BACKGROUND Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti–PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.)

This paper describes the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000. The purpose of the study was to assess dietary measurement error using two self-reported dietary instruments-the food frequency questionnaire (FFQ) and the 24-hour dietary recall (24HR)-and unbiased biomarkers of energy and protein intakes: doubly labeled water and urinary nitrogen. Participants were 484 men and women aged 40-69 years from Montgomery County, Maryland. Nine percent of men and 7% of women were defined as underreporters of both energy and protein intake on 24HRs; for FFQs, the comparable values were 35% for men and 23% for women. On average, men underreported energy intake compared with total energy expenditure by 12-14% on 24HRs and 31-36% on FFQs and underreported protein intake compared with a protein biomarker by 11-12% on 24HRs and 30-34% on FFQs. Women underreported energy intake on 24HRs by 16-20% and on FFQs by 34-38% and underreported protein intake by 11-15% on 24HRs and 27-32% on FFQs. There was little underreporting of the percentage of energy from protein for men or women. These findings have important implications for nutritional epidemiology and dietary surveillance.

Tumors may adopt normal physiologic checkpoints for immunomodulation leading to an imbalance between tumor growth and host surveillance. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. Nivolumab and pembrolizumab are the anti-PD-1 antibodies that are currently the furthest in clinical development, and anti-PD-L1 agents under investigation include MPDL3280A, MEDI4736, and BMS-936559. These agents have been used to treat advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other tumor types. In this article, we review the updated response results for early clinical trials, note recent FDA actions regarding this class of agents, and summarize results across trials looking at PD-L1 status as a predictor of response to anti-PD-1/PD-L1.

The safe and effective delivery of RNA therapeutics remains the major barrier to their broad clinical application. Here we develop a new nanoparticulate delivery system based on inorganic particles and biodegradable polycations. First, gold nanoparticles were modified with the hydrophilic polymer poly(ethylene glycol) (PEG), and then small interfering RNA (siRNA) was conjugated to the nanoparticles via biodegradable disulfide linkages, with ~30 strands of siRNA per nanoparticle. The particles were then coated with a library of end-modified poly(β-amino ester)s (PBAEs), previously identified as capable of facilitating intracellular DNA delivery. Nanoparticulate formulations developed here facilitate high levels of in vitro siRNA delivery, facilitating delivery as good or better than the commercially available lipid reagent, Lipofectamine 2000.RNA interference (RNAi) is an endogenous process whereby double-stranded RNA (dsRNA) can mediate the catalytic destruction of its homologous mRNA target. Short 22 nt dsRNA fragments called small interfering RNA (siRNA), are intermediates in the process and have shown their potential as therapeutics. 1-4 The development of RNAi based upon synthetic siRNA has led to a variety of potential therapeutic applications for diseases whose conventional treatments are limited. 5-9 The safe and effective intracellular delivery of siRNA remains the most challenging barrier to the broad application of siRNA in the clinic. [10][11][12][13][14] To date a number of carriers have been investigated for their potential as siRNA delivery agents 15 including cationic polymers, 16,17 lipids 8 or lipid-like materials, 18 iron oxide nanoparticles, 19 gold particles, 20-22 and semiconductor nanocrystals. 23,24 Alternatively, siRNA has been chemically modified and conjugated to small organic molecules 25,26 or polymeric materials 12,27,28 to enhance its stability and cellular uptake. 15 Poly(β-amino ester)s (PBAEs) have shown potential as delivery agents for DNA in various cell lines and therapeutic models. [29][30][31][32][33][34][35][36] To the best of our knowledge, however, these materials have not yet demonstrated their ability to deliver siRNA. The disorderly interactions of siRNA with polymer are likely to result in incomplete condensation of the polymer into a particulate due to the stiffer nature of an RNA molecule relative to DNA ( Figure 1A). 37 We hypothesized