Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study.

BACKGROUND: Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. METHODS: In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. CONCLUSION: Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.

Metastatic pericardial mass and cardiophrenic lymph nodes resection in ovarian cancer.

Introduction: Epithelial Ovarian cancer most commonly presents at advanced stages with extra-abdominal disease metastasis. Notably, enlarged cardiophrenic lymph nodes are found in 10.5-62 % of patients with advanced ovarian cancer. However, the safety and feasibility of cardiophrenic lymph nodes dissection as a component of debulking surgery remains controversial (Acs et al., 2022, Agusti et al., 2024). Case/methods: We present a surgical video demonstrating the technique of bulky pericardial mass and metastatic cardiophrenic lymph nodes resection by transdiaphragmatic approach in advanced ovarian cancer. After the complete excision of intra-abdominal disease at laparotomy, the diaphragm is exposed, following the liver mobilization. According to the preoperative radiological examinations, the pericardial mass in the diaphragmatic space is reconfirmed, and then carefully removed by blunt and sharp dissection. Next, the pericardial cavity is closed by continuous suture. Through the transdiaphragmatic access to thoracic cavity, the pericardial fat pad containing cardiophrenic lymph nodes is explored and completely resected in view throughout. The diaphragm incision is closed continuously using non-absorbable suture with a biofilm, meanwhile, performing air aspiration in thoracic cavity. Conclusion: We demonstrate that advanced ovarian cancer with extra-abdominal diseases, such as bulky pericardial mass and cardiophrenic lymph nodes, should not be an absolute contraindication to a planned complete debulking surgery. Based on our growing experience, transdiaphragmatic approach is a safe and feasible access for metastatic cardiophrenic lymph nodes dissection.

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

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

Mutational landscape of head and neck cancer and cervical cancer in Chinese and Western population.

BACKGROUND: We aimed to unbiasedly map the genetic mutation profile of HNSC and CESC associated with HPV status in the Chinese population (SYSU-cohort) and compare them with Western population (TCGA-cohort). METHODS: Fifty-one HNSC patients (SYSU-HNSC) and 38 CESC patients (SYSU-CESC) were enrolled in this study. Genomic alterations were examined, and the profile was produced using the YuanSuTM450 gene panel (OrigiMed, Shanghai, China). The altered genes were inferred and compared to Western patients from TCGA cohorts. RESULTS: Compared to the TCGA-HNSC cohort, FGFR3 mutation was identified as a novel target in SYSU-HNSC with therapeutic potential. Compared to the TCGA-CESC cohort, some epigenetic regulation-associated genes were frequently mutated in SYSU-CESC cohort (KMT2C, KMT2D, KDM5C, KMT2A). CONCLUSION: In summary, our study provides unbiased insights into the genetic landscape of HNSC and CESC in the Chinese population and highlights potential novel therapeutic targets that may benefit Chinese patients.

The prognosis of patients with small cell carcinoma of the cervix: a retrospective study of the SEER database and a Chinese multicentre registry.

BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.

An analysis of clinical characteristics and prognosis of endometrioid ovarian cancer based on the SEER database and two centers in China.

