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In recent years, the ubiquitin–proteasome system (UPS) has become a hot spot in medical research in cervical cancer (CC) and has received extensive attention. Among them, ubiquitin‐specific protease 14 (USP14) is involved in a wide variety of typical cell signaling pathways and is recognized to be involved in the progression of most known tumors. However, the expression and significance of USP14 in CC have not been directly studied. Through database analysis, we found that USP14 was overexpressed in CC, which influenced the FIGO stage and prognosis of CC patients, and it was positively correlated with the expression level of β‐catenin. In this study, USP14 promoted the G1‐S phase transition of Hela and Siha cells and inhibited cell apoptosis, thereby promoting the proliferation, migration, and invasion of CC cells. In addition, USP14 also significantly promoted the growth of subcutaneous tumor in nude mice. We also found that overexpression of USP14 significantly upregulated β‐catenin expression and increased the activity of Wnt/β‐catenin signaling pathway. While knockdown of USP14 resulted in the opposite. These results suggest that USP14 may promote the proliferation of CC by up‐regulating the expression of β‐catenin, contributing to a deeper understanding of the mechanisms of CC and providing a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Cervical adenocarcinomas (ADCs), including human papillomavirus (HPV)‐associated (HPVA) and non‐HPVA (NHPVA), though exhibiting a more malignant phenotype and poorer prognosis, are treated identically to squamous cell carcinoma (SCC). This clinical dilemma requires a deeper investigation into their differences. Herein a transcriptomic atlas of SCC, HPVA, and NHPVA‐ADC using single‐cell RNA (scRNA) and T‐cell receptor sequencing (TCR‐seq) is presented. Regarding structural cells, the malignancy origin of epithelial cells, angiogenic tip cells and two subtypes of fibroblasts is revealed. The promalignant properties of the structural cells using organoids are further confirmed. Regarding immune cells, myeloid cells with multiple functions other than antigen presentation and exhausted T lymphocytes contribute to immunosuppression. From the perspective of HPV infection, not only is HPV‐dependent and independent cervical cancer oncogenesis proposed but also three immune reaction patterns mediated by T cells (coordinated/inactive/imbalanced) are identified. Strikingly, diagnostic biomarkers to distinguish ADC from SCC are discovered and prognostic biomarkers with marker genes for malignant epithelial cells, tip cells, and SPP1/C1QC macrophages are generated. Importantly, the efficacy of anti‐CD96 and anti‐TIGIT, not inferior to anti‐PD1, in animal experiments is confirmed and targeted therapies specifically for HPV‐positive SCC, HPVA and NHPVA‐ADC, providing essential clues for further clinical trials, are proposed. [ABSTRACT FROM AUTHOR]

Background: The mechanism underlying cervical carcinogenesis that is mediated by persistent human papillomavirus (HPV) infection remains elusive. Aims: Here, for the first time, we deciphered both the temporal transition and spatial distribution of cellular subsets during disease progression from normal cervix tissues to precursor lesions to cervical cancer. Materials & Methods: We generated scRNA‐seq profiles and spatial transcriptomics data from nine patient samples, including two HPV‐negative normal, two HPV‐positive normal, two HPV‐positive HSIL and three HPV‐positive cancer samples. Results: We not only identified three 'HPV‐related epithelial clusters' that are unique to normal, high‐grade squamous intraepithelial lesions (HSIL) and cervical cancer tissues but also discovered node genes that potentially regulate disease progression. Moreover, we observed the gradual transition of multiple immune cells that exhibited positive immune responses, followed by dysregulation and exhaustion, and ultimately established an immune‐suppressive microenvironment during the malignant program. In addition, analysis of cellular interactions further verified that a 'homeostasis‐balance‐malignancy' change occurred within the cervical microenvironment during disease progression. Discussion: We for the first time presented a spatiotemporal atlas that systematically described the cellular heterogeneity and spatial map along the four developmental steps of HPV‐related cervical oncogenesis, including normal, HPV‐positive normal, HSIL and cancer. We identified three unique HPV‐related clusters, discovered critical node genes that determined the cell fate and uncovered the immune remodeling during disease escalation. Conclusion: Together, these findings provided novel possibilities for accurate diagnosis, precise treatment and prognosis evaluation of patients with precancer and cervical cancer. [ABSTRACT FROM AUTHOR]

