Research Spotlight

Miles, D., D. Cameron, I. Bondarenko, L. Manzyuk, J. C. Alcedo, R. I. Lopez, S. A. Im, J. L. Canon, Y. Shparyk, D. A. Yardley, N. Masuda, J. Ro, N. Denduluri, S. Hubeaux, C. Quah, C. Bais and J. O’Shaughnessy (2017). “Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation.” Eur J Cancer 70: 146-155.

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AIM: MERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC). METHODS: In this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m2 on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-Ahigh populations. RESULTS: Of 481 patients randomised (242 placebo-paclitaxel; 239 bevacizumab-paclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51-0.91; log-rank p = 0.0007) in the intent-to-treat population (median 8.8 months with placebo-paclitaxel versus 11.0 months with bevacizumab-paclitaxel) and 0.64 (96% confidence interval, 0.47-0.88; log-rank p = 0.0038) in the pVEGF-Ahigh subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade >/=3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade >/=3: 11% versus 4%). CONCLUSION: The significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.

Roberts, W. C., V. S. Won, A. Vasudevan and J. M. Guileyardo (2016). “Causes of death and heart weights in adults at necropsy in a tertiary texas hospital, 2013-2015.” Am J Cardiol 118(11): 1758-1768.

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The causes of death and heart weights at death appear to be quite different in the USA today than in the first few decades of the last century. We determined the causes of death and heart weights at necropsy in 231 adults and compared the heart weights to those reported in several studies in the first half of the 20th century. Of the 231 patients, 91 (39%) died of a cardiovascular (CV) condition, and 140 (61%), of a non-CV condition. Of the 91 fatal CV disease cases, 48 had fatal coronary artery disease (CAD); of the remaining 183 cases without fatal CAD, 25 had narrowing >75% of 1 or more major epicardial coronary arteries. Thus, 73 of the 231 (32%) patients at necropsy had severe CAD. Comparison between the fatal CV and fatal non-CV cases disclosed variable age (mean 64 years vs mean 57 years) and heart weight (529 g vs 449 g) to be significantly different. Heart weight was found to be the only significantly variable between men and women. Comparison of the heart weights in this study to those recorded as “normal” hearts 75 to 115 years earlier showed that today’s “average” heart is much larger than those reported earlier. In contrast to the earlier studies, heart weight presently appears to increase with age and with an increase in body mass index. In conclusion, early studies in heart weight did not take into account today’s longer survival and therefore a high prevalence of systemic hypertension, diabetes mellitus, obesity (and cardiac adiposity), and the presence of atherosclerotic CAD. Additionally, the cause of death (CV vs non-CV) was rarely considered in the early studies of heart weight.

Muller, D. W., R. S. Farivar, P. Jansz, R. Bae, D. Walters, A. Clarke, P. A. Grayburn, R. C. Stoler, G. Dahle, K. A. Rein, M. Shaw, G. M. Scalia, M. Guerrero, P. Pearson, S. Kapadia, M. Gillinov, A. Pichard, P. Corso, J. Popma, M. Chuang, P. Blanke, J. Leipsic and P. Sorajja (2016). “Transcatheter Mitral Valve Replacement for Patients With Symptomatic Mitral Regurgitation: A Global Feasibility Trial.” J Am Coll Cardiol. Dec 20. pii: S0735-1097(16)37122-4. doi: 10.1016/j.jacc.2016.10.068. [Epub ahead of print]

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BACKGROUND: Symptomatic mitral regurgitation (MR) is associated with high morbidity and mortality that can be ameliorated by surgical valve repair or replacement. Despite this, many patients with MR do not undergo surgery. Transcatheter mitral valve replacement (TMVR) may be an option for selected patients with severe MR. OBJECTIVES: This study aimed to examine the effectiveness and safety of TMVR in a cohort of patients with native valve MR who were at high risk for cardiac surgery. METHODS: Patients underwent transcatheter, transapical delivery of a self-expanding mitral valve prosthesis and were examined in a prospective registry for short-term and 30-day outcomes. RESULTS: Thirty patients (age 75.6 +/- 9.2 years; 25 men) with grade 3 or 4 MR underwent TMVR. The MR etiology was secondary (n = 23), primary (n = 3), or mixed pathology (n = 4). The Society of Thoracic Surgeons Predicted Risk of Mortality was 7.3 +/- 5.7%. Successful device implantation was achieved in 28 patients (93.3%). There were no acute deaths, strokes, or myocardial infarctions. One patient died 13 days after TMVR from hospital-acquired pneumonia. Prosthetic leaflet thrombosis was detected in 1 patient at follow-up and resolved after increased oral anticoagulation with warfarin. At 30 days, transthoracic echocardiography showed mild (1+) central MR in 1 patient, and no residual MR in the remaining 26 patients with valves in situ. The left ventricular end-diastolic volume index decreased (90.1 +/- 28.2 ml/m2 at baseline vs. 72.1 +/- 19.3 ml/m2 at follow-up; p = 0.0012), as did the left ventricular end-systolic volume index (48.4 +/- 19.7 ml/m2 vs. 43.1 +/- 16.2 ml/m2; p = 0.18). Seventy-five percent of the patients reported mild or no symptoms at follow-up (New York Heart Association functional class I or II). Successful device implantation free of cardiovascular mortality, stroke, and device malfunction at 30 days was 86.6%. CONCLUSIONS: TMVR is an effective and safe therapy for selected patients with symptomatic native MR. Further evaluation of TMVR using prostheses specifically designed for the mitral valve is warranted. This intervention may help address an unmet need in patients at high risk for surgery.