PURPOSE: To assess the clinical characteristics and the risk factors related to the unfavorable prognosis of endometrioid ovarian carcinoma (EOVC) based on data from the Surveillance, Epidemiology, and End Results (SEER) database and two clinical centers in China. METHODS: Data were extracted from the SEER database and two clinical centers in China (2010 ~ 2021), 884 cases and 87 patients with EOVC were selected, respectively. Overall survival (OS) and progression-free survival (PFS) were compared among the different groups using Kaplan-Meier analysis. The Cox proportional-hazards model was used to identify independent prognostic factors related to EOVC. A nomogram was constructed based on the risk factors of the SEER database affecting prognosis and the discrimination and calibration of the nomogram were evaluated by C-index and calibration curves. RESULTS: The average age at diagnosis of patients with EOVC in the SEER database and two centers in China was 55.77 ± 12.40 years and 47.14 ± 11.50 years, 84.7% and 66.6% of them were diagnosed at FIGO stage I ~ II, respectively. In the SEER database, age over 70 years, advanced FIGO stage, tumor grade 3, only unilateral salpingo-oophorectomy were independent risk factors of unfavorable prognosis. In two clinical centers in China, 27.6% of EOVC patients were diagnosed with synchronous endometriosis. Advanced FIGO stage, HE4 > 179 pmol/L and bilateral ovarian involvement significantly correlated with poor OS and PFS in Kaplan-Meier analysis. Body mass index (BMI) < 19.34 kg/m2 was an independent risk factor relating to OS and PFS. Additionally, C-index of internal and external verification for the nomogram were 0.812 and 0.754 respectively, revealing good accuracy and clinical applicability. CONCLUSIONS: Most patients were diagnosed at early stage, low grade and had better prognosis. Asian/Pacific Islander and Chinese diagnosed with EOVC were more likely to be younger than whites and blacks. Age, tumor grade and FIGO stage (SEER database) and BMI (two centers) are independent prognostic factors. HE4 appears to be more valuable in prognostic assessment compared with CA125. The nomogram had good discrimination and calibration for predicting prognosis, providing a convenient and reliable tool for clinical decision-making for patients with EOVC.

Development and external validation of nomograms for predicting individual survival in patients with ovarian clear cell carcinoma.

PURPOSE: Ovarian clear cell carcinoma (OCCC) is a distinct and highly malignant subtype of ovarian cancer with high individual heterogeneity in survival that requires specific prognostic predictive tools. Thus, this study aimed to construct and validate nomograms for predicting individual survival in OCCC patients. METHODS: In total, 91 patients with OCCC who were diagnosed and treated at Renji Hospital between 2010 and 2020 were extracted as the training cohort, then 86 patients from the First Affiliated Hospital of USTC were used as the external validation cohort. Prognostic factors that affect survival were identified using least absolute shrinkage and selection operator regression. Nomograms of progression-free survival (PFS) and overall survival (OS) were then established with the Cox regression model and the performance was subsequently evaluated using the concordance index (C-index), calibration plots, decision curve analysis (DCA), and risk subgroup classification. RESULTS: Advanced tumor, ascites of >400 mL, lymph node-positive, CA199 of >142.3 IU/mL, and fibrinogen of >5.36 g/L were identified as risk factors for OS while advanced tumor, ascites of >400 mL, lymph node-positive, and fibrinogen of >5.36 g/L were risk factors for PFS. The C-indexes for the OS and PFS nomograms were 0.899 and 0.731 in the training cohort and 0.804 and 0.787 in the validation cohort, respectively. The calibration plots showed that nomograms could provide better consistency in predicting patient survival than the FIGO staging system. DCA also demonstrated that nomograms were more clinically beneficial than the FIGO staging system. Additionally, patients could be classified into two risk groups based on scores using nomograms, with significant survival differences. CONCLUSIONS: We developed nomograms that could more objectively and reliably predict the individual survival of patients with OCCC compared with the FIGO staging system. These tools might assist in clinical decision-making and management of patients with OCCC to improve their survival outcomes.

APOBEC3B stratifies ovarian clear cell carcinoma with distinct immunophenotype and prognosis.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a challenging disease due to its intrinsic chemoresistance. Immunotherapy is an emerging treatment option but currently impeded by insufficient understanding of OCCC immunophenotypes and their molecular determinants. METHODS: Whole-genome sequencing on 23 pathologically confirmed patients was employed to depict the genomic profile of primary OCCCs. APOBEC3B expression and digital pathology-based Immunoscore were assessed by performing immunohistochemistry and correlated with clinical outcomes. RESULTS: An APOBEC-positive (APOBEC+) subtype was identified based on the characteristic mutational signature and prevalent kataegis events. APOBEC + OCCC displayed favourable prognosis across one internal and two external patient cohorts. The improved outcome was ascribable to increased lymphocytic infiltration. Similar phenomena of APOBEC3B expression and T-cell accumulation were observed in endometriotic tissues, suggesting that APOBEC-induced mutagenesis and immunogenicity could occur early during OCCC pathogenesis. Corroborating these results, a case report was presented for an APOBEC + patient demonstrating inflamed tumour microenvironment and clinical response to immune checkpoint blockade. CONCLUSIONS: Our findings implicate APOBEC3B as a novel mechanism of OCCC stratification with prognostic value and as a potential predictive biomarker that may inform immunotherapeutic opportunities.

