Huaiwu Lu

THBS1 Contributes to Chemoresistance in Ovarian Clear Cell Carcinoma via Promoting Epithelial–Mesenchymal Transition

ABSTRACT Objective Ovarian clear cell carcinoma (OCCC) is prone to primary platinum resistance and has a poor prognosis in advanced stages. Understanding the mechanisms underlying chemoresistance is essential to improving treatment outcomes. This study aimed to identify and validate molecular targets linked to platinum sensitivity in OCCC and explore their clinical and biological relevance. Methods The mRNA sequencing was performed on fresh‐frozen tumor tissues from six OCCC patients (three platinum‐resistant and three platinum‐sensitive). Differentially expressed genes (DEGs) were identified using edgeR and DESeq2. A random forest model ranked candidate genes by their predictive value, and prognostic associations with progression‐free survival (PFS) and overall survival (OS) were assessed via the database of the Cancer Science Institute of Singapore (CSIOVDB). The protein expression of THBS1 was compared between groups using immunohistochemistry. Functional effects of THBS1 knockdown were assessed through CCK‐8, colony formation, wound healing, transwell assays, and tube formation assays using HUVECs. Results A total of 1592 DEGs were identified, with 43 overlapping with GSEA‐defined platinum resistance pathways. Enrichment analysis indicated significant enrichment of cancer‐related signaling pathways and biological processes were enriched in the platinum‐resistant group. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) highlighted the platelet‐associated biological processes and immune relative pathway. The immune infiltration landscape indicated a prominent immunosuppressive microenvironment in the platinum‐resistant group. THBS1 ranked highly in the random forest model and was associated with shorter PFS ( p  = 0.0012) and OS ( p  = 0.0046) in CSIOVDB analysis. Immunohistochemistry confirmed elevated THBS1 expression in the platinum‐resistant group ( p  < 0.0001). In vitro, THBS1 knockdown reduced cell migration, invasion, angiogenesis, and cisplatin resistance. It also downregulated E‐cadherin while upregulating N‐cadherin and vimentin, suggesting EMT pathway involvement. Conclusion THBS1 promotes platinum resistance in OCCC through EMT activation and may serve as a prognostic biomarker and therapeutic target.

Molecular and Immune Correlates of Response to First-Line De-escalated Chemotherapy plus Penpulimab and Anlotinib in Advanced Cervical Cancer

Abstract The standard of care for advanced cervical cancer includes chemotherapy, antiangiogenic, and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. Deescalation chemotherapy together with immunotargeted therapies has been proven effective and less toxic in other cancers. In this study, we conducted a multicenter, single-arm, phase II study of first-line deescalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in patients with PD-L1–positive, persistent, recurrent, or metastatic cervical cancer. Of 32 efficacy-evaluable patients, 30 (93.8%, 95% confidence interval, 79.2%–99.2%) had an investigator-confirmed objective response. Single-nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells, and activated germinal center B cells portended optimal treatment response. Patients with a high tertiary lymphoid structure-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in patients with metastatic, persistent, or recurrent cervical cancer. Significance: We recruited 34 patients with advanced cervical cancer receiving two cycles of platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab, and showed safety and efficacy of this deescalation regimen. This work highlights the potential for personalized treatment strategies and feasibility of reduced-toxicity regimens.

Comprehensive clinical analysis of gastric-type endocervical adenocarcinoma: a real-world multicenter study

Gastric-type endocervical adenocarcinoma (G-EAC) is a rare malignancy, and its clinicopathological characteristics remain poorly defined. This study aimed to evaluate the real-world features, treatment patterns, and outcomes of patients with G-EAC. Clinical data from 124 patients diagnosed with G-EAC between 2012 and 2024 across four tertiary hospitals in China were retrospectively analyzed. Clinicopathological features, therapeutic approaches, and survival outcomes were assessed. Overall survival (OS) was the primary endpoint. Kaplan-Meier and Cox regression analyses were performed to identify prognostic factors. The median diagnostic age was 55 years (range, 33-82). At presentation, 62.1% of patients had invasion or metastasis, most commonly lymphovascular (47.6%). Surgery was performed in 81.5% of cases, and 84.7% received chemotherapy, primarily platinum-based (81.5%). Radiotherapy was administered to 69.4%. The 1-, 3-, and 5-year OS rates were 78.6%, 54.8%, and 46.1%, respectively. Older age (≥65 years; HR, 4.71; 95% CI, 1.52-14.58; G-EAC exhibits aggressive behavior and unfavorable prognosis, with a 5-year OS of 46.1%. Multimodal treatment, particularly surgery combined with chemotherapy, remains the cornerstone of management and may improve survival. Prospective multicenter studies are warranted to further define optimal therapeutic strategies for this rare entity.

