The efficacy of dose-enhancing gold nanoparticles (AuNPs) is negatively impacted by low tumor uptake, low cell membrane penetration, limited diffusion distance, and short lifetime of radiation-induced secondary particles. To overcome these limitations, we have developed a novel AuNP system capable of radiation-triggered release of nitrite, a precursor of reactive nitrogen species, and report here on the in vivo characterization of this system. AuNPs were functionalized through PEGylation, cell-penetrating peptides (CPP; AuNP@CPP), and nitroimidazole (nIm; AuNP@nIm-CPP). Mice with subcutaneous 4T1 tumors received either AuNP@nIm-CPP or AuNP@CPP intraperitoneally. Tumor and normal tissue uptake were evaluated 24 h post AuNP administration. A separate cohort of mice was injected and irradiated to a single-fraction dose of 18 Gy in a 225 kVp small animal irradiator 24 h post NP administration. The mice were followed for two weeks to evaluate tumor response. The mean physical and hydrodynamic size of both NP systems were 5 and 13 nm, respectively. NP nIm-loading of 1 wt% was determined. Tumor accumulation of AuNP@nIm-CPP was significantly lower than that of AuNP@CPP (0.2% vs 1.2%, respectively). In contrast, AuNP@nIm-CPP showed higher accumulation compared to AuNP@CPP in liver (16.5% vs 6.6%, respectively) and spleen (10.8% vs 3.1%, respectively). With respect to tumor response, no differential response was found between non-irradiated mice receiving either saline or AuNP@nIm-CPP alone. The combination of AuNP@CPP+ radiation showed no differential response from radiation alone. In contrast, a significant delay in tumor regrowth was observed in mice receiving AuNP@nIm-CPP+ radiation compared to radiation alone. AuNP functionalized with both CPP and nIm exhibited an order of magnitude less tumor accumulation compared to the NP system without nIm yet resulted in a significantly higher therapeutic response. Our data suggest that by improving the biokinetics of AuNP@nIm-CPP, this novel NP system could be a promising radiosensitizer for enhanced therapeutic response following radiation therapy.

Background Cyclophosphamide (CYC) has known cytotoxic effects on ovarian reserve and has been linked to premature ovarian failure (POF) in systemic lupus erythematosus (SLE). The concurrent use of gonadotropin-releasing hormone agonists (GnRHas) is postulated to preserve ovarian function by reducing the number of follicles exposed to CYC, but there is paucity of data to establish its efficacy. We conducted a meta-analysis to summarize the effect of concurrent GnRHa use in persevering ovarian function and pregnancy. Methods English language databases of PubMed, Embase, and Cochrane were searched to include studies published between 2000 and 2021. Studies in females with rheumatic diseases receiving concurrent GnRHa and CYC therapy to evaluate ovarian preservation as defined by amenorrhea, follicle stimulating hormone (FSH), anti-mullerian hormone (AMH), or estradiol levels or successful pregnancy were included. We used a fixed effect, exact, Mantel-Haenszel approach to estimate the overall odds ratio (OR) and associated 95% confidence intervals (95% CIs). Results Seven studies with 218 female patients were included. The ovarian function was preserved in 125/132 (94.6%) of women who received GnRHa concurrently with CYC compared to 50/86 (58%) of women who did not receive GnRHa (OR = 10.3, CI = 4.83–36.29). The OR for pregnancy with GnRHa use = 2.94 (CI = 1.04–9.89). Conclusion Our results based on limited published studies suggest that concurrent GnRHa use preserves ovarian function and increase odds of pregnancy. It can be considered for premenopausal SLE females receiving CYC. Long-term follow-up studies are needed to establish the efficacy and safety of GnRHa use for ovarian preservation.