Goraya, N. and D. E. Wesson (2017). “Is dietary red meat kidney toxic?” J Am Soc Nephrol 28(1): 5-7.

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Observational studies support that “unhealthy” compared with “healthy” diets are associated with increased risk for a variety of chronic diseases,1 including CKD.2,3 Consequently, investigators continue to try to identify dietary factors which promote CKD and/or exacerbate its progression, as well as identify ones which protect kidney health and avoid or reduce CKD-related morbidity and mortality. Success in these endeavors is anticipated to add to the armamentarium of strategies to slow or stop nephropathy progression, with the ultimate goal of preventing CKD and its devastating consequences altogether. Dietary protein has emerged as a target with therapeutic promise; restriction of total dietary protein in some small-scale studies suggests that it slows nephropathy progression.4 Despite this potential benefit, total protein restriction leads to protein-energy wasting in some CKD patients.5 Furthermore, the largest study to examine the effect of total dietary protein restriction on nephropathy progression, the Modification of Diet in Renal Disease Study, showed that GFR decline at three years was no different between subjects given a low protein diet (0.58 g/kg per day) and a usual protein diet (1.3 g/kg per day).6 These data have led investigators to examine if the type or source of ingested protein might instead mediate a dietary effect on kidney health.

Farmer, D., J. M. Tessier, J. M. Sanders, R. G. Sawyer, O. D. Rotstein, E. P. Dellinger, P. A. Lipsett, J. Cuschieri, P. Miller, C. H. Cook, C. A. Guidry, R. Askari, B. J. Moore and T. M. Duane (2016). “Age and its impact on outcomes with intra-abdominal infection.” Surg Infect (Larchmt): 2016 Dec [Epub ahead of print].

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BACKGROUND: Age has been shown to play a significant role in the etiology of complicated intra-abdominal infections (cIAIs), but the correlation between age and outcomes after therapy was not investigated in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial. PATIENTS AND METHODS: Data were obtained by post hoc analysis of the STOP-IT trial database. Patients were stratified by age <65 or >/=65 years. Primary outcomes were surgical site infection (SSI), recurrent IAI (recIAI), and death. Multivariable analysis was performed to identify independent predictors of outcomes. RESULTS: There were 398 subjects <65 and 120 >/= 65 years. Overall baseline characteristics of the two groups were similar. The site of infection was similar between groups except: Colon or rectum (48.3% vs. 29.9%, p = 0.0002) and biliary tree (16.7% vs. 9.1%, p = 0.02), which were more common in the older group, whereas small intestine (6.7% vs. 16.3%, p = 0.008) and appendix (4.2% vs.17.1%, p = 0.0004) were more common in the younger group. Among the primary outcomes, only death was significantly different between the age groups and was more prevalent in the >/=65 years group (4 [3.3%] vs. 1 [0.3%], p = 0.01). Surgical site infection (9.2% vs. 7.3%, p = 0.50), recIAI (15.8% vs. 14.4%, p = 0.69), and a composite outcome (26.7% vs. 20.4%, p = 0.14) were statistically similar between the age groups, and this remained true when controlling for other co-variables. Multivariable analyses did not reveal age as an independent predictor of the composite or individual outcomes. CONCLUSION: Patients with a more advanced age demonstrated variable sources of infection relative to the younger cohort, yet received similar treatments. Patient age was not an independent predictor of the undesired cIAI outcomes. These findings suggest that advanced age itself does not play a significant role in predicting these adverse outcomes for cIAIs and does not necessitate an altered treatment tactic.