The ESGO developed a list of fifteen quality indicators for cervical cancer surgery in order to audit and improve clinical practice in 2020. However, data from the developing countries with high incidence rates of cervical cancer is still lacking. Therefore, we conducted a retrospective study of 7081 cases diagnosed as cervical cancer between 2014 and 2019 in a Chinese single center according to the quality indicators proposed by ESGO. A total of 5952 patients underwent radical procedures, with an average of 992.0 per year. All surgeries were performed or supervised by a certified gynecologic oncologist as surgical qualification grading system has been established. Compared with the low-volume group, patients in the high-volume group (≥15 cases/year) had a shorter hospital stay (P <0.001), more free surgical margins (P =0.031), and less complications (P <0.001), but the 5-year recurrence-free survival and overall survival rates were similar (P >0.05). Treatment was not planned at a multidisciplinary team meeting but with the consultation system. The required preoperative workup was incomplete in 19.7% of patients with pelvic MRI and 45.7% of patients with PET-CT. A total of 1459 (20.6%) patients experienced at least one complication after surgery. The CDC grade IIIb or higher complications occurred in 80 patients, accounting for 5.5% complications. The urological fistula rate within 30 postoperative days were 0.3%. After primary surgical treatment, 97.4% patients had clear vaginal and parametrial margins. After restaging FIGO 2009 to FIGO 2018 system, 14.7% patients with a stage T1b disease were T-upstaged. After a median follow-up of 42 months, recurrence occurred in 448 patients, and 82.1% patients recurred within 2 years. The 2-year RFS rate of patients with pT1b1N0 was 97.3% in 2009 FIGO staging system. Lymph node staging was performed in 99.0% patients with a stage T1 disease. After a primary surgical treatment for a stage pT1b1N0 disease, 28.3% patients received adjuvant chemoradiotherapy. Above all, most of quality indicators reached the targets, except four quality indicators. The quality indicators of ESGO should be popularized and applied in China to guarantee quality of surgery. [ABSTRACT FROM AUTHOR]

Introduction: Cervical cancer has high mortality, high recurrence and poor prognosis. Although prognostic biomarkers such as clinicopathological features have been proposed, their accuracy and precision are far from satisfactory. Therefore, novel biomarkers are urgently needed for disease surveillance, prognosis prediction and treatment selection. Materials: Differentially expressed genes (DEGs) between cervical cancer and normal tissues from three microarray datasets extracted from the Gene Expression Omnibus platform were identified and screened. Based on these DEGs, a six‐gene prognostic signature was constructed using cervical squamous cell carcinoma and endocervical adenocarcinoma data from The Cancer Genome Atlas. Next, the molecular functions and related pathways of the six genes were investigated through gene set enrichment analysis and co‐expression analysis. Additionally, immunophenoscore analysis and the QuartataWeb Server were employed to explore the therapeutic value of the six‐gene signature. Results: We discovered 178 overlapping DEGs in three microarray datasets and established a six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) prognostic signature with stable and excellent performance in predicting overall survival in different subgroups. Intriguingly, the six‐gene signature was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature might be used for predicting response to immune checkpoint inhibitors (ICIs) and the six genes may serve as new drug targets for cervical cancer. Conclusion: Our study established a novel six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) signature that was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature was indicative of aggressive features of cervical cancer and therefore might serve as a promising biomarker for predicting not only overall survival but also ICI treatment effectiveness. Moreover, three genes (UPP1, ISG20 and GLTP) within the six‐gene signature have the potential to become novel drug targets. [ABSTRACT FROM AUTHOR]

Objective: To compare survival outcomes of minimally invasive surgery (MIS) and laparotomy in early‐stage cervical cancer (CC) patients. Methods: A multicenter retrospective cohort study was conducted with International Federation of Gynecology and Obstetrics (FIGO, 2009) stage IA1 (lymphovascular invasion)‐IIA1 CC patients undergoing MIS or laparotomy at four tertiary hospitals from 2006 to 2017. Propensity score matching and weighting and multivariate Cox regression analyses were performed. Survival was compared in various matched cohorts and subgroups. Results: Three thousand two hundred and fifty‐two patients (2439 MIS and 813 laparotomy) were included after matching. (1) The 2‐ and 5‐year recurrence‐free survival (RFS) (2‐year, hazard ratio [HR], 1.81;95% confidence interval [CI], 1.09‐3.0; 5‐year, HR, 2.17; 95% CI, 1.21‐3.89) or overall survival (OS) (2‐year, HR, 1.87; 95% CI, 1.03‐3.40; 5‐year, HR, 2.57; 95% CI, 1.29‐5.10) were significantly worse for MIS in patients with stage I B1, but not the cohort overall (2‐year RFS, HR, 1.04; 95% CI, 0.76‐1.42; 2‐year OS, HR, 0.99; 95% CI, 0.70‐1.41; 5‐year RFS, HR, 1.12; 95% CI, 0.76‐1.65; 5‐year OS, HR, 1.20; 95% CI, 0.79‐1.83) or other stages (2) In a subgroup analysis, MIS exhibited poorer survival in many population subsets, even in patients with less risk factors, such as patients with squamous cell carcinoma, negative for parametrial involvement, with negative surgical margins, negative for lymph node metastasis, and deep stromal invasion < 2/3. (3) In the cohort treated with (2172, 54%) or without adjuvant treatment (1814, 46%), MIS showed worse RFS than laparotomy in patients treated without adjuvant treatment, whereas no differences in RFS and OS were observed in adjuvant‐treatment cohort. (4) Inadequate surgeon proficiency strongly correlated with poor RFS and OS in patients receiving MIS compared with laparotomy. Conclusions: MIS exhibited poorer survival outcomes than laparotomy group in many population subsets, even in low‐risk subgroups. Therefore, laparotomy should be the recommended approach for CC patients. [ABSTRACT FROM AUTHOR]

