Research Spotlight

Posted June 15th 2017

Residual thromboxane activity and oxidative stress: influence on mortality in patients with stable coronary artery disease.

Peter McCullough M.D.

Peter McCullough M.D.

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2017). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis 28(4): 287-293.

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BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.


Posted June 15th 2017

A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.

Joanne L. Blum M.D.

Joanne L. Blum M.D.

Baselga, J., S. M. Morales, A. Awada, J. L. Blum, A. R. Tan, M. Ewertz, J. Cortes, B. Moy, K. J. Ruddy, T. Haddad, E. M. Ciruelos, P. Vuylsteke, S. Ebbinghaus, E. Im, L. Eaton, K. Pathiraja, C. Gause, D. Mauro, M. B. Jones and H. S. Rugo (2017). “A phase ii study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.” Breast Cancer Res Treat 163(3): 535-544.

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PURPOSE: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). METHODS: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] x 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd x 5 days/week. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd x 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. CONCLUSIONS: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.


Posted June 15th 2017

Pneumonia after cardiac surgery: Experience of the National Institutes of Health/Canadian Institutes of Health Research Cardiothoracic Surgical Trials Network.

Robert L. Smith, MD

Robert L. Smith, MD

Ailawadi, G., H. L. Chang, P. T. O’Gara, K. O’Sullivan, Y. J. Woo, J. J. DeRose, Jr., M. K. Parides, V. H. Thourani, S. Robichaud, A. M. Gillinov, W. C. Taddei-Peters, M. A. Miller, L. P. Perrault, R. L. Smith, L. Goldsmith, K. A. Horvath, K. Doud, K. Baio, A. C. Gelijns, A. J. Moskowitz, E. Bagiella, J. H. Alexander and A. Iribarne (2017). “Pneumonia after cardiac surgery: Experience of the national institutes of health/canadian institutes of health research cardiothoracic surgical trials network.” J Thorac Cardiovasc Surg 153(6): 1384-1391.

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RATIONALE: Pneumonia remains the most common major infection after cardiac surgery despite numerous preventive measures. OBJECTIVES: To prospectively examine the timing, pathogens, and risk factors, including modifiable management practices, for postoperative pneumonia and estimate its impact on clinical outcomes. METHODS: A total of 5158 adult cardiac surgery patients were enrolled prospectively in a cohort study across 10 centers. All infections were adjudicated by an independent committee. Competing risk models were used to assess the association of patient characteristics and management practices with pneumonia within 65 days of surgery. Mortality was assessed by Cox proportional hazards model and length of stay by a multistate model. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of pneumonia was 2.4%, 33% of which occurred after discharge. Older age, lower hemoglobin level, chronic obstructive pulmonary disease, steroid use, operative time, and left ventricular assist device/heart transplant were risk factors. Ventilation time (24-48 vs 48 hours HR, 4.67; 95% CI, 2.70-8.08), nasogastric tubes (HR, 1.80; 95% CI, 1.10-2.94), and each unit of blood cells transfused (HR, 1.16; 95% CI, 1.08-1.26) increased the risk of pneumonia. Prophylactic use of second-generation cephalosporins (HR, 0.66; 95% CI, 0.45-0.97) and platelet transfusions (HR, 0.49, 95% CI, 0.30-0.79) were protective. Pneumonia was associated with a marked increase in mortality (HR, 8.89; 95% CI, 5.02-15.75) and longer length of stay of 13.55 +/- 1.95 days (bootstrap 95% CI, 10.31-16.58). CONCLUSIONS: Pneumonia continues to impose a major impact on the health of patients after cardiac surgery. After we adjusted for baseline risk, several specific management practices were associated with pneumonia, which offer targets for quality improvement and further research.


Posted June 15th 2017

Influence of practice patterns on outcome among countries enrolled in the SYNTAX trial: 5-year results between percutaneous coronary intervention and coronary artery bypass grafting.

Michael J. Mack M.D.

Michael J. Mack M.D.

Milojevic, M., S. J. Head, M. J. Mack, F. W. Mohr, M. C. Morice, K. D. Dawkins, D. R. Holmes, Jr., P. W. Serruys and A. P. Kappetein (2017). “Influence of practice patterns on outcome among countries enrolled in the syntax trial: 5-year results between percutaneous coronary intervention and coronary artery bypass graftingdagger.” Eur J Cardiothorac Surg: 2017 May [Epub ahead of print].

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OBJECTIVES: To examine differences among participating countries in baseline characteristics, clinical practice, medication strategies and outcomes of patients randomized to coronary artery bypass grafting and percutaneous coronary intervention in the SYNTAX trial. METHODS: In SYNTAX, centres in 18 different countries enrolled 1800 patients, of which 8 countries enrolled >/=80 patients, what was projected to be a large enough sample size to be included in the analysis. Baseline characteristics, practice patterns and clinical outcomes were compared between the USA ( n = 245), the UK ( n = 267), Italy ( n = 197), France ( n = 208), Germany ( n = 179), Netherlands ( n = 148), Belgium ( n = 91) and Hungary ( n = 83). The remaining patients from other participating countries were pooled together ( n = 382). RESULTS: Five-year results demonstrated significantly different outcomes between countries. After adjustment, percutaneous coronary intervention patients in France had lower rates of major adverse cardiac and cerebrovascular events [hazard ratio (HR) = 0.60, 95% confidence interval (CI) 0.37-0.98], while the incidence of repeat revascularization was higher in Hungary (HR = 1.89, 95% CI 1.14-3.42). Coronary artery bypass grafting showed the lowest rate of repeat revascularization in the UK (HR = 0.32, 95% CI 0.12-0.85). There were numerous differences in the risk profile of patients between participating countries, as well as marked differences in surgical practice across countries in the use of blood cardioplegia (range 3.1-89.0%; P < 0.001), bilateral internal mammary artery usage (range 7.8-68.2%; P < 0.001) and off-pump procedures (range 3.9-44.4%; P < 0.001). Variation was also found for percutaneous coronary intervention in the number of implanted stents (range 4.0 +/- 2.3 to 6.1 +/- 2.6; P < 0.001) as well as for the entire stents length (range 69.0 +/- 45.1 to 124.1 +/- 60.9; P < 0.001). Remarkable differences were observed in the prescription of post-coronary artery bypass grafting medication in terms of acetylsalicylic acid (range 79.6-95.0%; P = 0.004), thienopyridine (6.8-31.1%; P < 0.001) and statins (41.3-89.1%; P < 0.001). CONCLUSIONS: Patient characteristics and clinical patterns are significantly different between countries, resulting in significantly different 5-year outcomes. This article presents specific data that can further improve outcomes in each country.


Posted June 15th 2017

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

Thomas Hutson D.O.

Thomas Hutson D.O.

Rini, B. I., V. Gruenwald, E. Jonasch, M. N. Fishman, Y. Tomita, M. D. Michaelson, J. Tarazi, L. Cisar, S. Hariharan, A. H. Bair, B. Rosbrook and T. E. Hutson (2017). “Long-term duration of first-line axitinib treatment in advanced renal cell carcinoma.” Target Oncol 12(3): 333-340.

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OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naive patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus /=10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade >/=3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.