Medication errors at the time of hospital admission are common, and some have the potential to cause harm. Better methods of ensuring an accurate medication history at the time of hospital admission are needed.

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379 Background: A single priming dose of T (anti-CTLA-4) added to D (anti-PD-L1) in the STRIDE (Single T Regular Interval D) regimen, formerly T300+D, showed encouraging clinical activity and limited toxicity in a phase 2 uHCC study (Study 22, NCT02519348), suggesting single exposure to T is sufficient to improve upon D activity. HIMALAYA (NCT03298451) evaluated the efficacy and safety of STRIDE or D vs sorafenib (S) in uHCC. Methods: HIMALAYA is an open-label, multicenter, phase 3 study, in which pts with uHCC and no prior systemic therapy were initially randomized to STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg every 4 weeks [Q4W]), D (1500 mg Q4W), S (400 mg twice daily), or T 75 mg Q4W (4 doses) plus D 1500 mg Q4W (T75+D). Recruitment to T75+D ceased after a planned analysis of Study 22 showed T75+D did not meaningfully differ from D. The primary objective was overall survival (OS) for STRIDE vs S. The secondary objective was OS noninferiority (NI) of D to S (NI margin: 1.08). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR; RECIST v.1.1), duration of response (DoR), and safety. Results: In total, 1171 pts were randomized to STRIDE (N=393), D (N=389), or S (N=389). At data cutoff (DCO), the primary objective was met: OS was significantly improved for STRIDE vs S (hazard ratio [HR], 0.78; 96% confidence interval [CI], 0.65–0.92; p=0.0035; Table). D met the objective of OS NI to S (HR, 0.86; 96% CI, 0.73–1.03). ORRs were higher for STRIDE (20.1%) and D (17.0%) than for S (5.1%). No new safety signals were identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (D), and 36.9% (S) of pts. Grade 3/4 hepatic TRAEs occurred in 5.9% (STRIDE), 5.2% (D), and 4.5% (S) of pts. No TRAE of esophageal varices hemorrhage occurred. Rates of TRAEs leading to discontinuation were 8.2% (STRIDE), 4.1% (D), and 11.0% (S). Conclusions: HIMALAYA was the first large phase 3 trial with a diverse, representative uHCC population and extensive long-term follow-up to assess both mono- and combination immunotherapy. D was noninferior to S with favorable safety. The combination of a single priming dose of T plus D in STRIDE displayed superior efficacy and a favorable benefit-risk profile vs S. STRIDE is a proposed, novel, first-line standard of care systemic therapy for uHCC. Clinical trial information: NCT03298451. [Table: see text]

The existence of dimers and oligomers for many G protein-coupled receptors has been described by us and others. Since many G protein-coupled receptor subtypes are highly homologous to each other, we examined whether closely related receptors may interact with each other directly and thus have the potential to create novel signaling units. Using -and ␦-opioid receptors, we show that each receptor expressed individually was pharmacologically distinct and could be visualized following electrophoresis as monomers, homodimers, homotetramers, and higher molecular mass oligomers. When -and ␦-opioid receptors were coexpressed, the highly selective synthetic agonists for each had reduced potency and altered rank order, whereas endomorphin-1 and Leu-enkephalin had enhanced affinity, suggesting the formation of a novel binding pocket. No heterodimers were visualized in the membranes coexpressing -and ␦-receptors by the methods available. However, heterooligomers were identified by the ability to co-immunoprecipitate -receptors with ␦-receptors and vice versa using differentially epitope-tagged receptors. In contrast to the individually expressed -and ␦-receptors, the coexpressed receptors showed insensitivity to pertussis toxin and continued signal transduction, likely due to interaction with a different subtype of G protein.In this study, we provide, for the first time, evidence for the direct interaction of -and ␦-opioid receptors to form oligomers, with the generation of novel pharmacology and G protein coupling properties.Opioid receptors have distinct pharmacological profiles and discrete but overlapping distributions in brain. The relatively recent cloning of opioid receptors has established that the products of three genes form the known subtypes (the -, ␦-, and -opioid receptors) that interact with the complex family of endogenous opioid peptides (reviewed in Ref. 1). The endogenous opioid peptide-receptor systems mediate important physiological functions related to pain perception, locomotion, motivation, reward, autonomic function, immunomodulation, and hormone secretion.The analysis of the contribution of each receptor type to the various opioid functions documented has been limited by the selectivity and cross-reactivity of the available opioid ligands and the postulation that multiple receptor subtypes are present. Since the cloning of the opioid receptors, the individual pharmacological and biochemical profiles of the -, ␦-, and -opioid receptors have been better defined; however, there are many aspects of opioid receptor biology that still remain poorly understood. A major problem that still remains is that the pharmacology of opioid receptors in brain tissue predicts a greater number of receptor subsites than revealed by opioid receptor cloning (1, 2). One possible explanation may be that the precise receptor-effector interactions present in endogenous brain regions may have not been adequately replicated in the heterologous expression systems in which the cloned receptors have been studied or, alternativel...