, the study demonstrates that the combination of JX06‐NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+.

Analysis of pregnancy-associated factors after fertility-sparing therapy in young women with early stage endometrial cancer or atypical endometrial hyperplasia

Abstract Background Fertility-sparing therapy is an alternative conservative treatment for patients with early stage endometrioid cancer or atypical endometrial hyperplasia. In this study, we investigated pregnancy outcomes and pregnancy-associated factors in young patients receiving hormonal therapy. Methods We retrospectively analyzed 68 patients who attempted to conceive after fertility-sparing therapy and achieving complete remission (CR). They were divided into a pregnancy group and a non-pregnancy group. A Cox proportional hazard regression model was applied for univariate and multivariate analysis to determine factors associated with pregnancy. Kaplan–Meier analysis, combined with the log-rank test, was used to calculate a patient’s pregnancy probability and the distribution of recurrence-free survival (RFS). Results A total of 36 patients became pregnant with 47 pregnancies. Univariate and multivariate Cox analysis revealed that several factors were associated with pregnancy, including BMI at the time of pregnancy permission, the time to CR, prolonged treatment time, the number of hysteroscopy procedures, the endometrium thickness after CR, and relapse before pregnancy. The mean RFS of patients who achieved pregnancy, and those who did not, was 27.6 months and 14.8 months, respectively (P = 0.002). No significant difference was detected in terms of cumulative RFS when compared between assisted reproductive technology (ART) cases and those involving natural conception (NC) (P = 0.707). Conclusions Normal BMI, a shorter time to CR, a prolonged three-month treatment, fewer hysteroscopy procedures, and a thicker endometrium may be positive indicators for successful pregnancies, while relapse before pregnancy may have a negative effect on conception. Moreover, a successful pregnancy protects the endometrium while ART does not increase the risk of recurrence.

Cutaneous metastases of endometrial carcinoma: report of an unusual case and literature review

Cutaneous metastases of endometrial carcinoma are rare. We report a case of a 54-year-old woman who developed cutaneous metastases from an endometrial carcinoma, and review the related literature to offer insight into this rare and serious condition. The clinical and pathological data and therapy delivered to a patient from Peking University People's Hospital, were retrieved from her medical records. A systematic literature search regarding this unusual disease progression was conducted through PubMed/MEDLINE. A postmenopausal patient diagnosed with stage IB endometrioid carcinoma rapidly developed cutaneous metastases. 10 months postoperatively, the patient developed multiple lymph node metastases, and 22 months later, cutaneous metastases appeared on both breasts. She was then treated with chemotherapy, immunotherapy and hormone therapy. The skin lesions eased temporarily but deteriorated quickly. Ultimately, she died in 7 months subsequent to the appearance of cutaneous lesions. Cutaneous metastases from endometrial carcinoma have usually been incurable and associated with a limited prognosis.

Prognostic significance of lymphovascular space invasion in patients with endometrioid endometrial cancer: a retrospective study from a single center

This study aims to analyze factors associated with lymphovascular space invasion (LVSI) and evaluate the prognostic significance of LVSI in Chinese endometrioid endometrial cancer (EEC) patients. Five-hundred eighty-four EEC patients undergoing surgery in our center from 2006 to 2016 were selected for analysis. Univariate analysis and multivariate logistic regression were used to examine relevant factors of LVSI. To evaluate the prognostic role of LVSI, survival analyses were conducted. In survival analyses, both multivariate Cox regression and propensity score matching were used to control the confounders. The incidence of LVSI was 12.16% (71/584). Diabetes history (p=0.021), lymph node metastasis (p=0.005), deep myometrial invasion (p<0.001) and negative PR expression (p=0.007) were independently associated with LVSI. Both Kaplan-Meier method and univariate Cox regressions showed LVSI negative and positive cases had similar tumor-specific survival (TSS) and disease-free survival (DFS). After adjusting for the influence of adjuvant therapy and other clinicopathological factors with multivariate Cox regressions, LVSI still could not bring additional survival risk to the patients (p=0.280 and p=0.650 for TSS and DFS, respectively). This result was verified by Kaplan-Meier survival analyses after propensity score matching (p=0.234 and p=0.765 for TSS and DFS, respectively). LVSI does not significantly compromise the survival outcome of Chinese EEC patients.

