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To support a phase III randomized trial of the multi-targeted tyrosine kinase inhibitor cabozantinib in neuroendocrine tumors, we developed a high-performance liquid chromatography mass spectrometry method to quantitate cabozantinib in 50 μL of human plasma. After acetonitrile protein precipitation, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 μm, 2 × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water over a 5-min run time. Detection was performed on a Quattromicro quadrupole mass spectrometer with electrospray, positive-mode ionization. The assay was linear over the concentration range 50–5000 ng/mL and proved to be accurate (103.4–105.4%) and precise (

PURPOSE: To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study. METHODS: Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC-MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC-MS/MS monitoring of CYP specific metabolite formation. RESULTS: Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity. CONCLUSION: CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug-drug interactions.

Objective Cancer caregivers are at increased risk for cardiovascular disease (CVD) and mortality. The aims of this study were to examine psychosocial and behavioral predictors of metabolic syndrome, an intermediate endpoint of CVD. Methods Cancer caregivers were administered a battery of questionnaires assessing sociodemographic characteristics, depressive symptoms, perceived stress, caregiver quality of life, sleep, physical activity, alcohol and tobacco use, social support, relationship quality, and loneliness. Metabolic syndrome was defined using the American Heart Association guidelines and the National Cholesterol Education Program's Adult Treatment Panel (ATP) III, which includes the presence of at least three of the following abnormalities: blood pressure, glucose, abdominal girth, high-density lipoprotein (HDL), and triglycerides. Results Of the 104 caregivers, 77% were female, 94% were Caucasian, and the mean age was 59.5 (SD = 12.8). Of the 104 caregivers, 35.6% reported depressive symptoms in the clinical range of the Center for Epidemiologic Studies-Depression (CES-D) and 69.2% reported Perceived Stress Scale scores at least one standard deviation above the general population norms. A total of 16.3% of caregivers currently used tobacco, 28.8% consumed alcohol, and 26.7% were overweight (BMI = 25-29.9) and 48.5% were obese (BMI ≥ 30). Forty-nine percent of the caregivers met the criteria for metabolic syndrome. After age, gender, and race were adjusted, the following remained as significant predictors of metabolic syndrome: low levels of caregiver quality of life (Odds Ratio (OR) = 1.067; 95% CI, 1.019-1.117; P = .006), high levels of hostility (OR = 1.142; 95% CI, 1.030-1.267; P = .012), and current alcohol use (OR = 4.193; 95% CI, 1.174-14.978; P = .027). Conclusion Development of interventions to reduce the risk of metabolic syndrome in cancer caregivers is recommended.

e23174 Background: Cancer caregivers are at increased risk for cardiovascular disease. The aims of the present study were to develop an instrument to identify cancer caregivers at risk for the development of cardiovascular disease. Methods: Cancer caregivers were enrolled in a prospective study examining predictors of metabolic syndrome. Predictors included perceived stress, caregiver stress, depression, hostility, physical activity, diet, alcohol and tobacco use, social support and relationship with the patient. Regression analyses and factor analyses was performed to reduce the number of items to develop an instrument that would identify cancer caregivers at risk for cardiovascular disease. Internal consistency and Area Under the Receiver Operator Curve was also performed to test the new instrument. Results: A total of 111 caregivers were included in the analyses. The mean age of caregivers was 59.6 ( SD= 12.7) and the majority of caregivers were female (74.8%), Caucasian (94.6%), and were the spouse of the cancer patient (65.8%).Using regression analyses, the items from the caregiver stress, hostility, and social support questionnaires were most likely to predict metabolic syndrome. Preliminary findings suggest that a 35-item instrument was predictive of metabolic syndrome [B = 0.067, HR = 1.07, p = 0.001]. The reliability of the instrument was good with a Cronbach Alpha = 0.83. The Area Under the Receiver Operator Curve was also fair (AUROC = 0.703; 95% CI = 0.597-0.808, p = 0.001). Based on the AUROC, the best cut point to detect metabolic syndrome would be a score of 24 (Sensitivity = 0.75 and Specificity = 0.55). Conclusions: Preliminary findings suggest that this 35-item questionnaire may be useful in identifying cancer caregivers at risk for metabolic syndrome, an intermediate endpoint for cardiovascular disease. The questionnaire may be used to screen cancer caregivers for interventions to reduce metabolic syndrome.