Research Spotlight

Posted December 15th 2016

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.

Thomas Hutson D.O.

Thomas Hutson D.O.

Rini, B. I., D. F. McDermott, H. Hammers, W. Bro, R. M. Bukowski, B. Faba, J. Faba, R. A. Figlin, T. Hutson, E. Jonasch, R. W. Joseph, B. C. Leibovich, T. Olencki, A. J. Pantuck, D. I. Quinn, V. Seery, M. H. Voss, C. G. Wood, L. S. Wood and M. B. Atkins (2016). “Society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.” J Immunother Cancer 4: 81.

Full text of this article.

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.


Posted December 15th 2016

Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial.

Milton Packer M.D.

Milton Packer M.D.

Desai, A. S., O. Vardeny, B. Claggett, J. J. McMurray, M. Packer, K. Swedberg, J. L. Rouleau, M. R. Zile, M. Lefkowitz, V. Shi and S. D. Solomon (2016). “Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: A secondary analysis of the paradigm-hf trial.” JAMA Cardiol: 2016 Nov [Epub ahead of print].

Full text of this article.

Importance: Consensus guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for selected patients with symptomatic heart failure and reduced ejection fraction (HFrEF) to reduce morbidity and mortality; however, the use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system increases the risk of hyperkalemia. Objective: To determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF is reduced by sacubitril/valsartan in comparison with enalapril. Design, Setting, and Participants: The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8399 patients with chronic HF, New York Heart Association class II to IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016. Main Outcomes and Measures: Incident hyperkalemia and severe hyperkalemia. Results: In comparison with the 3728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs 2.2 per 100 patient-years; HR, 1.37 [95% CI, 1.06-1.76]; P = .02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43 [95% CI, 1.13-1.81]; P = .003). Conclusions and Relevance: Among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF.


Posted December 15th 2016

Improving National Trauma Data Bank® coding data reliability for traumatic injury using a prospective systems approach.

Michael L. Foreman M.D.

Michael L. Foreman M.D.

Ewing, M., G. A. Funk, A. M. Warren, N. Rapier, M. Reynolds, M. Bennett, C. Mastropieri and M. L. Foreman (2016). “Improving national trauma data bank(r) coding data reliability for traumatic injury using a prospective systems approach.” Health Informatics J 22(4): 1076-1082.

Full text of this article.

Trauma centers manage an active Trauma Registry from which research, quality improvement, and epidemiologic information are extracted to ensure optimal care of the trauma patient. We evaluated coding procedures using the Relational Trauma Scoring System to determine the relative accuracy of the Relational Trauma Scoring System for coding diagnoses in comparison to the standard retrospective chart-based format. Charts from 150 patients admitted to a level I trauma service were abstracted using standard methods. These charts were then randomized and abstracted by trauma nurse clinicians with coding software aide. For charts scored pre-training, percent correct for the trauma nurse clinicians ranged from 52 to 64 percent, while the registrars scored 51 percent correct. After training, percentage correct for the trauma nurse clinicians increased to a range of 80-86 percent. Our research has demonstrated implementable changes that can significantly increase the accuracy of data from trauma centers.


Posted December 15th 2016

Impingement of Single-Tilting Disc Mitral Prosthesis During Transcatheter Aortic Valve Replacement.

J. Michael DiMaio M.D.

J. Michael DiMaio M.D.

Squiers, J. J., K. R. Hebeler, J. M. DiMaio, P. Ogbue, M. Szerlip and W. T. Brinkman (2016). “Impingement of single-tilting disc mitral prosthesis during transcatheter aortic valve replacement.” Ann Thorac Surg 102(6): e529-e531.

Full text of this article.

An 80-year-old woman with a medical history of mitral valve replacement with single-tilting disc prosthesis underwent transcatheter aortic valve replacement (TAVR). The tilting disc was noted to have abnormal motion after re-ballooning of the TAVR valve. Cardiopulmonary bypass was initiated, and the procedure was converted to surgical aortic valve replacement. After removal of the TAVR valve, the tilting disc moved freely. Although TAVR in patients with mitral prostheses is technically feasible, particular caution is necessary, and postdeployment dilation should be avoided.


Posted December 15th 2016

Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection.

Jason A. Skinner Ph.D.

Jason A. Skinner Ph.D.

Gideon, H. P., J. A. Skinner, N. Baldwin, J. L. Flynn and P. L. Lin (2016). “Early whole blood transcriptional signatures are associated with severity of lung inflammation in cynomolgus macaques with mycobacterium tuberculosis infection.” J Immunol 197(12): 4817-4828.

Full text of this article.

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20-56 d postinfection, during which fluctuation of innate and adaptive immune response-related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [18F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection.