Henk Johan Streefkerk

The authors wish to make the following corrections to this paper

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm² on 400 cm², with a mean C_avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C_avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

TPS6590 Background: Effective targeted therapies are needed for HNSCC that is lethal despite recent advances with immunotherapy. A major challenge to personalize treatment is that most genomic alterations are in tumor suppressors, including NOTCH1 that is mutated in ~20% of HNSCC. We recently published that HNSCC cell lines harboring NOTCH1 LOF mutations undergo cell death in vivo and in vitro following PI3K inhibition, in contrast to PIK3CA mutant cell lines that merely undergo cell cycle arrest when exposed to the same drugs. Based on these results we initiated a novel genomic biomarker-driven phase II clinical trial treating NOTCH1 mutant HNSCC pts with the dual PI3K/mTOR inhibitor bimiralisib (PQR309). Methods: The primary objective is to determine the objective response rate (ORR) of recurrent/metastatic HNSCC harboring NOTCH1 LOF mutations to bimiralisib. Pts who have already received standard platinum chemotherapy and immunotherapy will receive bimiralisib orally twice per wk unless progression or intolerable toxicity occurs. Tumors will be evaluated using RECIST q 6 wks. A Simon’s optimal two-stage design is used. To have 80% power to detect an ORR of 30%, (one-sided α = 0.05, β = 0.20) 10 pts will be enrolled in the first stage. If ≤1 pts respond, the trial will be closed for futility. If ≥2 pts have an OR, the study will enroll an additional 19 pts in the second stage. The null hypothesis (ORR ≤ 10%) will be rejected if ≥ 6 in 29 pts have an OR. Seven pts have enrolled. The algorithm for determining NOTCH1 mutation function is based on the patterns of mutations in HNSCC vs. leukemia where mutations are activating. It may be difficult to determine whether NOTCH1 mutations are homo- or heterozygous due to normal cell contamination. Therefore, levels of activated NOTCH1 in pretreatment tumors may be assessed by IHC with an antibody against activated NOTCH1 (NICD). In parallel with the trial, to further confirm NOTCH1 LOF, we can use site-directed mutagenesis to re-create NOTCH1 mutations from trial pts that will then be introduced into NOTCH1-null cell lines to assay for NICD and growth inhibition with culture on NOTCH1 ligand. All pts will have serial collection of blood for pharmacokinetics and for ctDNA to examine clonal evolution associated with acquired resistance. Samples with high NOTCH1 mutation ctDNA VAF will be analyzed by WES and compared with pretreatment tissue. In the second stage, IHC and WES may be performed on pre- and post- treatment (day 15 and progression) tissue to examine pharmacodynamics and mechanisms of resistance. Clinical trial information: NCT03740100.

Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce.

Data incompleteness in pharmacovigilance (PV) health records limits the use of current causality assessment methods for drug-induced liver injury (DILI). In addition to the inherent complexity of this adverse event, identifying cases of high causal probability is difficult.

To establish the response of cardiac flow and function to adenosine stress using phase-contrast magnetic resonance (pcMR) and cine steady-state free precession (SSFP) cardiac magnetic resonance (CMR). Healthy volunteers (n = 10) were scanned on 1.5T at rest and under adenosine stress utilizing short-axis SSFP sequences and pcMR of the aorta and pulmonary trunk. Adenosine-induced increase in heart rate was 62.7% (P < 0.001). Left and right-ventricular stroke volumes (SVs) increased by 12.2% (P = 0.048) and 11.9% (P = 0.044), left-ventricular ejection fraction by 11.8% (P = 0.002), and left-ventricular and right-ventricular cardiac output (CO) by 81.0% (P < 0.001) and 81.8% (P = 0.005). Average flow velocities in the ascending aorta and pulmonary trunk increased by 77.3% (P < 0.001) and 73.6% (P < 0.001), and peak flow velocities in the ascending aorta and pulmonary trunk by 27.2% (P < 0.001) and 22.4% (P = 0.003). End-systolic volumes in the left ventricle (LV) and right ventricle (RV) decreased by 16.4% (P = 0.020) and 19.2% (P = 0.028). Planimetric cine SSFP and pcMR-derived SV showed an excellent correlation. In healthy volunteers, response to adenosine stress is characterized by an increase in heart rate, CO and SV of both ventricles. Excellent correlation is demonstrated between these increases and the increased blood flow velocities in the aorta and the pulmonary trunk. Thus, results support the use of flow measurements as an internal control of planimetric measurements of ventricular SV and CO.

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis. Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m² high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations. Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration–time curve (AUC) from time zero to infinity was 61 % (haemodialysis at 48 h) and 41 % (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17 % higher (haemodialysis at 48 h) and 16 % lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2 % of oral clearance and the mean fraction eliminated from circulation was 10 and 12 % in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred. The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

To practice microsurgical skills, several experimental models are available that diminish the need for experimental animals. We defined criteria with which such models should comply, and we tested whether the models described in literature, as well as our own practice model, comply with these criteria. We defined the criteria to which these models should comply, and we performed a literature search on microvascular practice models. During the development of the Excimer laser-assisted nonocclusive anastomosis technique, we designed our own Excimer laser-assisted nonocclusive anastomosis Practice Model (EPM) according to those criteria, and we compared that model with the models described in the literature. All practice models could be categorized into three groups: beginner, moderate, and advanced. Our EPM complies with almost all criteria defined in the beginner and moderate groups and has much in common with the models that are categorized in the advanced group. In consideration of the methods to learn microvascular surgical techniques, the EPM can be used for a very long time before the need for living animals arises. This last aspect remains an inescapable condition for practicing microsurgical skills. However, with use of the EPM or another practice model, the amount of experimental animals can be drastically reduced.