Qing Xu

Monitoring circulating cell-free HPV DNA in metastatic or recurrent cervical cancer: clinical significance and treatment implications

Background:Monitoring circulating HPV cell-free DNA (cfDNA) offers a minimally invasive method for surveillance in HPV-associated cancers, particularly cervical cancer. However, the role of dynamic HPV cfDNA monitoring in guiding clinical treatment decisions for recurrent or metastatic cervical cancer remains underexplored.Methods:In this prospective pilot observational study, levels of HPV cfDNA in serum samples from 28 patients with recurrent or metastatic HPV-positive cervical cancer were measured via digital droplet polymerase chain reaction. Results for HPV cfDNA levels were matched to clinical outcomes and to serum levels of squamous cell carcinoma antigen (SCC-Ag) to assess the clinical potential of HPV cfDNA as a tumor marker.Results:HPV cfDNA was detected in all 28 patients. Notably, median baseline HPV cfDNA levels varied according to the metastatic pattern observed in individual patients (p=0.019). All participants exhibited changes in HPV cfDNA levels over a median monitoring period of 2 months (range 0.3–16.9 months) prior to evaluations for treatment response or disease progression. Among 26 patients initially diagnosed with squamous cell cervical cancer, the positivity rate was 100% for HPV cfDNA and 69.2% for SCC-Ag (p=0.004, 95% confidence interval (CI), 0–0.391). Among 20 patients longitudinally monitored for squamous cell cervical cancer, the concordance with changes in disease status was 90% for HPV cfDNA and 50% for SCC-Ag (p=0.014, 95% CI, 0.022–0.621).Conclusions:Our study demonstrates that HPV cfDNA is a promising tumor marker for monitoring of recurrent or metastatic HPV-positive cervical cancer.Funding:This work was supported by the Key R&D Program of Zhejiang (2022C04001), the Zhejiang Province Medicine and Health Science and Technology Program (2020KY454), the Zhejiang Science and Technology Department Public Welfare Project (LGF22H160075).

Significant prognostic value of cell-cycle proteins in early-stage small cell carcinoma of cervix

Small cell carcinoma of cervix (SCCC) was a highly aggressive tumor with dismal prognosis. Current treatment strategies manifested poor survival outcomes and novel treatment options were needed exploration. We aimed to investigate several prognostic biomarkers for SCCC and conducted a novel risk-score system to predict cancer specific survival (CSS) in early-stage SCCC. Seven cell-cycle proteins were detected by immunohistochemistry in 88 SCCCs. Univariate and multivariate analysis were performed to identify prognostic proteins and establish a predicting model. Total patients were divided into two groups by the median risk-score: the high-risk group and the low-risk group. Logistic regression and Wilcoxon test were used to investigate the association between clinical variables and the risk-score system. Seven cell cycle proteins were overexpressed in SCCC. The expression of CDC20, MAD2L1, MCM2 and BUBR1 were correlated to survival outcomes with P < 0.05. A novel risk-score system consisting of CDC20, MAD2L1 and BUBR1 was significantly an independent prognostic factor for CSS and the high-risk group possessed worse survival (P < 0.001). The c-indexes for clinical model, risk-score system and the combined model were 0.668, 0.718 and 0.727, respectively. The AUCs for these three models were 0.730, 0.775 and 0.823, respectively. Furthermore, we discovered that patients with high-risk scores were inclined to possessing older age, parametrial invasion and higher FIGO stage (IIA vs IA/IB) with P < 0.05. This risk-score system consisting of CDC20, MAD2L1 and BUBR1 presented good discrimination and predictability for SCCC. Novel biomarkers in this study might have some merits in providing guidance of novel treatment strategies for SCCC.

