Research Spotlight

Dvir, D., T. Bourguignon, C. M. Otto, R. T. Hahn, R. Rosenhek, J. G. Webb, H. Treede, M. E. Sarano, T. Feldman, H. C. Wijeysundera, Y. Topilsky, M. Aupart, M. J. Reardon, G. B. Mackensen, W. Y. Szeto, R. Kornowski, J. S. Gammie, A. P. Yoganathan, Y. Arbel, M. A. Borger, M. Simonato, M. Reisman, R. R. Makkar, A. Abizaid, J. M. McCabe, G. Dahle, G. S. Aldea, J. Leipsic, P. Pibarot, N. E. Moat, M. J. Mack, A. P. Kappetein and M. B. Leon (2018). “Standardized Definition of Structural Valve Degeneration for Surgical and Transcatheter Bioprosthetic Aortic Valves.” Circulation 137(4): 388-399.

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Bioprostheses are prone to structural valve degeneration, resulting in limited long-term durability. A significant challenge when comparing the durability of different types of bioprostheses is the lack of a standardized terminology for the definition of a degenerated valve. This issue becomes especially important when we try to compare the degeneration rate of surgically inserted and transcatheter bioprosthetic valves. This document, by the VIVID (Valve-in-Valve International Data), proposes practical and standardized definitions of valve degeneration and provides recommendations for the timing of clinical and imaging follow-up assessments accordingly. Its goal is to improve the quality of research and clinical care for patients with deteriorated bioprostheses by providing objective and strict criteria that can be utilized in future clinical trials. We hope that the adoption of these criteria by both the cardiological and surgical communities will lead to improved comparability and interpretation of durability analyses.

Driver, S., M. Reynolds, A. Woolsey, L. Callender, P. K. Prajapati, M. Bennett and K. Kramer (2018). “Impact of a Community-Based Healthy Lifestyle Program on Individuals With Traumatic Brain Injury.” J Head Trauma Rehabil. Jan 30. [Epub ahead of print].

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OBJECTIVES: To examine adherence with and effect of an evidence-based healthy lifestyle intervention modified for individuals with traumatic brain injury (TBI). DESIGN: Pre-/postintervention without control. SETTING: Community. PARTICIPANTS: Eighteen individuals with TBI: primarily male (61%), white (67%), with private insurance (50%). Mean age was 45.6 +/- 12.3 years, weight 210 +/- 42.6 lb, and body mass index 31.8 +/- 4.6 (obese category) at baseline. INTERVENTIONS: The primary goal of the Diabetes Prevention Program Group Lifestyle Balance program is 5% to 7% weight loss through increased physical activity and improved dietary behaviors. MAIN OUTCOME MEASURE(S): Adherence (ie, session attendance and self-monitoring of dietary behaviors), physiologic changes (ie, weight loss, blood pressure; waist and arm circumference; and lipid profile), and quality of life (ie, self-reported health, quality of life, and step count). RESULTS: Average participant attendance (85% over 12 months) and self-monitoring (90% over 6 months) were high. Significant decreases were observed in diastolic blood pressure and waist and arm circumference from baseline through 12 months and from baseline to 3 months only for weight and total cholesterol. No significant changes were observed in self-reported health, quality of life, or step count. CONCLUSIONS: Participants demonstrated high adherence with the program, suggesting that individuals with TBI are able to successfully engage in the program and achieve significant weight loss and changes in key physiologic outcomes.

Deshpande, D., S. Srivastava, P. Bendet, K. R. Martin, K. N. Cirrincione, P. S. Lee, J. G. Pasipanodya, K. Dheda and T. Gumbo (2018). “Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.” Antimicrob Agents Chemother 62(2).

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The modern chemotherapy era started with Fleming’s discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the beta-lactamase inhibitor avibactam, benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M. tuberculosis was 6.80 +/- 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 +/- 2.31 mg/liter, while for intracellular M. tuberculosis it was 2.42 +/- 0.14 log10 CFU/ml at an EC50 of 6.70 +/- 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical M. tuberculosis strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of >/=65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth M. tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M. tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M. tuberculosis, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log10 CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

Cowey, C. L., F. X. Liu, J. Black-Shinn, K. Stevinson, M. Boyd, J. R. Frytak and S. W. Ebbinghaus (2018). “Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices.” J Immunother 41(2): 86-95.

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The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P<0.01) of decreased survival. Treatment-related toxicity was a discontinuation reason for 25% (29/117) of patients, and for 10 of these 29 patients (6% of the full-study cohort) treatment-related toxicity was the only reported reason. The real-world effectiveness and safety of pembrolizumab for advanced melanoma are consistent with clinical trial findings.

Copeland, L. A., C. S. Swendsen, D. M. Sears, A. A. MacCarthy and C. J. McNeal (2018). “Association between triglyceride levels and cardiovascular disease in patients with acute pancreatitis.” PLoS One 13(1): e0179998.

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Conventional wisdom supports prescribing “fibrates before statins”, that is, prioritizing treatment of hypertriglyceridemia (hTG) to prevent pancreatitis ahead of low-density lipoprotein cholesterol to prevent coronary heart disease. The relationship between hTG and acute pancreatitis, however, may not support this approach to clinical management. This study analyzed administrative data from the Veterans Health Administration for evidence of (1) temporal association between assessed triglycerides level and days to acute pancreatitis admission; (2) association between hTG and outcomes in the year after hospitalization for acute pancreatitis; (3) relative rates of prescription of fibrates vs statins in patients with acute pancreatitis; (4) association of prescription of fibrates alone versus fibrates with statins or statins alone with rates of adverse outcomes after hospitalization for acute pancreatitis. Only modest association was found between above-normal or extremely high triglycerides and time until acute pancreatitis. CHD/MI/stroke occurred in 23% in the year following AP, supporting cardiovascular risk management. Fibrates were prescribed less often than statins, defying conventional wisdom, but the high rates of cardiovascular events in the year following AP support a clinical focus on reducing cardiovascular risk factors.