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This study sought to examine the effects of magnesium on epicardial action potential duration in patients during early myocardial ischemia.

IMPORTANCE: Three years of adjuvant imatinib mesylate therapy is associated with reduced recurrence rates and improved overall survival in patients with high-risk primary gastrointestinal stromal tumor (GIST) compared with patients who receive 1 year of treatment. The impact of a longer duration of therapy is unknown. OBJECTIVE: To determine whether adjuvant treatment for primary GIST with imatinib for 5 years is tolerable and efficacious. DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib [PERSIST-5]) included adult patients with primary GIST (expressing KIT) at 21 US institutions who underwent a macroscopically complete resection and were at intermediate or high risk of recurrence, defined as primary GIST at any site measuring 2 cm or larger with 5 or more mitoses per 50 high-power field or nongastric primary GIST measuring 5 cm or larger. Data were collected from August 5, 2009, through December 20, 2016. INTERVENTIONS: Imatinib, 400 mg once daily, orally for 5 years or until discontinuation of therapy because of progression or intolerance. MAIN OUTCOMES AND MEASURES: The primary end point was recurrence-free survival (RFS). The secondary end point was overall survival. RESULTS: Of the 91 patients enrolled, 48 (53%) were men with a median age of 60 years (range, 30-90 years). Median tumor size was 6.5 cm (range, 2.3-30.0 cm). Median treatment duration was 55.1 months (range, 0.5-60.6 months); 46 patients (51%) completed 5 years of imatinib therapy. Estimated 5-year RFS was 90% (95% CI, 80%-95%), and overall survival was 95% (95% CI, 86%-99%). Recurrence was noted in 7 patients: 1 had disease recur while receiving imatinib (PDGFRA D842V mutation) and died; 6 had disease recur after discontinuation of imatinib therapy. Two additional deaths were unrelated to treatment or tumor progression. Forty-five patients (49%) stopped treatment early because of patient choice (10 [21%]), adverse events (15 [16%]), or other (11 [12%]). All 91 patients experienced at least 1 adverse event, and 17 (19%) experienced grade 3 or 4 adverse events. CONCLUSIONS AND RELEVANCE: In this first adjuvant trial, to our knowledge, of patients with resected primary GIST who received 5 years of imatinib therapy, no patient with imatinib-sensitive mutations had disease recur during therapy. For patients in whom disease recurred, recurrence was within 2 years of discontinuation of imatinib therapy. Approximately half of the patients discontinued treatment early, most commonly because of patient choice, thus emphasizing the importance of close clinical monitoring to continue imatinib treatment for patients at appropriate risk. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00867113

Angiotensin II (Ang II) levels are increased as a function of blockade of the AT1 receptor, thus it is an important pharmacodynamic parameter in patients taking angiotensin receptor blockers (ARBs). The purpose of this study is to determine the effects of multiple doses of valsartan, an ARB, on Ang II levels in healthy subjects. Fourteen healthy volunteers had baseline Ang II levels drawn in the fasting state, between 6 and 8 AM. These subjects then received valsartan 80 mg QD for 7 days. Ang II levels were again drawn on day 7 prior to valsartan dosing (trough) and 6 h after dosing (peak). Ang II levels were determined from plasma using a highly specific monoclonal antibody after solid phase extraction (crossreactivity with other angiotensin peptides <0.1%). Day 7 predose (trough) Ang II levels were significantly higher than at baseline (13.8 ± 11.7 pg/ml vs 6.9 ± 2.4 pg/ml, p < 0.01). Day 7, 6 h postdose (peak) Ang II levels were significantly higher than day 7 predose (51.2 ± 35.1 pg/ml vs 13.8 ± 11.7 pg/ml, p < 0.001) and baseline levels (51.2 ± 35.1 pg/ml vs 6.9 ± 2.4 pg/ml, p < 0.001). These results show that Ang II levels remain elevated 24 h after multiple doses of valsartan 80 mg QD in healthy subjects. This suggests that the pharmacodynamic effects of AT1 receptor blockade with valsartan persist 24 h after dosing.