Patterns of response in patients with advanced melanoma treated with Pembrolizumab (MK-3475) and evaluation of immune-related response criteria (irRC)

Unique patterns of response have been observed with immunotherapies. Notably, objective response and prolonged disease stabilization can occur after an initial increase in tumor burden. irRC were developed to better characterize response to immunotherapy based on data for Ipilimumab. We previously showed that patients with melanoma treated with the anti-PD-1 monoclonal antibody Pembrolizumab may also experience unique patterns of response and that conventional response criteria may underestimate the therapeutic benefit of Pembrolizumab [1]. We updated our initial analysis to include an additional 6 months of follow-up

Effect of Body Mass Index on Treatment of Complicated Intra-Abdominal Infections in Hospitalized Adults: Comparison of Ertapenem with Piperacillin-Tazobactam

Background: Complicated intra-abdominal infections (cIAI) are a common problem in surgical practice. The effect of body mass index (BMI) on the outcome is poorly understood. We compared the association of BMI and type of antibiotic therapy for cIAI described in a previously published trial of ertapenem vs. piperacillin-tazobactam (Namias N, Solomkin JS, Jensen EH, et al. Randomized, multicenter, double-blind study of efficacy, safety, and tolerability of intravenous ertapenem versus piperacillin/tazobactam in treatment of complicated intra-abdominal infections in hospitalized adults. Surg Infect 2007;8:15–28). Methods: A post-hoc analysis was performed using data obtained from the published study. The effect of BMI and type of antibiotic used for therapy were calculated for clinically favorable outcomes at early follow-up assessment (EFA). Results: The 231 patients who were microbiologically evaluable at EFA were stratified by BMI (<30 or ≥30 kg/m 2 ). Twelve patients were excluded because of missing BMI data, leaving 219 patients for analysis. There were some differences in baseline characteristics between patients with a BMI <30 kg/m 2 , including the source of intra-abdominal infection (more appendicitis in BMI <30 group; p=0.01) and gender (more men in the BMI <30 group; p=0.03). There was no difference in cure rates between the groups (82.9% for BMI <30 kg/m 2 vs. 74.5% for those with BMI ≥30 kg/m 2 ; 8% difference in proportions, 95% confidence interval [CI] −5%, 25%). There was an 80% favorable clinical response to ertapenem in the BMI <30 group compared with an 81% favorable rate in the BMI ≥30 group (−1% difference in proportions; 95% CI −22%, 19%). This compared with an 86% favorable response rate to piperacillin-tazobactam in the BMI <30 group vs. a 65% favorable clinical response rate in the BMI ≥30 group (21% difference in proportions; 95% CI −1%, 47%). Conclusions: There was no difference in the cure rate of patients with cIAI in the BMI <30 and BMI ≥30 kg/m 2 groups. There were no statistically significant differences in the likelihood of response to an antibiotic regimen. However, there was a nominally 21% lower cure rate in the high BMI group receiving piperacillin-tazobactam (86% vs. 65%; 21% difference in proportions; 95% CI −1%, 47%), whereas there was only a 1% difference in the cure rate between BMI groups in the patients receiving ertapenem. This difference may be related to gender and etiology of infection. Although limited by the small number of high BMI patients and post-hoc methodology, these results merit consideration of the design of future prospective antibiotic trials to include stratification for BMI and consideration of the effect of BMI on pharmacokinetics and pharmacodynamics

Postdose 3 G1 serum neutralizing antibody as correlate of protection for pentavalent rotavirus vaccine

Although clinical trials of the pentavalent rotavirus vaccine (RotaTeq®, RV5) have demonstrated efficacy against RV gastroenteritis (RGE) in low and high-income settings, a clear correlate of protection or a measure of immune response that could predict efficacy has yet to be identified. This is the first time that immunogenicity data with both serum neutralized antibody (SNA) titers and anti-RV IgA titers from several clinical efficacy trials were pooled to provide a unique context for evaluating the correlation between immunogenicity and RGE risk or efficacy of RV5. The correlation between immunogenicity and RGE risk is evaluated with data at the individual subject level. The analyses show that higher Postdose 3 (PD3) G1 SNA titers are associated with lower odds of contracting any RGE. The correlation between immunogenicity and efficacy is assessed using aggregated population level data, which shows higher efficacy associated with higher PD3 G1 SNA geometric mean titer (GMT) ratio (between RV5 and placebo) and PD3 serum anti-RV IgA GMT ratio. Among high-income countries, efficacy plateaus over the range of PD3 G1 SNA GMT ratios and PD3 serum anti-RV IgA GMT ratios. From both individual- and population-level analyses, PD3 G1 SNA titers correlated most closely with the RGE risk or efficacy for RV5

Combining ECG criteria for left ventricular hypertrophy improves risk prediction in patients with hypertension

Background: Patients with hypertension with ECG left ventricular hypertrophy (LVH) have higher cardiovascular morbidity and mortality, but single ECG criteria may underestimate risk. Whether continued presence or new development of ECG LVH by 2 criteria can further concentrate risk during blood pressure lowering is unclear. Methods and Results: Incident stroke, myocardial infarction, cardiovascular death, the composite of these outcomes, and all‐cause mortality were examined in relation to the presence of on‐treatment ECG LVH by Cornell product and/or Sokolow‐Lyon voltage during a mean of 4.8±0.9 years follow‐up in 9193 patients with hypertension randomized to losartan‐ or atenolol‐based regimens. Patients were categorized into 4 groups according to the presence or absence of ECG LVH by each criterion at baseline and yearly during the study. At baseline, LVH by both criteria was present in 960 patients (10.4%). Compared with the absence of ECG LVH by both criteria, persistence or development of ECG LVH by both criteria entered as a time‐varying covariate was associated with >3‐fold increased risks of events in multivariable Cox analyses adjusting for randomized treatment, baseline risk factors, and on‐treatment heart rate and systolic and diastolic blood pressures. Patients with ECG LVH by either Cornell product or Sokolow‐Lyon voltage had 45% to 140% higher risks of all end points. Conclusions: Persistence or development of ECG LVH by both Cornell product and Sokolow‐Lyon voltage criteria during antihypertensive therapy is associated with markedly increased risks of cardiovascular end points and all‐cause mortality. Further study is indicated to determine whether additional therapy in these patients can reduce their risk

On-treatment HDL cholesterol predicts incident atrial fibrillation in hypertensive patients with left ventricular hypertrophy

Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined. Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels. Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90–1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16–2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78–1.31). Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF. Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=