Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP–binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, MCC patients also exhibited enhanced ABCB5 positivity following carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy.

Objectives: Andexanet alfa is the first approved antidote in the management of life-threatening bleeds in patients treated with Xa inhibitors. The ANNEXA-4 study was successful in reducing factor Xa levels during time of administration but lacked correlation to improved patient outcomes. Given its novel mechanism of action, U.S. boxed warning, cost of up to $58,000 per dose, and limited efficacy data compared with standard of care, hospitals are faced with a dilemma with its addition to formulary and process for ensuring optimized use. The objective of this study was to evaluate adherence to institution restriction criteria and the clinical outcomes of treatment for patients for whom andexanet alfa is requested. Design: Retrospective cohort study of andexanet alfa requests within a 12-month time period. Setting: A 600-bed community teaching hospital. Patients: Patients whom pharmacists received request for dispensing andexanet alfa. Interventions: None. MEASUREMENTS AND MAIN RESULTS: Quality outcomes reviewed compliance to restriction criteria. Clinical outcomes evaluated use of adjunctive blood products, ICU length of stay, hospital length of stay, and hospital mortality. Safety outcomes evaluated incidence of thrombotic events. Andexanet alfa was requested for 16 patients from November 2018 to November 2019. It was administered in nine patients, with compliance to restriction criteria of 66.6%, average ICU length of stay 5.6 days, hospital length of stay 8.6 days, hospital mortality in 44.4%, and thrombotic events in 33.3%. Orders were rejected in seven patients with compliance to restriction criteria of 100%, ICU length of stay 3.2 days, hospital length of stay 5.5 days, hospital mortality in 14%, and thrombotic events in 14%. Conclusions: A greater rate of adverse effects and mortality was identified with the use of andexanet alfa compared with clinical trials. This is potentially due to its use in a more severely ill patient population and lack of adherence to restriction criteria.

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Purpose: To evaluate the benefits of postgraduate year 1 (PGY1) pharmacy residency program expansion on clinical outcomes, pharmacy services, educational outreach, costs, and preceptor time at a community teaching hospital. Methods: During academic years 2014 to 2016, two PGY1 resident positions existed, expanding to four PGY1 resident positions during 2016 to 2018. Quantitative analyses comparing the aforementioned periods evaluated clinical interventions, adverse drug events prevented, community and hospital educational programs provided, departmental costs, and documented preceptor hours as a result of program growth. The outcomes were assessed using descriptive statistics. Results: The mean number of documented clinical interventions completed by the resident classes with two residents was 2906 when compared to 5324 with four residents. The mean number of prevented adverse drug events was 56 during the years with two residents and 220 in the years with four residents. The number of community outreach programs increased from 2 to 18 per year. The number of resident lectures provided to allied health professionals increased from 11 to 16 sessions per year. The net economic impact associated with two residents in 2014 was +$4661 USD, while in 2017 the net impact was −$5262 USD. The mean preceptor hours spent per year related to residency activities with two residents was 1005 hours compared to 1109.5 hours with four residents. Conclusion: Through strategic modification, expansion of the PGY1 residency program led to increased documentation of clinical interventions, prevented adverse drug events, and educational programs provided with minimal change in preceptor burden.