Different surgical methods for FIGO stage IVB cervical cancer patients receiving chemotherapy: a population-based study

To assess survival differences between non-extensive surgery (NES) and extensive surgery (ES) in International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemotherapy from a population-based database, the Surveillance, Epidemiology and End Results. Propensity matching was conducted to minimize heterogeneity. Survival analysis was performed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A total of 154 patients met screening criteria, among whom 84 patients (84/154) underwent NES while 70 patients (70/154) underwent ES. After matching, no survival advantage was observed in ES group compared with NES group (p=0.066; hazard ratio [HR]=1.54; 95% confidence interval [CI]=0.97-2.42). Stratified analyses suggested ES prolonged overall survival in patients with histology other than squamous cell carcinoma and adenocarcinoma (p=0.028; HR=0.36; 95% CI=0.15-0.89) and American Joint Committee on Cancer (AJCC) T stage T1 (p=0.009; HR=0.18; 95% CI=0.05-0.66). Despite no survival benefit after regional lymph node surgery (p=0.629; HR=0.88; 95% CI=0.53-1.47), subgroup analyses demonstrated that patients younger than 50 (p=0.006; HR=0.21; 95% CI=0.07-0.64), with AJCC T stage T1 (p=0.002; HR=0.09; 95% CI=0.02-0.42), T3 (p=0.001; HR=0.02; 95% CI=0.00-0.21), hematogenous metastasis (p=0.036; HR=0.27; 95% CI=0.08-0.92) and without surgery of other sites (p In conclusion, ES or regional lymph node surgery may provide survival advantage for certain subgroup of FIGO IVB cervical cancer patients receiving chemotherapy. However, it deserves large scale prospective clinical trials to confirm.

Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer

Abstract Background Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. Here, we investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC). Methods We characterised TANs using flow cytometric analysis and immunofluorescence analysis. The prognostic merit of TANs in EOC was evaluated using cox regression analysis. Furthermore, we explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment. Results High level of TANs is associated with a dismal prognosis and immune tolerance in EOC. TANs impaired cytotoxic effects of CD8+ T cells partly through Jagged2 (JAG2). Notch pathway blocked using γ-secretase inhibitor LY3039478 and anti-JAG2 antibody led to retarded tumour growth and augmented cytotoxic effects of CD8+ T cells. IL-8 contributes to the recruitment of TANs and the induction of JAG2 expression in TANs. Blockade of CXCR2 signalling reduces tumour growth rate, accompanied by a decreasing amount of TANs and increasing activity of CD8+ T cells. JAG2+TANs is an independent predictor of clinical outcomes. Conclusion JAG2+TANs are closely linked to IL-8-driven immune evasion microenvironment and may serve as a promising therapeutic target for the reinvigoration of anti-tumour immunity.

Pigment epithelium-derived factor, an anti-VEGF factor, delays ovarian cancer progression by alleviating polarization of tumor-associated macrophages

Ovarian cancer (OC) is one of the most dangerous gynecological malignancies with no effective treatment so far. Pigment epithelium-derived factor (PEDF) has been reported to have ideal anti-tumor effects, but its relationship with the regulation of tumor-associated macrophage polarization is currently unclear. In this study, the mRNA expression of PEDF and macrophage markers were determined in OC tissues from clinic patients and five OC (A2780, SKOV3, CAOV3, OVCAR3, and OVCA433) cell lines through quantitative reverse transcription PCR. Afterwards, tumor growth, cell proliferation and apoptosis, and macrophage polarization in OC tumor-bearing mice with PEDF overexpression were recorded and investigated. Finally, the polarization of macrophages was explored in the presence of lentiviral PEDF overexpression, adipose triglyceride lipase (ATGL) and laminin receptor (LR) knockdown, and mitogen-activated protein kinase (MAPK) pathway inhibition. Our results suggest that PEDF mRNA level is significantly decreased in OC tissues and cells and has a significant negative correlation with OC progression and the level of tumor-related macrophage markers. Furthermore, OC tumors overexpressing PEDF show suppressed growth viability and increased apoptosis rate. The fluorescence activated cell sorting (FACS) analysis reveals that PEDF can promote macrophage polarization in OC tumors towards M1 subtype. Mechanistically, we found that ATGL and extracellular-regulated kinase 1/2 (ERK1/2) signaling are involved in the regulation of macrophage polarization in OC tumors by PEDF. Taken together, these data indicate that the role of PEDF in regulating the polarization of tumor-associated macrophages may make it a potential therapeutic strategy for the treatment of OC in the future.