Novel prognostic nomograms in cervical cancer based on analysis of 1075 patients.

OBJECTIVE: To explore the factors affecting the prognosis of cervical cancer (CC), and to construct and evaluate predictive nomograms to guide individualized clinical treatment. METHODS: The clinicopathological and follow-up data of CC patients from June 2013 to December 2019 in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively analyzed. Log-rank test was used for univariate survival analysis, and Cox multivariate regression was used to identify independent prognostic factors, based on which nomogram models were established and evaluated in multiple aspects. RESULTS: Patients were randomly assigned into the training (n = 746) and validation sets (n = 329). Survival analysis of the training set identified cervical myometrial invasion, parametrial involvement, and malignant tumor history as prognosticators of postoperative DFS and pathological type, cervical myometrial invasion, and history of STD for OS. C-index was 0.799 and 0.839 for the nomograms for DFS and OS, respectively. Calibration curves and Brier scores also indicated high performance. Importantly, decision curve analysis suggested great clinical applicability of these nomograms. CONCLUSIONS: In this study, we analyzed a cohort of 1075 CC patients and identified DFS- or OS-associated clinicohistologic characteristics. Two nomograms were subsequently constructed for DFS and OS prognostication, respectively, and showed high performance in terms of discrimination, calibration, and clinical applicability. These models may facilitate individualized treatment and patient selection for clinical trials. Future investigations with larger cohorts and prospective designs are warranted for validating these prognostic models.

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

BACKGROUND: Patients with epithelial ovarian cancer (EOC) can benefit from poly- (ADP ribose) polymerase inhibitors (PARPi) therapy. However, PARPi resistance has become a challenge in clinical practice, and its mechanism requires further exploration. METHODS: We established three PARPi-resistant cell strains following olaparib exposure. CCK-8, clonogenic survival, transwell, wound healing, cell cycle, RT-qPCR and western blot assays were performed to explore the functional phenotype of the resistant cells. Whole-exome sequencing and RNA-sequencing were performed to identify the altered genes. Stable knockdown and overexpression were used to investigate the role of EP300, an upstream regulator of E-cadherin and epithelial-mesenchymal transition (EMT), in cell lines. We further validated the finding in clinical ovarian cancer samples by immunohistochemistry. RESULTS: We combined public datasets to obtain an integrated PARPi sensitivity profile in EOC cells, which indicated that primary PARPi resistance could not be fully explained by mutations in BRCA1/2 or homologous recombination deficiency related genes. Genomic and transcriptome analyses revealed distinct mechanisms between primary and acquired resistance. Long-term PARPi treatment induced accumulation of de novo single nucleotide variants (SNV), and the complete frame-shift deletion of PARP1 was detected in the A2780 resistant strain. Additionally, the depressed histone acetyltransferase of EP300 could cause resistant phenotype through activated EMT process in vitro, and associated with PARPi-resistance in EOC patients. CONCLUSION: Long-term PARPi treatment led to evolutionary genomic and transcriptional alterations that were associated with acquired resistance, among which depressed EP300 partly contributed to the resistant phenotype.

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies.

Breast cancer and gynecological tumors seriously endanger women's physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

PRKCI Mediates Radiosensitivity via the Hedgehog/GLI1 Pathway in Cervical Cancer.