414 Background: Stereotactic body radiation therapy (SBRT) for pancreatic cancers has been shown to improve local control, and is an important option for treatment, especially for unresectable disease. Verifying the tumor location prior to delivery of SBRT is challenging, so fiducial markers are used to track tumor location. There is currently no standard of which fiducials to use in treatment. This study would like to compare outcomes of patients treated with SBRT using different fiducial markers. Methods: Records of patients diagnosed with primary pancreas cancer who were treated with chemotherapy and SBRT were reviewed from 2006-2019. Patients were excluded if they were treated with Cyberknife, were metastatic at presentation, recurrence /persistent disease after Whipple/radiation therapy, were secondary metastatic disease (from another primary), and if they were resected after SBRT. Patients were categorized according to the fiducial used for tumor tracking during SBRT treatment: gold seeds, intrabiliary stent, or both. Cumulative incidence of local recurrence (CIR) was analyzed with death as competing event, and time to over-all survival was estimated using Kaplan-Meier curves. Results: A total of 129 patients with available fiducial information were included in this study, of which 64 (49.6%) were treated with SBRT using gold seeds, 23 (17.8%) using intrabiliary stent, and 42 (32.6%) using both the seeds and stent. There were no difference between groups in terms of baseline characteristics such as age (p = 0.169), sex (p = 0.293), and stage grouping (p = 0.293). Median follow-up time was 15 months (range: 0.3-37.3 months). The 6- and 12-month CIR were 1.5% (95%CI, 0.1%-7.4%) and 11% (95%CI, 4.8%-20.2%) for patients treated with seeds, 4.3% (95%CI, 0.2%-18.6%) and 30.4% (95%CI, 13.1%-49.8%) for patients treated with stent, and 4.8% (95%CI, 0.8%-14.6%) and 19.5% (95%CI, 9.0%-32.9%) for patients treated with both (p = 0.007). Median time to overall survival was 15.3 months (95%CI, 13-17.8 months) for patients treated with seeds, 21.3 months (95%CI, 14.7-29.6 months) for patients treated with stent, and 15.7 months (95%CI, 11.5-19.7 months) for patients treated with both (p = 0.307). Univariate analysis for predictors of local failure did not show significance for age (p = 0.812), or advanced stage (p = 0.483), but was significant for the presence of seeds (p = 0.006). Conclusions: The type of fiducial marker used for tracking during pancreas SBRT treatment was associated with local failure but no difference in overall survival. Further analysis is warranted to see which clinical factors contribute to this difference.

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INTRODUCTION:Systemic lupus erythematosus (SLE) female patients with severe disease manifestations are treated with cyclophosphamide (CYC), which causes ovarian cytotoxicity. Gonadotropin-releasing hormone agonist (GnRH-a) is often co-administered with CYC to preserve ovarian function and reproductive potential. However, there is a lack of evidence to support this use of GnRH-a. We conducted a retrospective study and questionnaire of SLE patients who received CYC with or without GnRH-a to evaluate its efficacy in preserving ovarian function.METHODS:This study was approved by the IRB of the National Institutes of Health (IRB#:001011). Review of medical records resulted in 50 female SLE patients treated with CYC who were less than 40 year old at the time of treatment: CYC only (n=20, group 1), CYC and GnRH-a (n=30, group 2). These patients were age/gender-matched with 50 SLE patients not treated with CYC (group 3). Data about demographics, SLE disease activity, damage accrual, cumulative CYC exposure, and pregnancy outcomes were collected by chart review. Self-reported questionnaires were used to collect data assessing menses cycles, pregnancies and their outcome, or infertility.RESULTS:There was no significant difference in SLE disease activity, baseline demographics, total damage accrual, or other clinical parameters between groups 1 and 2. The mean cumulative CYC dose was 1.2 g (group 1) and 1.5 g (group 2) (P=.16). Number of pregnancies were similar: mean (SD) group 1=2 (1.6); group 2=1.2 (1.4); group 3=1.3 (1.4) (P=.18). There were more miscarriages in group 1 compared to groups 2 and 3 (P=.015).CONCLUSION:Our data suggest use of GnRH-a improves pregnancy outcomes in SLE patients on CYC, but prospective studies are needed to establish its safety and efficacy.