Research Spotlight

Mumtaz, M., H. Gada, M. J. Mack and M. J. Reardon (2017). “Who’s afraid of the big bad wolf?” J Thorac Cardiovasc Surg 153(6): 1287-1289.

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Surgical aortic valve replacement (SAVR) for the treatment of symptomatic severe aortic stenosis is arguably one of the most successful cardiac procedures ever developed. Since the introduction of SAVR in 1960, millions of lives have been saved and improved. Although never tested against the previous standard of care, medical therapy, we as surgeons knew it was the right choice because without SAVR these patients were resigned to heart failure and death. We did track our outcomes both individually and nationally by the creation of the Society of Thoracic Surgery Adult Cardiac Surgery database, which now encompasses more than 6.1 million patients contributed by more than 95% of cardiac surgeons in the United States.

Packer, M. (2017). “Tetralogy of fallow: Four trials and tribulations.” JACC Heart Fail 5(6): 408-410.

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When Chris O’Connor became the Founding Editor of JACC: Heart Failure, he opened a dead letter office (1) to welcome old trials that had been completed and reported years before but had never been published. Their results had been fully analyzed and presented at scientific meetings, and often drafts of the primary papers had been written…Once the papers were sidelined, it was easy to fantasize that they would eventually be published. Yet, despite the overwhelming ethical mandate to place the results in print, there was always a reason to pursue different priorities and to follow other paths of immediate interest. The papers were left fallow; they were plots of land that had been plowed and harrowed but remained unsown, presumably under the premise that doing so would restore their fertility. It was this false premise that allowed time to pass…

Paul, C., C. Leonardi, A. Menter, K. Reich, L. S. Gold, R. B. Warren, A. Moller and M. Lebwohl (2017). “Calcipotriol plus betamethasone dipropionate aerosol foam in patients with moderate-to-severe psoriasis: Sub-group analysis of the pso-able study.” Am J Clin Dermatol 18(3): 405-411.

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BACKGROUND: Fixed-combination calcipotriol 50 mug/g plus betamethasone 0.5 mg/g (Cal/BD) aerosol foam is a new topical treatment for psoriasis. Although moderate-to-severe psoriasis is typically treated with systemic/biologic therapies, a topical treatment that is efficacious in these patients may be a significant cost-saving alternative to systemic therapy. OBJECTIVE: The objective of this study was to assess the response to Cal/BD foam and gel in patients with moderate-to-severe psoriasis enrolled in the phase III, 12-week PSO-ABLE study. METHODS: Patients eligible for this analysis had moderate-to-severe psoriasis, defined by the ‘Rule of Tens’: body surface area >/=10% or Psoriasis Area and Severity Index (PASI) [excluding head; modified PASI (mPASI)] >10 or Dermatology Life-Quality Index >10. Endpoints included: proportion of patients achieving mPASI75 or mPASI90; change in body surface area; proportion of patients clear/almost clear with a >/=2 grade improvement (i.e., treatment success); change in Dermatology Life-Quality Index. RESULTS: Seventy-seven Cal/BD foam patients and 82 gel patients had moderate-to-severe psoriasis. A greater proportion achieved mPASI75 and mPASI90 with Cal/BD foam than gel at weeks 4, 8, and 12 (57.1 vs. 35.4%; p = 0.006 and 15.6 vs. 12.2% at week 12, respectively); overall reduction in mPASI from baseline to week 12 was 64% with the foam vs. 51% with the gel. Overall reduction in body surface area at week 12 was 50% with the foam and 39% with the gel. Treatment success rates were higher with the Cal/BD foam than the gel at weeks 1, 2, 4, 8 (p = 0.0089), and 12, and a greater proportion of foam patients achieved a Dermatology Life-Quality Index score of 0/1 at weeks 4 (p = 0.004), 8, and 12 (p = 0.001). CONCLUSION: Cal/BD foam can be considered as a treatment option in some patients with moderate-to-severe psoriasis who are potential candidates for systemic therapy.

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.

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.