A Patient Experience Course Syllabus: Integrating Service Sciences Research to Enhance Health-Care Delivery.

We present here a syllabus for teaching patient experience that draws on service sciences to address the current state of patient experience. The syllabus was the result of an ongoing collaboration between educators at the Hotel College and the School of Medicine at the University of Nevada at Las Vegas. The syllabus was developed after a thorough literature review in the field of services marketing, patient experience, hospitality marketing, management and leadership, health-care administration, and health-care communication and after consultation with subject matter experts. We believe that the syllabus provides an action plan for universities and hospitals to introduce and teach the topic of hospitality and patient experience as part of the medical and nursing school curriculum. The syllabus can also be adapted for teaching in executive education programs.

Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors.

BACKGROUND: To determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors. PATIENTS AND METHODS: Patients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose. RESULTS: Overall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30-86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies. CONCLUSIONS: The recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations. TRIAL REGISTRATION NUMBER: NCT02713529.

A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma.

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.

A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors.

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

Postformulation peptide drug loading of nanostructures.

Cytolytic peptides have commanded attention for their anticancer potential because the membrane-disrupting function that produces cell death is less likely to be overcome by resistant mutations. Congruently, peptides that are involved in molecular recognition and biological activities become attractive therapeutic candidates because of their high specificity, better affinity, reduced immunogenicity, and reduced off target toxicity. However, problems of inadequate delivery, rapid deactivation in vivo, and poor bioavailability have limited clinical application. Therefore, peptide drug development for clinical use requires an appropriate combination of an effective therapeutic peptide and a robust delivery methodology. In this chapter, we describe methods for the postformulation insertion of peptide drugs into lipidic nanostructures, the physical characterization of peptide-nanostructure complexes, and the evaluation of their therapeutic effectiveness both in vitro and in vivo.

Cytolytic peptide nanoparticles ('NanoBees') for cancer therapy.

Cytolytic peptides are an attractive class of anticancer candidates because of their wide-spectrum lytic properties. However, their therapeutic potential cannot be realized without a proper delivery vehicle, because of their off-target toxicity, nonspecificity, and unfavorable pharmacokinetics. The physical properties of perfluorocarbon (PFC)-core surfactant-coated nanoparticles render them a highly promising delivery vehicle for targeted therapeutic applications of cytolytic peptides. This article provides an overview of the mechanism underlying the anticancer efficacy of cytolytic peptides, the limitations in clinic applications, and the advantages of PFC nanoparticles over traditional FDA-approved nanocarriers such as liposomes. Recent reports of successful anticancer therapeutics delivered by PFC nanoparticles will be discussed, as well as new applications. WIREs Nanomed Nanobiotechnol 2011 3 318-327 DOI: 10.1002/wnan.126 For further resources related to this article, please visit the WIREs website.

Lipid membrane editing with peptide cargo linkers in cells and synthetic nanostructures.

Current strategies for deploying synthetic nanocarriers involve the creation of agents that incorporate targeting ligands, imaging agents, and/or therapeutic drugs into particles as an integral part of the formulation process. Here we report the development of an amphipathic peptide linker that enables postformulation editing of payloads without the need for reformulation to achieve multiplexing capability for lipidic nanocarriers. To exemplify the flexibility of this peptide linker strategy, 3 applications were demonstrated: converting nontargeted nanoparticles into targeting vehicles; adding cargo to preformulated targeted nanoparticles for in vivo site-specific delivery; and labeling living cells for in vivo tracking. This strategy is expected to enhance the clinical application of molecular imaging and/or targeted therapeutic agents by offering extended flexibility for multiplexing targeting ligands and/or drug payloads that can be selected after base nanocarrier formulation.

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth.

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides.

The therapeutic potential of cytolytic peptides is plagued by nonspecificity and enzymatic degradation. We report the first stable incorporation of melittin (a 26 amino acid amphipathic peptide) into an outer lipid monolayer of perfluorocarbon nanoparticles. Melittin binds avidly to the nanoparticles (dissociation constant approximately 3.27 nM) and retains its pore-forming activity after contact-mediated delivery to model bilayer membrane (liposomes) thereby demonstrating the effectiveness of perfluorocarbon nanoparticles as unique nanocarriers for cytolytic peptides.

Acoustic activation of targeted liquid perfluorocarbon nanoparticles does not compromise endothelial integrity.

Perfluorocarbon nanoparticles consisting essentially of liquid perfluoro-octyl bromide (PFOB) core surrounded by a lipid monolayer can serve as highly specific site-targeted contrast and therapeutic agents after binding to cellular biomarkers. Based on previous findings that ultrasound applied at 2 MHz and 1.9 mechanical index (MI) for a 5-min duration dramatically enhances the cellular interaction of targeted PFOB nanoparticles with melanoma cells in vitro without inducing apoptosis or other harmful effects to cells that are targeted, we sought to define mechanisms of interaction and the safety profile of ultrasound used in conjunction with liquid perfluorocarbon nanoparticles for targeted drug delivery, as compared with conventional microbubble ultrasound contrast agents under identical insonification conditions. Cell-culture inserts were used to grow a confluent monolayer of human umbilical vein endothelial cells. Definity in conjunction with continuous wave ultrasound (2.25 MHz for 1 and 5 min) increased the permeability of monolayer by four to six times above the normal, decreased transendothelial electrical resistance (a sign of reduced membrane integrity), and decreased cell viability by approximately 50%. Histological evaluation demonstrated extensive disruptions of cell monolayers. Nanoparticles (both nontargeted and targeted) elicited no changes in these different measures under similar insonification conditions and did not disrupt cell monolayers. We hypothesize that ultrasound facilitates drug transport from the perfluorocarbon nanoparticles not by cavitation-induced effects on cell membrane but rather by direct interaction with the nanoparticles that stimulate lipid exchange and drug delivery.