An integrated model for prognosis in vulvar squamous cell carcinoma.

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) is a relatively rare gynecologic cancer. Unlike cervical squamous cell carcinoma (CSCC), in which nearly all cases are caused by HPV infection, most VSCCs are HPV-independent. Patients with VSCC also have worse overall survival (OS) than those with CSCC. Unlike CSCC, the risk factors of VSCC have not been extensively studied. Here, we investigated the prognostic values of clinicopathological parameters as well as biomarkers in patients with VSCC. METHODS: In total, 69 cases of VSCC accessions were selected for analysis between April 2010 and October 2020. The risk factors of VSCC were screened using Cox models to establish nomograms for predicting survival outcomes. RESULTS: Following the multivariate COX model for OS, independent predictors including advanced age (hazard ratio [HR] 5.899, p = 0.009), HPV positivity (HR 0.092, p = 0.016), high Ki-67 index (HR 7.899, p = 0.006), PD-L1-positivity (HR 4.736, p = 0.077), and CD8 + tumor-infiltrating lymphocytes (TILs) (HR 0.214, p = 0.024) were included in the nomogram for OS; multivariate COX model for progression-free survival (PFS) was used to screen prognostic factors including advanced age (HR 2.902, p = 0.058), lymph node metastasis (HR 5.038, p = 0.056), HPV positivity (HR 0.116, p = 0.011), high Ki-67 index (HR 3.680, p = 0.042), PD-L1-positivity (HR 5.311, p = 0.045), and CD8 + TILs (HR 0.236, p = 0.014) to establish the PFS nomogram model. Based on the C-index (0.754 for OS and 0.754 for PFS) from our VSCC cohort and the corrected C-index (0.699 for OS and 0.683 for PFS) from an internal validation cohort, the nomograms demonstrated good predictive and discriminative ability. Kaplan-Meier curves also supported the excellent performance of the nomograms. CONCLUSION: Our prognostic nomograms suggested that (1) shorter OS and PFS were associated with PD-L1-positivity, high Ki-67 index, and low CD8 + TILs; (2) HPV-independent tumors were associated with poorer survival outcome, and mutant p53 status showed no prognostic significance.

Identification of MKNK1 and TOP3A as ovarian endometriosis risk-associated genes using integrative genomic analyses and functional experiments.

The risk of endometriosis (EM), which is a common complex gynaecological disease, is related to genetic predisposition. However, it is unclear how genetic variants confer the risk of EM. Here, via Sherlock integrative analysis, we combined large-scale genome-wide association studies (GWAS) summary statistics on EM (N = 245,494) with a blood-based eQTL dataset (N = 1490) to identify EM risk-related genes. For validation, we leveraged two independent eQTL datasets (N = 769) for integration with the GWAS data. Thus, we prioritised 14 genes, including GIMAP4, TOP3A, and NMNAT3, which showed significant association with susceptibility to EM. We also utilised two independent methods, Multi-marker Analysis of GenoMic Annotation and S-PrediXcan, to further validate the EM risk-associated genes. Moreover, protein-protein interaction network analysis showed the 14 genes were functionally connected. Functional enrichment analyses further demonstrated that these genes were significantly enriched in metabolic and immune-related pathways. Differential gene expression analysis showed that in peripheral blood samples from patients with ovarian EM, TOP3A, MKNK1, SIPA1L2, and NUCB1 were significantly upregulated, while HOXB2, GIMAP5, and MGMT were significantly downregulated compared with their expression levels in samples from the controls. Immunohistochemistry further confirmed the increased expression levels of MKNK1 and TOP3A in the ectopic and eutopic endometrium compared to normal endometrium, while HOBX2 was downregulated in the endometrium of women with ovarian EM. Finally, in ex vivo functional experiments, MKNK1 knockdown inhibited ectopic endometrial stromal cells (EESCs) migration and invasion. TOP3A knockdown inhibited EESCs proliferation, migration, and invasion, while promoting their apoptosis. Convergent lines of evidence suggested that MKNK1 and TOP3A are novel EM risk-related genes.

Lymphocyte and macrophage infiltration in omental metastases indicates poor prognosis in advance stage epithelial ovarian cancer.

OBJECTIVE: To investigate the prognostic value of immune cells within omental metastases originating from advanced epithelial ovarian cancer (EOC). METHODS: We performed immunohistochemical analysis to determine the levels of CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and CD68+ tumor-associated microphages (TAMs) in omental specimens from 100 patients with advanced EOC. Significant prognostic factors, including immune cells and clinical parameters, were assessed by Kaplan-Meier survival analysis and Cox models. RESULTS: Cox regression analysis showed that elevated levels of CD68+ TAMs and intra-islet CD4+ TILs in omental metastases were the main risk factors associated with worse survival outcomes for advanced EOC. Moreover, the survival analysis of relationships between omental immune cells and favorable clinical predictors revealed additional prognostic stratification information. CONCLUSION: Omental immune cells (TAMs and TILs) provide alternative prognostic factors in advanced EOC. In contrast to markers of the EOC tumor microenvironment at the primary site, elevated CD68+ TAMs and intra-islet CD4+ TILs in omental metastases serve as negative prognostic markers in advanced EOC and imply an unfavorable outcome.

PD-L1 Expression in Endometrial Serous Carcinoma and Its Prognostic Significance.

PURPOSE: Programmed death-ligand 1 (PD-L1) has been widely used as a prognostic biomarker and an immunotherapeutic target in numerous cancers, but information on the clinical significance of its expression in endometrial serous carcinoma (ESC) is largely lacking. Here, we evaluate the predictive value of PD-L1 expression in ESC. MATERIALS AND METHODS: A total of 79 cases of ESC accessioned between January 2003 and September 2015 were selected for further analysis. PD-L1 expression was evaluated in whole tissue sections of these cases by using the tumor proportion score (TPS, cut-off 1%) and combined positive score (CPS, cut-off 1) scoring methods. RESULTS: Overall, there was a heterogeneous expression of PD-L1, focal or patchy, in ESCs. PD-L1 positivity was observed in 43.0% of ESCs by TPS and 73.4% of ESCs by CPS. Kaplan-Meier survival analysis showed that patients with PD-L1-positive tumors suffered significantly worse OS and PFS, when compared with PD-L1 negative tumors (log-rank p = 0.037 and p = 0.003, respectively). In contrast, PD-L1 positivity by CPS within the ESC cases showed no statistical significance for OS and PFS (log-rank p = 0.720 and p = 0.928, respectively). Multivariate Cox analysis showed that PD-L1 positivity by TPS was significantly associated with PFS (HR = 1.921, p = 0.039) but not OS (HR = 1.229, p = 0.631). CONCLUSION: PD-L1 expression is frequently found in ESC, suggesting a potential role of the PD-1/PD-L1 pathway as a potential therapeutic target for these tumors. PD-L1 expression by TPS also serves as a negative prognostic marker in ESC and implies an unfavorable outcome.