Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. Cancers 2022, 14, 1510.

The authors wish to make the following corrections to this paper [...].

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial.

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 Cavg 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 Cavg 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.

Preliminary Results of a Novel Algorithmic Method Aiming to Support Initial Causality Assessment of Routine Pharmacovigilance Case Reports for Medication-Induced Liver Injury: The PV-RUCAM.

INTRODUCTION: 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. OBJECTIVE: The aim was to evaluate the performance of an improved, algorithmic and standardised method called the Pharmacovigilance-Roussel Uclaf Causality Assessment Method (PV-RUCAM), to support assessment of suspected DILI. Performance was compared in different settings with regard to applicability and differentiation capacity. METHODS: A PV-RUCAM score was developed based on the seven sections contained in the original RUCAM. The score provides cut-off values for or against DILI causality, and was applied on two datasets of bona fide individual case safety reports (ICSRs) extracted randomly from clinical trial reports and a third dataset of electronic health records from a global PV database. The performance of PV-RUCAM adjudication was compared against two standards: a validated causality assessment method (original RUCAM) and global introspection. RESULTS: The findings showed moderate agreement against standards. The overall error margin of no false negatives was satisfactory, with 100% sensitivity, 91% specificity, a 25% positive predictive value and a 100% negative predictive value. The Spearman's rank correlation coefficient illustrated a statistically significant monotonic association between expert adjudication and PV-RUCAM outputs (R = 0.93). Finally, there was high inter-rater agreement (K w = 0.79) between two PV-RUCAM assessors. CONCLUSION: Within the PV setting of a pharmaceutical company, the PV-RUCAM has the potential to facilitate and improve the assessment done by non-expert PV professionals compared with other methods when incomplete reports must be evaluated for suspected DILI. Prospective validation of the algorithmic tool is necessary prior to implementation for routine use.

Pharmacokinetics of aliskiren in patients with end-stage renal disease undergoing haemodialysis.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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 m(2) 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. RESULTS: 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. CONCLUSION: 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.

The excimer laser-assisted nonocclusive anastomosis practice model: development and application of a tool for practicing microvascular anastomosis techniques.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long-term reendothelialization of excimer laser-assisted nonocclusive anastomoses compared with conventionally sutured anastomoses in pigs.

OBJECT: In contrast to conventional anastomosis methods, the excimer laser-assisted nonocclusive anastomosis (ELANA) technique involves a platinum ring and intima-adventitia apposition with a rim of medial and adventitial layers exposed to the bloodstream. The authors assessed the reendothelialization of porcine carotid arteries through ELANA compared with conventional anastomosis by using scanning electron microscopy. METHODS: In 28 pigs a bypass with one ELANA and one conventional anastomosis was made on the left common carotid artery. All patent anastomoses were evaluated intraoperatively with the aid of an ultrasonographic flowmeter and postoperatively by using scanning electron microscopy at 2 weeks, 2 months, 3 months, and 6 months thereafter. Twenty-four of 28 bypasses (48 of 56 end-to-side anastomoses) were fully patent at the time of evaluation. On scanning electron microscopic evaluation of the bypasses, all 48 patent anastomoses showed complete reendothelialization, including all 24 ELANAs in which the endothelium covered the rim and the laser-ablated edge completely. No endothelial difference was observed between conventional anastomoses and ELANAs, aside from the obvious anatomical differences like the platinum ring, which had been completely covered with endothelium. At 6 months postsurgery, remodeling of the ELANA was observed, leaving the ring covered with a layer of endothelium as the most narrow part of the anastomosis. CONCLUSIONS: In long-term experiments, ELANA allows reendothelialization comparable to that achieved with conventional anastomosis. Considering its nonocclusive and high-flow characteristics, the ELANA technique is preferable in cerebral revascularization procedures.

Construction of a new posterior communicating artery in a patient with poor posterior fossa circulation: technical case report.

OBJECTIVE AND IMPORTANCE: The carotid and the vertebrobasilar circulation were connected, effectively creating a new posterior communicating artery (PComA). The excimer laser-assisted nonocclusive anastomosis technique is a new anastomosis technique whereby formerly untreatable patients may be treated with an intracranial artery-to-intracranial artery bypass procedure. This report is the first one in which an angiographically proved patent internal carotid artery-posterior cerebral artery segment P1 bypass is presented. CLINICAL PRESENTATION: Our patient presented with repeated episodes of vertebrobasilar ischemia because of vertebral artery occlusion and stenosis. INTERVENTION: An internal carotid artery-posterior cerebral artery segment P1 bypass procedure was performed. Because the patient experienced transient ischemia in the left cerebral hemisphere at the end of postoperative angiography procedure, no radiological intervention was performed, and the patient refused to undergo a new radiological intervention at a later stage. TECHNIQUES: Both anastomoses were made using the excimer laser-assisted nonocclusive anastomosis technique. CONCLUSION: Intraoperative flowmetry was performed using an ultrasound flowmeter, which disclosed blood flow of 35 ml/min through the bypass. We hope that this new PComA suffices to protect the patient from infarction in the territory of the vertebrobasilar circulation.