Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: Subgroup analysis of the DISTINCT randomised trial

The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy

Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known

High perioperative morbidity and mortality in patients with malignant nonfunctional adrenal tumors

Both functional (hormone hypersecreting) and nonfunctional (nonhypersecreting) adrenal tumors can have benign or malignant pathology. This study compares perioperative in-hospital outcomes after adrenalectomy in patients with benign versus malignant nonfunctional primary adrenal tumors. A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample database (2006-2011) to identify patients who underwent unilateral open or laparoscopic adrenalectomy for nonfunctional primary adrenal tumors. Patients were subdivided by benign and malignant final pathology. Demographics, comorbidities, and perioperative complications were compared between groups using bivariate and multivariate logistic regression. Of 23,297 patients, 89.7% (n = 20,897) had benign tumors, whereas 10.3% (n = 2400) had malignant tumors. Those with malignant tumors had higher Charlson Comorbidity Index scores and were more likely to undergo adrenalectomy at high volume centers. For both laparoscopic and open approach, patients with malignant nonfunctional tumors had higher rates of intraoperative complications including vascular and splenic injury (P < 0.01), as well as postoperative complications including hematoma, shock, acute kidney injury, venous thromboembolism, and pneumothorax (P < 0.01). In addition, the malignant group had higher rates of blood transfusions, longer hospital stay, and higher in-hospital mortality (P < 0.05) than benign counterparts. On risk-adjusted multivariate analysis, malignant nonfunctional primary adrenal tumors were independently associated with increased risk of complications following adrenalectomy. Patients with malignant nonfunctional primary adrenal tumors have higher perioperative morbidity and mortality compared to patients with benign nonfunctional adrenal tumors. Such patients should be medically optimized before adrenalectomy, and surgeons must remain vigilant in preventing perioperative complications

Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression.

Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI in vivo Correlative studies in human specimens demonstrated that cathepsin B-producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400-14. ©2017 AACR

Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: Distinct randomized trial results

OBJECTIVES: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) aimed to determine the dose-response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension. METHODS: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP. RESULTS: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose-response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [-23.8/-16.5 mmHg; P < 0.01 versus placebo (-5.3/-6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.). CONCLUSION: N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults

In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response