Objective: Insensitivity to radiotherapy accounts for the majority of therapeutic failures in cervical cancer (CC) patients who undergo radical radiotherapy. We aimed to elucidate the molecular mechanisms underlying radiosensitivity to identify methods to improve the overall 5-year survival rate. The atypical protein kinase C iota (aPKCι) gene PRKCI exhibits tumor-specific copy number amplification (CNA) in CC. We investigated how PRKCI decreases radiosensitivity in CC and assessed the interplay between PRKCI and the Hedgehog (Hh)/GLI1 pathway in the present research. Methods: The biological functions of PRKCI in CC radiosensitivity were explored through immunohistochemistry, colony formation, Cell Counting Kit-8 (CCK-8), cell cycle, apoptosis assays, and xenograft models. qRT-PCR, Western blotting analysis, and immunofluorescence assays were utilized to evaluate the interplay between PRKCI and the Hh/GLI1 pathway and its mechanism in PRKCI-decreased radiosensitivity in CC. Furthermore, the effect of auranofin (AF), a selective inhibitor of PKCι, on CC cells was explored through biochemical assays in vitro and in vivo. Results: We found that high PRKCI expression was responsible for decreased survival in CC. PRKCI was intimately associated with radiation-triggered alterations in proliferation, the cell cycle, apoptosis, and xenograft growth. The Hh/GLI1 pathway was activated when PRKCI expression was altered. PRKCI functions downstream of the Hh/GLI1 pathway to phosphorylate and activate the transcription factor GLI1. AF acts as a radiosensitizer and showed biological effects in vitro and in vivo. Conclusions: PRKCI is a therapeutic target for regulating radiosensitivity in CC. This molecule regulates radiosensitivity by modulating GLI1 relocalization and phosphorylation in CC via the Hh/GLI1 pathway.

Detection of ovarian cancer using plasma cell-free DNA methylomes.

BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC. EXPERIMENTAL DESIGN: Plasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method. RESULTS: The DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples. CONCLUSIONS: This study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.

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

AIM: The 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. METHODS: We 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. RESULTS: All 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. CONCLUSION: Round 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.

STUDY OBJECTIVES: The purpose of this study was to evaluate the feasibility of "cuff-sleeve" sutures for reconstructing a functional neocervix in laparoscopic radical trachelectomy (RT). DESIGN: A retrospective analysis of a case series. SETTING: A teaching hospital. PATIENTS: Twenty-five patients who were diagnosed as early-stage cervical cancer from June 2017 to October 2020 in Sun Yat-sen Memorial Hospital. INTERVENTIONS: Laparoscopic RT with the "cuff-sleeve" suture method for cervicovaginal reconstruction. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSION: 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.

Efficacy of neoadjuvant hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer (the NHIPEC trial): study protocol for a randomised controlled trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an important treatment option for patients with ovarian cancer. Although intravenous NACT can improve optimal resection rates and decrease surgical morbidity and mortality, these advantages do not translate into a survival benefit. Ovarian carcinoma is mainly confined to the peritoneal cavity, which makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Our previous study showed that HIPEC could be used in the neoadjuvant setting, which was named neoadjuvant HIPEC (NHIPEC). Since hyperthermia is an excellent chemosensitiser, we hypothesised that the combination of NHIPEC and intravenous NACT could show superior efficacy to intravenous NACT alone. METHODS: This study is a single-centre, open-label, randomised (1:1 allocation ratio) phase 2 trial. A total of 80 patients will be randomly assigned into an experimental group (NHIPEC+intravenous NACT) or a control group (intravenous NACT). Patients in the experimental group will receive NHIPEC following laparoscopic evaluation, and four tubes will be placed via the laparoscopic ports, which will be used to administer NHIPEC. Then, perfusion with docetaxel (60-75 mg/m2) will be performed (43°C for 60 min, Day 0) followed by cisplatin (75 mg/m2, Day 1) infusion (43°C for 60 min) 24 hours later. After NHIPEC, two cycles of intravenous NACT will be given. Patients in the control group will receive three cycles of intravenous NACT. The primary endpoint is the proportion of patients who achieve a Chemotherapy Response Score (CRS) of 3 according to the CRS system. The secondary endpoints include progression-free survival, overall survival and the rates of complete resection and NHIPEC-related adverse events. ETHICS APPROVAL AND DISSEMINATION: This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number: 2020-ky-050). Results will be submitted to peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000038173.

Prognostic impact of hepatitis B virus infection in patients with primary cervical cancer.