Fertility and prognosis assessment between bleomycin/etoposide/cisplatin and paclitaxel/carboplatin chemotherapy regimens in the conservative treatment of malignant ovarian germ cell tumors: a multicenter and retrospective study

To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.

Multi-omic and immune landscapes of HPV-negative versus HPV-positive cervical cancer reveal implications for immunotherapy

HPV-negative cervical cancer (3-8% of cases) presents distinct clinical challenges and poorer prognosis compared to HPV-positive disease. We aimed to conduct an exploratory study to characterize its unique tumor immune microenvironment (TIME) and molecular drivers to inform immunotherapy development. We analyzed 70 cervical cancer patients (50 HPV-positive/HPV-A, 20 HPV-negative/HPV-I) using targeted next-generation sequencing and multiplex immunofluorescence. Clinical features, mutational profiles, immune cell infiltrates, and prognostic factors were compared between groups. Strict FDR correction and effect size analysis (Cliff's Delta) were applied to statistical comparisons. HPV-I tumors showed significant association with gastric-type adenocarcinoma (p < 0.001) and higher CA125 levels (p = 0.011). Molecularly, HPV-I tumors were substantially enriched for TP53 mutations (46.2% vs 2.2%, OR = 0.030, p < 0.001), while PIK3CA mutations predominated in HPV-A tumors (41.3% vs 7.7%, OR = 7.78, p = 0.047), suggesting notable mutual exclusivity. Immunologically, HPV-A tumors showed substantially higher stromal M2 macrophage density (Cliff's Delta = -0.51, Large Effect), while HPV-I tumors displayed significantly higher stromal immune cell ratios: M1/M2 (5.34 vs 0.87, p = 0.003), CD8+/M2 (13.65 vs 2.66, p = 0.004), and NK/M2 (8.43 vs 0.59, p = 0.012), revealing the paradox of favorable immune balance coexisting with immune exclusion. In HPV-I subgroup analysis, high CD8+/M2 ratio was associated with superior progression-free survival (16.7% vs 71.4% event rates, p = 0.014). HPV-negative and HPV-positive cervical cancers represent distinct entities with unique molecular and immunological profiles. Our exploratory findings suggest that HPV-I tumors exhibit the paradox of favorable stromal immune cell ratios coexisting with immune-excluded phenotype, while HPV-A tumors show higher M2 macrophage infiltration. The prognostic significance of CD8+/M2 ratio in HPV-I patients may provide a valuable biomarker and suggest specific therapeutic strategies targeting immune exclusion and macrophage polarization based on HPV status.

FOXA2 sensitizes endometrial carcinoma to progestin-mediated conservative therapy by triggering PR transcriptional activation

Progesterone receptor (PR) expression correlates strongly with progestin sensitivity in fertility-sparing therapy for endometrial carcinoma (EC). However, the mechanisms governing PR expression remain incompletely defined. Here, by stratifying EC patients into PR-high and PR-low groups, we observe that PR-low tumors exhibit enhanced invasion and metastasis signatures, whereas PR-high tumors display increased fatty acid metabolism. Through integrated network analysis, transcriptional correlation across multiple cohorts, and single-cell transcriptomic profiling, FOXA2 is identified as a master regulator of PR expression. Specifically, FOXA2 directly binds the PR promoter, which, in turn, transcriptionally activates PR expression and increases the sensitivity of EC cells to medroxyprogesterone acetate (MPA), an oral progestin used in clinical. Overexpression of FOXA2 markedly inhibits tumor progression, evidenced with reduced cell proliferation and migration while elevated apoptosis. Moreover, FOXA2 is critically involved in lipid metabolic modulation and the administration of Orlistat, an FDA-approval inhibitor of fatty acid synthase, elevates FOXA2 and PR expression, subsequently enhancing progestin sensitivity both in vitro and in vivo. Collectively, our findings identify FOXA2 as a key regulator in controlling PR levels in EC cells and propose the activation of FOXA2-PR axis via Orlistat treatment as a promising therapeutic strategy to improve progestin responsiveness in EC patients.

Effect of Physical Activity Intervention on Overweight and Obese Patients With Endometrial Cancer

This study evaluated the clinical outcome of exercise management on patients with endometrial cancer treated with fertility preservation, including the effect of complete response rate, complete response time, recurrence rate, recurrence time, etc., and physical composition, to evaluate the effectiveness of physical activity on weight management.