Stereotactic body radiation therapy and thermal ablation for treatment of NSCLC: A systematic literature review and meta-analysis.

RATIONALE: Stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early stage non-small cell lung cancer (NSCLC). Use of image guided thermal ablation (IGTA; including microwave ablation [MWA] and radiofrequency ablation [RFA]) has increased in NSCLC, however there are no studies comparing all three. OBJECTIVE: To compare the efficacy of IGTA (including MWA and RFA) and SBRT for the treatment of NSCLC. METHODS: Published literature databases were systematically searched for studies assessing MWA, RFA, or SBRT. Local tumor progression (LTP), disease-free survival (DFS), and overall survival (OS) were assessed with single-arm pooled analyses and meta-regressions in NSCLC patients and a stage IA subgroup. Study quality was assessed with a modified methodological index for non-randomized studies (MINORS) tool. RESULTS: Forty IGTA study-arms (2,691 patients) and 215 SBRT study-arms (54,789 patients) were identified. LTP was lowest after SBRT at one and two years in single-arm pooled analyses (4% and 9% vs. 11% and 18%) and at one year in meta-regressions when compared to IGTA (OR = 0.2, 95%CI = 0.07-0.63). MWA patients had the highest DFS of all treatments in single-arm pooled analyses. In meta-regressions at two and three-years, DFS was significantly lower for RFA compared to MWA (OR = 0.26, 95%CI = 0.12-0.58; OR = 0.33, 95%CI = 0.16-0.66, respectively). OS was similar across modalities, timepoints, and analyses. Older age, male patients, larger tumors, retrospective studies, and non-Asian study region were also predictors of worse clinical outcomes. In high-quality studies (MINORS score ≥ 7), MWA patients had better clinical outcomes than the overall analysis. Stage IA MWA patients had lower LTP, higher OS, and generally lower DFS, compared to the main analysis of all NSCLC patients. CONCLUSIONS: NSCLC patients had comparable outcomes after SBRT and MWA, which were better than those with RFA.

Stimulatory effects of combined endocrine disruptors on MA-10 Leydig cell steroid production and lipid homeostasis.

Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from individual exposures. These studies identified fetal and adult Leydig cells as sensitive targets for low dose endocrine disruptor (ED) mixtures. To further investigate the direct effects and mechanisms of toxicity of GEN and DEHP, MA-10 mouse tumor Leydig cells were exposed in-vitro to varying concentrations of GEN and MEHP, the principal bioactive metabolite of DEHP. Combined 10µM GEN+10µM MEHP had a stimulatory effect on basal progesterone production. Consistent with increased androgenicity, the mRNA of steroidogenic and cholesterol mediators Star, Cyp11a, Srb1 and Hsl, as well as upstream orphan nuclear receptors Nr2f2 and Sf1 were all significantly increased uniquely in the mixture treatment group. Insl3, a sensitive marker of Leydig endocrine disruption and cell function, was significantly decreased by combined GEN+MEHP. Lipid analysis by high-performance thin layer chromatography demonstrated the ability of combined 10µM combined GEN+MEHP, but not individual exposures, to increase levels of several neutral lipids and phospholipid classes, indicating a generalized deregulation of lipid homeostasis. Further investigation by qPCR analysis revealed a concomitant increase in cholesterol (Hmgcoa) and phospholipid (Srebp1c, Fasn) mediator mRNAs, suggesting the possible involvement of upstream LXRα agonism. These results suggest a deregulation of MA-10 Leydig function in response to a combination of GEN+MEHP. We propose a working model for GEN+MEHP doses relevant to human exposure involving LXR agonism and activation of other transcription factors. Taken more broadly, this research highlights the importance of assessing the impact of ED mixtures in multiple toxicological models across a range of environmentally relevant doses.