Importance Cytotoxic CD8⁺tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8⁺TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8⁺TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8⁺TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8⁺TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8⁺TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8⁺TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8⁺TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8⁺TILs, respectively (Pvalue for trend = 4.2 × 10⁻¹⁶). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8⁺TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8⁺TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8⁺TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Several parameters of preoperative complete blood count (CBC) and inflammation-associated blood cell markers derived from them have been reported to correlate with prognosis in patients with epithelial ovarian cancer (EOC), but their prognostic importance and optimal cutoffs are still needed be elucidated. Clinic/pathological parameters, 5-year follow-up data and preoperative CBC parameters were obtained retrospectively in 654 EOC patients underwent primary surgery at Mayo Clinic. Cutoffs for neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were optimized by receiver operating characteristic (ROC) curve. Prognostic significance for overall survival (OS) and recurrence free survival (RFS) were determined by Cox proportional hazards models and Kaplan-Meier method. Associations of RDW and NLR with clinic/pathological parameters were analyzed using non-parametric tests. RDW with cutoff 14.5 and NLR with cutoff 5.25 had independent prognostic significance for OS, while combined RDW and NLR scores stratified patients into low (RDW-low and NLR-low), intermediate (RDW-high or NLR-high) and high risk (RDW-high and NLR-high) groups, especially in patients with high-grade serous ovarian cancer (HGSOC). Moreover, high NLR was associated with poor RFS as well. Elevated RDW was strongly associated with age, whereas high NLR was strongly associated with stage, preoperative CA125 level and ascites at surgery.

This study was aimed at investigating the role and molecular mechanism of Sam68 in cervical cancer lymph node metastasis. Sam68 expression profile was detected by quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Short hairpin RNA interfering approach was employed to suppress endogenous Sam68 expression in cervical cancer cells to determine its role in metastasis and the possible mechanism. Sam68 expression in cervical cancer was significantly up-regulated at both messenger RNA and protein levels compared with that in normal cervical tissues. The high expression level of Sam68 and its cytoplasmic localization were significantly associated with risk factors including pelvic lymph node metastasis (P < 0.001), and served as independent prognostic factors for predicting shortening of the overall survival time and disease-free survival time in patients with early-stage cervical cancer. Moreover, down-regulation of Sam68 in cervical cancer cells remarkably inhibited cellular motility and invasion. In addition, down-regulation of Sam68 reversed epithelial–mesenchymal transition through inhibiting the Akt/ GSK-3β/Snail pathway. This study demonstrated that Sam68 could induce cervical cancer lymph node metastasis through regulating epithelial-mesenchymal transition, and Sam68 expression profile possessed the potential to serve as predictors of pelvic lymph node metastasis in cervical cancer patients.

Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.