Cancer testis antigen burden (CTAB): a novel biomarker of tumor-associated antigens in lung cancer.

BACKGROUND: Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. METHODS: Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB "high" and "low". Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan-Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher's exact test. RESULTS: The CTAs were highly co-expressed (p < 0.05) in the discovery cohort. There was no correlation between CTAB and PD-L1 expression (R = 0.011, p = 0.45) but some correlation with TMB (R = 0.11, p = 9.2 × 10-14). Kaplan-Meier survival analysis of the immunotherapy-treated NSCLC cohort revealed better OS for the pembrolizumab monotherapy treated patients with high CTAB (p = 0.027). The combination group demonstrated improved OS compared to pembrolizumab monotherapy group (p = 0.04). The pembrolizumab monotherapy patients with high CTAB had a greater ORR than the combination therapy group (p = 0.02). CONCLUSIONS: CTA co-expression can be reliably measured using CGIP in solid tumors. As a biomarker, CTAB appears to be independent from PD-L1 expression, suggesting that CTAB represents aspects of tumor immunogenicity not measured by current standard of care testing. Improved OS and ORR for high CTAB NSCLC patients treated with pembrolizumab monotherapy suggests a unique underlying aspect of immune response to these tumor antigens that needs further investigation.

Cetyltrimethylammonium Bromide Disrupts Mesenchymal Characteristics of Human Tongue Squamous Cell Carcinoma SCC4 Cells Through Modulating Canonical TGF-ß/Smad/miR-181b/TIMP3 Signaling Pathway.

BACKGROUND/AIM: This study investigated the anti-metastatic effects of cetyltrimethylammonium bromide (CTAB) on tongue squamous cell carcinoma (TSCC) SCC4 cells. MATERIALS AND METHODS: Cell morphology, viability, cell cycle distribution, adhesion, migration, invasion and the expression levels of associated proteins were examined using microscopy, WST-1, wound-healing, Boyden chamber assays, and western blotting, respectively. RESULTS: CTAB significantly affected SCC4 cell morphology from spindle-shaped to cobblestone-shaped and resulted in loss of adherence. CTAB significantly inhibited cell adhesion, migration, and invasion of SCC4 cells, independent of cell viability. CTAB reduced expression of matrix metalloproteinases (MMPs) such as MMP3, MMP7, and MMP14 in a concentration-dependent manner, while it increased expression of tissue inhibitors of metalloproteinase 3 (TIMP3). In addition, CTAB reduced the phosphorylation of mothers against decapentaplegic homolog 2/3 (Smad2/3) proteins, which mediated CTAB-inhibited migration and invasion in SCC4 cells. These effects were reversed by TGF-ß1. CONCLUSION: CTAB attenuates the mesenchymal characteristics through upregulation of TIMP3 by inhibiting the canonical TGF-ß/Smad/miR-181b/TIMP3 signaling involved in extracellular matrix remodeling in SCC4 cells and might be a promising anti-metastatic therapeutic agent for TSCC.

Povidone-iodine 1% is the most effective vaginal antiseptic for preventing post-cesarean endometritis: a systematic review and network meta-analysis.

BACKGROUND: Direct comparison metaanalyses have reported benefits with presurgical vaginal preparation before cesarean delivery for the reduction of endometritis. These reports did not perform a multitreatment comparison of the various antiseptic solutions assessed in previous studies. OBJECTIVE: The purpose of this study was to review the literature systematically and quantitate and summarize indirectly the comparative efficacy of antiseptic formulations and their concentrations that are used for the preparation of the vagina before cesarean delivery in the prevention of endometritis and other infectious complications. STUDY DESIGN: We used MEDLINE, EMBASE (from their inception to November 2018) and Cochrane databases, biographies, and conference proceedings. We used randomized clinical trials of patients who underwent surgical preparation of the vagina with antiseptic formulations before cesarean delivery with the aim of reducing the risk of infectious morbidity. Our systematic review was registered and followed the Preferred Reporting Items for Systematic Review and Meta-analysis Extension for network meta-analysis guidelines. Network meta-analysis was performed with computerized software and used user-written programs to assess consistency, inconsistency, ranking probabilities, and graphing results. Direct and indirect pairwise comparisons of the various formulations and their concentrations were performed with the use of multivariate random-effects models and metaregression. A frequentist inference method was employed for the fitted model to estimate the ranking probabilities. Subgroup analyses for patients in labor, not in labor, and with ruptured membranes were conducted. RESULTS: For the prevention of endometritis, we identified 23 studies that comprised 7097 women who were allocated to the following treatments: povidone-iodine (1%, 5%, 10%), chlorhexidine (0.2%, 0.4%), metronidazole gel, cetrimide, or normal saline solution/no treatment. Direct and indirect pairwise comparisons indicated that, when compared with saline solution or no treatment, all antiseptic formulations decreased rates of endometritis (5.2% vs 9.1%; odds ratio, 0.48; 95% confidence interval, 0.35-0.65; 22 studies/6994 women). Individually, povidone-iodine (odds ratio, 0.43; 95% confidence interval, 0.28-0.64; 16 studies/5968 women), cetrimide (odds ratio, 0.34; 95% confidence interval, 0.13-0.90; 1 study/200 women), and metronidazole (odds ratio, 0.38; 95% confidence interval, 0.16-0.90; 1 study/224 women) significantly reduced the risk of endometritis. Rankings of vaginal preparations indicated that povidone-iodine 1% had the highest probability (72.7%) of being the most effective treatment for the prevention of endometritis. For the secondary outcomes of postoperative wound infection and fever, a significant reduction was found only with povidone-iodine (odds ratio, 0.61; 95% confidence interval, 0.48-0.78; 16 studies/5968 women; and odds ratio, 0.58; 95% confidence interval, 0.40-0.83; 12 studies/4667 women). Subgroup analyses also found that povidone-iodine significantly reduced risk of endometritis for women in labor (odds ratio, 0.42; 95% confidence interval, 0.20-0.88; 5 studies/1211 women), with ruptured membranes(odds ratio, 0.21; 95% confidence interval, 0.10-0.44; 4 studies/476 women), and undergoing planned cesarean delivery (odds ratio, 0.39; 95% confidence interval, 0.27-0.57; 8 studies/1825 women). CONCLUSION: Among patients who underwent cesarean delivery, presurgical vaginal irrigation with povidone-iodine had the highest probability of reducing the risk of endometritis, postoperative wound infections, and fever.