Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial.

BACKGROUND: We evaluated the significance of hypertension developing during vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR-TKI) treatment and a group of cytokines and angiogenic factors (CAFs) in advanced non-clear cell renal cell carcinoma (nccRCC) patients treated with sunitinib in a phase II study. MATERIALS AND METHODS: Using multiplex assays, we analyzed the levels of 38 CAFs in plasma at baseline and after 4 weeks of sunitinib therapy. Sunitinib benefit was defined as a partial response or stable disease using the Response Evaluation Criteria in Solid Tumors lasting ≥4 months. Cox proportional hazards regression models were used to assess the associations among hypertension, CAFs, and progression-free (PFS) and overall survival (OS). RESULTS: Fifty-seven patients were evaluable; 53 had baseline CAF levels available. The median PFS and OS were 2.9 months (95% confidence interval [CI], 1.4-5.5) and 16.8 months (95% CI, 10.7-27.4), respectively. Sunitinib benefit was observed in 21 patients (37%). However, 33 patients (60%) developed hypertension during treatment, although no association was found with survival or response. Elevated baseline soluble tumor necrosis factor (TNF) receptor I, interleukin-8, growth-regulated oncogene, transforming growth factor-α, and VEGFR-2 levels were associated with an increased risk of death on multivariate analysis. CONCLUSION: We found no association between the development of hypertension and survival or sunitinib benefit in advanced nccRCC. TNF and angiogenic/immunomodulatory mediators were identified for evaluation as markers of prognosis and VEGFR-TKI benefit in future studies.

Arm exercise myocardial perfusion imaging for prognostication of long-term outcome.

INTRODUCTION: Pharmacologic evaluations constitute ≥50% of imaging stress tests, but exercise reduces adverse effects, improves myocardial perfusion imaging (MPI) quality and diagnostic results, and provides powerful prognostic and clinically important information on exercise capacity and cardiovascular responses to the relevant physiologic stress of exercise. Thus, our purpose was to determine whether arm exercise and MPI variables predict long-term outcome in patients who cannot perform leg exercise. METHODS: We performed arm exercise MPI stress tests in 253 consecutive patients age 64.5 (10.7) yr (mean (SD)) from 1997 to 2002 and investigated associations of arm exercise and abnormal MPI variables with all-cause mortality, myocardial infarction (MI), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI) during follow-up of 12.0 (1.3) yr. RESULTS: There were 156 deaths (61.7%), 47 patients suffered MI (18.6%), 24 underwent CABG (9.5%), and 50 had PCI (19.8%). Arm exercise capacity and delta HR (peak - resting) were strongly associated with survival after adjustment for significant demographic and clinical variables (Cox multivariate P < 0.0001 and 0.001, respectively). MPI was abnormal in 157 patients (62.1%). An abnormal arm exercise MPI was borderline predictive of mortality by Cox analysis (71.8% vs 46.4% for normal study; univariate P < 0.0001; multivariate P = 0.07) but resulted in 58% relative incremental integrated discrimination improvement over clinical variables for predicting death. Perfusion defect size also strongly predicted mortality (Cox multivariate P = 0.003). An abnormal arm exercise MPI study, perfusion defect type, and size all prognosticated PCI (all P ≤ 0.03) but not MI or CABG. CONCLUSIONS: Arm exercise MPI is a valuable approach for outcome prediction in patients unable to perform leg exercise.

Arm exercise as an alternative to pharmacologic stress testing: arm exercise stress testing and outcome.

BACKGROUND: Treadmill exercise variables are powerful predictors of all-cause mortality but are unobtainable in at least 50% of patients because of disabilities precluding lower extremity exercise. Arm exercise stress testing is a potentially cost-effective alternative, but no long-term outcome data are available. METHODS: We performed arm ergometer stress tests on 446 veterans aged 64.0 (11.1) years (mean [SD]) between 1997 and 2002 and investigated whether arm exercise capacity in resting metabolic equivalents, heart rate recovery (in beats per minute), delta (peak resting) heart rate (in beats per minute), and other exercise variables predict long-term all-cause mortality, myocardial infarction (MI), or coronary revascularization. RESULTS: During follow-up of 12.0 (1.3) years, 255 patients died (57.2%), 70 had MI (15.7%), and 118 underwent coronary revascularization (26.4%). After adjustment for significant demographic and clinical variables, death was predicted by arm metabolic equivalents (hazard ratio/SD 0.59, 95% CI 0.46-0.75, P < .001), heart rate recovery (hazard ratio/SD 0.64, 95% CI 0.49-0.83, P < .001), and delta heart rate (hazard ratio/SD 0.75, 95% CI 0.63-0.91, P < .001). No exercise variables prognosticated MI, but coronary revascularization was predicted by stress-induced ST-segment deviations (hazard ratio 2.64, 95% CI 1.16-4.33, P < .001), limiting angina (hazard ratio 4.70, 95% CI 1.81-12.22, P < .001), and an abnormal perfusion imaging result (hazard ratio 2.0, 95% CI 1.14-3.51, P < .02). CONCLUSIONS: Arm exercise capacity, heart rate recovery, and delta heart rate predict 12-year all-cause mortality and arm exercise-induced ST changes, limiting angina, and an abnormal nuclear imaging result portend coronary revascularization in lower extremity disabled veterans.

Arm exercise stress perfusion imaging predicts clinical outcome.

Treadmill exercise capacity in resting metabolic equivalents (METs) and stress hemodynamic, electrocardiographic (ECG), and myocardial perfusion imaging (MPI) responses are independently predictive of adverse clinical events. However, limited data exist for arm ergometer stress testing (AXT) in patients who cannot perform leg exercise because of lower extremity disabilities. We sought to determine the extent to which AXT METs, hemodynamic, ECG, and MPI responses to arm exercise add independent incremental value to demographic and clinical variables for prediction of all-cause mortality, myocardial infarction (MI), or late coronary revascularization, individually or as a composite. A prospective cohort of 186 patients aged 64 ± 10 (SD) yr, unable to perform lower extremity exercise, underwent AXT MPI for clinical reasons between 1997 and 2002, and were followed for 62 ± 23 mo, to an endpoint of death or 12/31/2006. Average annual rates were 5.4% for mortality, 2.2% for MI, 2.5% for late coronary revascularization, and 8.0% for combined events. After adjustment for age and clinical variables, AXT METs [P < 0.05; hazard ratio (HR) = 0.59; confidence interval (CI) = 0.35-0.84] and abnormal MPI (P < 0.01; HR = 2.48; CI = 2.15-2.81) were independently predictive of mortality. A positive AXT ECG (P < 0.05; HR = 2.61; CI = 2.13-3.10) was predictive of MI. Death and MI combined were prognosticated by METs (P < 0.05; HR = 0.63; CI = 0.41-0.85), MPI (P < 0.05; HR = 1.77; CI = 1.49-2.05), and a positive AXT ECG (P < 0.05; HR = 1.86; CI = 1.55-2.17). In conclusion, for high risk older patients who cannot perform leg exercise because of lower extremity disabilities, AXT METs are as important as MPI for prediction of mortality alone and death and MI combined, and a positive AXT ECG prognosticates MI alone and death and MI combined.

Chemotherapy-induced cardiomyopathy.

Improvement in cancer therapy has led to an increasing number of cancer survivors, some of whom may suffer from the cardiotoxic effects of chemotherapy. Cardiomyopathy can occur years after completion of the chemotherapy and it is important to recognize this early, as complete recovery of cardiac function is possible in some cases. In this article we will review chemotherapy-induced cardiomyopathy and discuss its treatment options.