BACKGROUND: Hepatitis B virus (HBV) infection has been associated with an increased risk of a few malignancies. However, the prognostic impact of HBV infection remains unclear in cervical cancer. OBJECTIVE: To explore the association between HBV infection and survival outcomes of patients with primary cervical cancer, using overall survival (OS) and disease-free survival (DFS) as primary endpoints. METHODS: This analysis was performed retrospectively with newly diagnosed cervical cancer patients admitted to the Department of Gynecologic Oncology at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University from June 2013 to October 2019, who were enrolled and followed up. The Kaplan-Meier method and Cox proportional hazard analysis were used to examine the performance of HBV infection in predicting OS and DFS. RESULTS: Patients were followed up for a median of 37.17 months (95% CI, 34.69-39.65). Among the 695 patients, 87 (12.5%) were serologically positive for hepatitis B surface antigen (HBsAg), and 276 (39.7%) had a prior history of HBV infection. There was no significant difference between HBsAg-positive group and HBsAg-negative patients concerning OS or DFS. Multivariate analysis showed prior HBV infection was an independent favorable prognosticator for OS (HR, 0.335; 95% CI, 0.153-0.0.734; p = 0.006) and DFS (HR, 0.398; 95% CI, 0.208-0.691; p = 0.002). CONCLUSION: We provide the first clinical evidence that suggests prior HBV infection as an independent favorable prognostic factor for patients with primary cervical cancer.

Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer.

Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.

Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer.

BET bromodomain inhibitors (BETi) are promising therapeutic regimens for epithelial ovarian cancer (EOC). However, early-stage clinical trials indicate that drug tolerance may limit their anti-tumor efficacy. Here, we show that JQ1-refractory EOC cells acquire reversible resistance to BET inhibition and remain dependent on BRD4 function. The insensitivity is driven by a unique non-genetic mechanism that involves clonal selection for a pre-existing cell subpopulation with ample acetylated histones and sufficient nuclear phase-separated BRD4 droplets to counteract BETi antagonism. A vertical combination approach by co-blocking BET proteins and downstream Aurora kinases proves to achieve more complete responses than single inhibitors. Collectively, our study implicates epigenetic heterogeneity in therapeutic resistance to chromatin-targeted agents and proposes a rational strategy to address this anticipated clinical dilemma.

HHLA2 predicts better survival and exhibits inhibited proliferation in epithelial ovarian cancer.

PURPOSE: The role of HHLA2, a new immune checkpoint ligand, is gradually being elucidated in various solid tumours. However, its role in ovarian cancer remains unclear; thus, its expression profile and clinical significance in ovarian cancer must be examined. METHODS: We performed immunohistochemistry to examine HHLA2 expression in 64 ovarian cancer tissues and 16 normal ovarian tissues. The relationships between HHLA2 expression and clinicopathological features, prognosis, and CD8+ tumour-infiltrating lymphocytes (TILs) in patients were analysed. Additionally, the Cancer Cell Line Encyclopedia database was used to analyse the correlation between HHLA2 expression and PD-L1 or B7x expression. Furthermore, the biological function of HHLA2 in ovarian cancer cells was initially explored. RESULTS: Only 17.2% of ovarian cancer patients showed HHLA2 expression, which was significantly associated with the differentiation of ovarian cancer cells (p = 0.027), and well-differentiated tumours expressed higher levels of HHLA2. The density of CD8+ TIL was associated with increased HHLA2 expression (p = 0.017), and the CD8+ TIL count was higher in the HHLA2-positive group than that in the HHLA2-negative group (p = 0.023). Moreover, multivariate analysis identified HHLA2 expression as an independent prognostic factor that predicted improved survival (p = 0.049; HR = 0.156; 95% CI = 0.025-0.992). Additionally, we also found that overexpressing HHLA2 inhibited the proliferation of ovarian cancer cells. CONCLUSION: HHLA2 is associated with tumour differentiation and high CD8+ TIL levels; and predicts improved survival in ovarian cancer. Along with previously reported findings that HHLA2 behaves as a co-stimulatory ligand, our study suggests that the loss of HHLA2 may contribute to the immunosuppressive microenvironment and progression of ovarian cancer.