Purpose: Circular RNAs (circRNAs) are novel type of noncoding RNAs that play important roles and serve as noninvasive biomarkers in various cancers. In the present study, we focused on circFoxO3a and aimed to investigate its prognostic value as a novel serum biomarker for squamous cervical cancer (SCC). Patients and Methods: Our study included 103 SCC patients from Obstetrics and Gynecology Hospital of Fudan University. Expression levels of circFoxO3a in the serum of patients with SCC were examined by reverse transcription‑quantitative PCR (RT‑qPCR). The correlation between serum circFoxO3a expression and clinicopathologic factors was analyzed. The Kaplan–Meier method and multivariate Cox regression analysis were applied to evaluate the independent prognostic factors for SCC. A prognostic predictive nomogram was constructed using R software. Results: Levels of serum circFoxO3a were decreased in SCC patients compared with controls. Low expression of circFoxO3a was correlated with deeper stromal invasion and positive lymph node metastasis. Moreover, SCC patients with lower expression of serum circFoxO3a showed poorer prognosis, including both overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox analysis indicated low serum circFoxO3a levels to be an unfavorable prognostic factor for both OS and RFS, independent of positive lymph node metastasis. Notably, the predictive nomogram we established further confirmed that serum circFoxO3a is a useful tool for predicting survival in SCC. Conclusion: Altogether, our findings demonstrated that serum circFoxO3a could serve as a potential novel noninvasive predictive prognostic biomarker and therapeutic target for SCC. [ABSTRACT FROM AUTHOR]

Objective: This study aims to describe cervical cancer during pregnancy (CCP) and investigate factors associated with survival outcomes. Methods: This retrospective matched study included CCP patients from May 2007 to August 2021 and matched non‐pregnant cervical cancer patients (1:2) based on age (±5 years), year at diagnosis (±2 years), histological type and stage (2018 FIGO). The Kaplan–Meier method and multivariate Cox regression analyses were used to assess the impact of pregnancy and clinicopathologic factors on prognosis. Results: Thirty‐eight CCP patients (stage IA to IIIC) and 76 non‐pregnant patients were included. Most CCP patients were diagnosed in the first (31.6%) or second (47.4%) trimester. CCP patients had a longer waiting time than non‐pregnant patients. Pregnancy continued in 42.1% (continuation of pregnancy [COP] group) and was terminated in 57.9% (termination of pregnancy [TOP] group) of patients. Survival analysis showed no significant differences in recurrence‐free survival (RFS) or overall survival (OS) between pregnant and non‐pregnant patients or between the COP and TOP groups. At the end of the follow‐up period (range 12–178 months), 23 children born to CCP patients exhibited normal development. Conclusion: Pregnancy does not impact cervical cancer prognosis. The oncologic outcomes of the TOP and COP groups were comparable. A pregnancy‐preserving strategy could be considered for managing CCP patients. Synopsis: Pregnancy does not adversely impact the survival of cervical cancer, and pregnancy‐preserving strategies could be considered for managing CCP patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prognostic performance of the revised 2018 FIGO staging system for cervical cancer. Methods: This retrospective multicenter study enrolled cervical cancer patients with 2009 FIGO Stage IA1–IIA2 who underwent surgeries between January 2006 and December 2017 in four tertiary hospitals. Patients were restaged according to the 2018 FIGO staging system by reviewing their medical data. Results: Of 3238 cervical cancer patients included, 1841 (56.9%) patients were restaged: 641 (34.9%) due to tumor size, 544 (29.5%) due to lymph node metastasis, 614 (33.4%) due to the inconsistency between pre‐ and postoperative assessments, and 42 due to the cancellation of invasion width in Stage IA. After restaging, a clear tendency of decreased recurrence‐free survival (RFS) and overall survival (OS) with increasing stage was observed. Multivariate Cox analysis showed that 2018 FIGO stage, parametrial involvement, and histology were independent prognostic factors for both OS and RFS (P < 0.05). Based on these factors, we established predictive nomograms with c‐indexes of 0.735 and 0.721, showing good predictive ability for cervical cancer. Conclusion: The revised 2018 FIGO staging system can better reflect the survival of cervical cancer patients. Based on it, we established a nomogram that can predict the prognosis of cervical cancer patients more precisely. Synopsis: The 2018 FIGO staging system for cervical cancer can better reflect the survival of patients; based on it, a prognostic nomogram was established. [ABSTRACT FROM AUTHOR]