Search

Supplementary Figures and Tables

Purpose:The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors.Patients and Methods:Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing).Results:The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 μg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6–30+ months).Conclusions:NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.See related commentary by Lyerly et al., p. 9

Objective:Assessing performance validity is imperative in both clinical and research contexts as data interpretation presupposes adequate participation from examinees. Performance validity tests (PVTs) are utilized to identify instances in which results cannot be interpreted at face value. This study explored the hit rates for two frequently used PVTs in a research sample of individuals with and without histories of bipolar disorder (BD).Method:As part of an ongoing longitudinal study of individuals with BD, we examined the performance of 736 individuals with BD and 255 individuals with no history of mental health disorder on the Test of Memory Malingering (TOMM) and the California Verbal Learning Test forced choice trial (CVLT-FC) at three time points.Results:Undiagnosed individuals demonstrated 100% pass rate on PVTs and individuals with BD passed over 98% of the time. A mixed effects model adjusting for relevant demographic variables revealed no significant difference in TOMM scores between the groups, a = .07, SE = .07, p = .31. On the CVLT-FC, no clinically significant differences were observed (ps < .001).Conclusions:Perfect PVT scores were obtained by the majority of individuals, with no differences in failure rates between groups. The tests have approximately >98% specificity in BD and 100% specificity among non-diagnosed individuals. Further, nearly 90% of individuals with BD obtained perfect scores on both measures, a trend observed at each time point.

There is debate in the literature regarding how manipulating the focus of attention (FOA) influences ground reaction forces during the standing long jump (SLJ) and gaps in understanding as to which phases of the SLJ are affected (takeoff, flight, and landing) and whether FOA manipulation benefits remain when tasks are performed in fixed body postures.

Background NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w). Methods This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety. Results Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging. Conclusion Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546).

Der Fachkraftemangel im Gesundheitswesen macht es dem OP-Management in vielen Kliniken schwer, den unterschiedlichen Anforderungen und Herausforderungen gerecht zu werden. Durch wertschatzenden Umgang im Miteinander, eine effiziente OP-Ablaufsteuerung, Transparenz und eine gute Kommunikation generiert man hochmotivierte und zufriedene OP-Teams, die wiederum eine hohe Prozess- und Ergebnisqualitat liefern. Die Tatigkeiten sind vielfaltig, Entscheidungen mal groser und mal kleiner, doch alle haben ihre Funktion im Rahmen des OP-Managements. Gut funktionierende Ablaufe und ein ausgezeichnetes Management werden sichtbar in den alltaglichen Aufgaben und Erleben eines OP-Tages.

This cohort study assesses whether increasing time to surgery is associated with sentinel lymph node status in patients with cutaneous melanoma stage T1b or higher.

Funder: Oticon Centre of Excellence for Hearing and Speech Sciences (CHeSS), It has been suggested that a specialized high-temporal-acuity brainstem pathway can be activated by stimulating more apically in the cochlea than is achieved by cochlear implants (CIs) when programmed with contemporary clinical settings. We performed multiple experiments to test the effect on pitch perception of phantom stimulation and asymmetric current pulses, both supposedly stimulating beyond the most apical electrode of a CI. The two stimulus types were generated using a bipolar electrode pair, composed of the most apical electrode of the array and a neighboring, more basal electrode. Experiment 1 used a pitch-ranking procedure where neural excitation was shifted apically or basally using so-called phantom stimulation. No benefit of apical phantom stimulation was found on the highest rate up to which pitch ranks increased (upper limit), nor on the slopes of the pitch-ranking function above 300 pulses per second (pps). Experiment 2 used the same procedure to study the effects of apical pseudomonophasic pulses, where the locus of excitation was manipulated by changing stimulus polarity. A benefit of apical stimulation was obtained for the slopes above 300 pps. Experiment 3 used an adaptive rate discrimination procedure and found a small but significant benefit of both types of apical stimulation. Overall, the results show some benefit for apical stimulation on temporal pitch processing at high pulse rates but reveal that the effect is smaller and more variable across listeners than suggested by previous research. The results also provide some indication that the benefit of apical stimulation may decline over time since implantation.