A gene-based predictive model for lymph node metastasis in cervical cancer: superior performance over imaging techniques

Abstract Objective Lymph node metastasis (LNM) critically impacts the prognosis and treatment decisions of cervical cancer patients. The accuracy and sensitivity of current imaging techniques, such as CT and MRI, are limited in assessing lymph node status. This study aims to develop a more accurate and efficient method for predicting LNM. Methods Three independent cohorts were merged and divided into training and internal validation groups, with our cohort and those from other centers serving as external validation. A predictive model for LNM in cervical cancer was established using the LASSO regression and multivariate logistic regression. The diagnostic performance of the predictive model was compared with that of CT/MRI in terms of accuracy, sensitivity, specificity, and AUC. Results Using RNA-seq data, four independent predictive genes (MAPT, EPB41L1, ACSL5, and PRPF4B) were identified through LASSO regression and multivariate logistic regression, and a predictive model was constructed to calculate the LNM risk score. Compared with CT/MRI, the model demonstrated higher diagnostic efficiency, with an accuracy of 0.840 and sensitivity of 0.804, compared to CT/MRI’s accuracy of 0.713 and sensitivity of 0.587. The predictive model corrected 81% of misdiagnoses by CT/MRI, demonstrating significant improvements in accuracy and sensitivity. Conclusion The predictive model developed in this study, based on gene expression data, significantly improves the preoperative assessment accuracy of LNM in cervical cancer. Compared to traditional imaging techniques, this model shows superior sensitivity and accuracy. This study provides a robust foundation for developing precise diagnostic tools, paving the way for future clinical applications in individualized treatment planning.

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

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). 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. 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. 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.

Round ligament suspension and vaginal purse‐string suture: Newly optimized techniques to prevent tumor spillage in laparoscopic radical trachelectomy for cervical cancer

AbstractAimThe purpose of this study was to investigate the surgical techniques and clinical feasibility of nonuterine manipulator and enclosed colpotomy to avoid cancer cell spillages in laparoscopic radical trachelectomy (LRT) for patients with early‐stage cervical cancer.MethodsWe performed the newly optimized surgical techniques of round ligament suspension and vaginal purse‐string suture in LRT in 12 patients with early‐stage cervical cancer from May 2019 to October 2020. Surgical information and postoperative results were recorded.ResultsAll 12 patients successfully underwent LRT with round ligament suspension and vaginal purse‐string suture, and no conversion to laparotomy was required. The median operation time was 268.5 min (range 200–320 min), including 5 min of round ligament suspension, and the median blood loss was 20 mL (range 5–50 mL). The median number of pelvic lymph nodes removed was 27 (range 19–35), and median amounts of paracervical tissue was 24 mm (range 21–26 mm) and vaginal tissue was 18 mm (range 16–26 mm). No intraoperative complication or serious postoperative complications were reported.ConclusionRound ligament suspension and vaginal purse‐string suture techniques are feasible and effective in LRT. They can replace uterine manipulator and unprotected colpotomy with satisfactory perioperative outcomes.

Feasibility of the “Cuff-Sleeve” Suture Method for Functional Neocervix Reconstruction in Laparoscopic Radical Trachelectomy: A Retrospective Analysis

The purpose of this study was to evaluate the feasibility of "cuff-sleeve" sutures for reconstructing a functional neocervix in laparoscopic radical trachelectomy (RT). A retrospective analysis of a case series. A teaching hospital. Twenty-five patients who were diagnosed as early-stage cervical cancer from June 2017 to October 2020 in Sun Yat-sen Memorial Hospital. Laparoscopic RT with the "cuff-sleeve" suture method for cervicovaginal reconstruction. Twenty-five patients successfully underwent the laparoscopic RT with the "cuff-sleeve" suture method for cervicovaginal reconstruction, and no intraoperative complications occurred or conversion to laparotomy was needed. For all patients, approximately 80% of the cervical length was removed. Surgical radicality and negative surgical margins were also confirmed. During a median follow-up time of 29 months (range 8-48 months), no severe postoperative complications were observed. No cervical stenosis or secondary abnormal menstruation was reported. After the removal of the uterine stent 6 months after surgery, the neocervix length was approximately 14 mm (range 10-19 mm) and almost all the neocervixes were restored closely to the original anatomy. Four of 8 patients attempting actively to conceive were successful, and the cervical length of these pregnant patients was greater than or equal to 15 mm in all but one measurement at different gestational age. Three patients were ongoing pregnant, and the other had delivered successfully with a 16- mm cervix at term without cerclage. The "cuff-sleeve" suture method in cervicovaginal reconstruction is feasible in laparoscopic RT. This simplified suture technique can provide a functional neocervix to reduce cervical stenosis and incompetence.