Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment

The Overfilled Face

The desire for longevity, beauty, and health is as old as the history of human culture. Minimizing tissue damage and invasive surgeries has led to a variety of options in the 21 (st) century medicine. In the past 20 years, hyaluronic acid filler injections have thus become a popular modality of treatment for facial rejuvenation due to low costs for patients with immediately visible results. Ideally, the treated face looks natural. We aim at stopping time, maybe tweaking the handles of our clocks a bit backward to counteract aging processes, but creating a natural look and maintaining the individual appearance

Objective Assessment of Nasal Patency

The aim to objectify nasal airflow and patency is ongoingmany methods have been suggested, often lacking clinical relevance or showing weak correlations with patients' symptoms. It is crucial to thoroughly consult our patients presenting with nasal obstructionand to inform them about realistic possible surgical outcomes. Often, a perfect-looking internal nose with a straight septum and normal-appearing turbinates does not guarantee a happy, symptom-free owner. A review of the literature and the current technical market is presented here to facilitate the rhinosurgeon's decision to perform pre- and postoperative objective measurements of nasal airflow. Recommendations by the societies have been included

Taste-strip gustometry in cochlear implanted patients

Objective Investigation of the gustatory function in a large cohort of cochlear implanted patients using lateralized taste-strip tests. Patients and Methods One hundred and seven unilaterally or bilaterally profoundly hearing impaired or deaf patients who received cochlear implants (n = 113) were included in this study. Data on gustometry, subjective gustatory dysfunction, and the detailed surgical procedure were acquired retrospectively. Gustatory function, assessed using lateralized taste-strip tests, was performed the day before, 3 days after cochlear implantation, and on the day of the initial CI adjustment (39 days +/- 7.3 SD). Results Averaged taste-strip scores of the cohort declined significantly from preoperatively 12.3 [11.8; 12.7] (mean [95% confidence intervals]) to 10.5 [9.7; 11.2] on the implanted side about 6 weeks after surgery. Patients with intraoperatively exposed and rerouted, or a severed, chorda tympani nerve (CTN) showed significantly reduced unilateral postoperative scores (10.1 [8.8; 11.4] and 9.3 [8.1; 10.5], respectively), when compared to not exposing or to leaving a bony layer over the CTN. Total taste-strip test scores showed a significant decline 6 weeks postoperatively in CI-patients expressing a subjective gustatory dysfunction (from 23.6 [21.4; 25.8] to 17.5 [14.2; 20.8]), as opposed to patients with a documented subjectively normal taste. Conclusion We consider postoperative gustatory dysfunction as a relevant side effect post cochlear implantation, at least within the first month. Taste-strip based gustometry is a suitable diagnostic tool to assess taste function in CI patients and is recommended to be performed routinely. Level of Evidence 3, retrospective, nonrandomized follow-up study

On the Sustainability of Guideline Implementation

Background Allergic rhinitis (AR) is a disorder associated with a high financial burden and is considered an important risk factor for the development of asthma. The ARIA guideline (Allergic Rhinitis and its Impact on Asthma) addresses this problem and provides recommendations for treating allergic rhinitis. The objective of the present analysis was to estimate the compliance with guidelines among ear, nose and throat (ENT) specialists and general practitioners.Methods The data of 121,593 patients collected during 9 prospective observational studies carried out from 1998 to 2005 were examined using individual patient data meta-analysis method.Results Only 14.8% of patients with allergic rhinitis were treated according to the recommendations. Of the others, 73.8% received insufficient treatment. In addition, 36.1% of the patients who were treated by ENT specialists received therapy according to guidelines, whereas only 16% of the general practitioners heeded the recommendations. Patients suffering from rhinitis and asthma were treated by ENT specialists according to the ARIA guideline in 50% of cases. It could be observed that the rate of guideline compliance was highest in the year of publication.Conclusion The results are evidence of the successful implementation process of the ARIA guidelines. However, they have not yet found their way into the daily routine of general practitioners. Keywords: allergic rhinitis, treatment, guidelines, compliance, ARIA, ENT specialist

Assessment techniques of nasal patency

The need for objective assessment of nasal patency in the fields of rhinosurgery and allergy has led to the development of various methods for the evaluation of nasal patency. These methods include active anterior rhinomanometry, PNIF, acoustic rhinometry, rhinostereometry, optical rhinometry, minimal cross- sectional area endoscopy, nasal sound spectral analysis, magnetic resonance imaging and numerical flow simulation. This article provides a brief overview of currently common procedures