A phase 1 study to investigate the absorption, distribution, metabolism and excretion of brepocitinib in healthy males using a 14 C-microdose approach.

AIMS: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa ) using a 14 C microtracer approach. METHODS: This was a phase 1 open-label, nonrandomized, fixed sequence, two-period, single-dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14 C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 µg dose of 14 C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed. RESULTS: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported. CONCLUSION: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug-related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039.

Quality of life outcomes in incidental and operated meningiomas (QUALMS): a cross-sectional cohort study.

INTRODUCTION: Few studies have evaluated meningioma patients' longer-term health-related quality of life (HRQoL) following diagnosis and treatment, particularly in those with incidental, actively monitored tumours. METHODS: A single-center, cross-sectional study was completed. Adult patients with surgically managed or actively monitored meningioma with more than five years of follow-up were included. The patient-reported outcome measures RAND SF-36, EORTC QLQ-C30 and QLQ-BN20 were used to evaluate HRQoL. HRQoL scores were compared to normative population data. Outcome determinants were evaluated using multivariate linear regression analysis. RESULTS: 243 patient responses were analyzed, and the mean time from diagnosis was 9.8 years (range 5.0-40.3 years). Clinically relevant, statistically significant HRQoL impairments were identified across several SF-36 and QLQ-C30 domains. Increasing education level (ß = 2.9, 95% CI 0.9 to 4.9), P = .004), employment (ß = 7.7, 95% CI 2.2 to 13.1, P = .006) and absence of postoperative complications (ß=-6.7, 95% CI -13.2 to (-)0.3, P = .041) were associated with a better QLQ-C30 summary score. Other tumour and treatment variables were not. CONCLUSION: This study highlights the longer-term disease burden of patients with meningioma nearly one decade after diagnosis or surgery. Patients with actively monitored meningioma have similar HRQoL to operated meningioma patients. Healthcare professionals should be mindful of HRQoL impairments and direct patients to sources of support as needed.

The growth rate and clinical outcomes of radiation induced meningioma undergoing treatment or active monitoring.

INTRODUCTION: Radiation induced meningioma (RIM) incidence is increasing in line with improved childhood cancer survival. No optimal management strategy consensus exists. This study aimed to delineate meningioma growth rates from tumor discovery and correlate with clinical outcomes. METHODS: Retrospective study of patients with a RIM, managed at a specialist tertiary neuroscience center (2007-2019). Tumor volume was measured from diagnosis and at subsequent interval scans. Meningioma growth rate was determined using a linear mixed-effects model. Clinical outcomes were correlated with growth rates accounting for imaging and clinical prognostic factors. RESULTS: Fifty-four patients (110 meningiomas) were included. Median duration of follow-up was 74 months (interquartile range [IQR], 41-102 months). Mean radiation dose was 41 Gy (standard deviation [SD] = 14.9) with a latency period of 34.4 years (SD = 13.7). Median absolute growth rate was 0.62 cm3/year and the median relative growth rate was 72%/year. Forty meningiomas (between 27 patients) underwent surgical intervention after a median follow-up duration of 4 months (IQR 2-35). Operated RIMs were clinically aggressive, likely to be WHO grade 2 at first resection (43.6%) and to progress after surgery (41%). Median time to progression was 28 months (IQR 13-60.5). A larger meningioma at discovery was associated with growth (HR 1.2 [95% CI 1.0-1.5], P = 0.039) but not progression after surgery (HR 2.2 [95% CI 0.7-6.6], P = 0.181). Twenty-seven (50%) patients had multiple meningiomas by the end of the study. CONCLUSION: RIMs exhibit high absolute and relative growth rates after discovery. Surgery is recommended for symptomatic or rapidly growing meningiomas only. Recurrence risk after surgery is high.

Prevalence of nonaccidental trauma among children at American College of Surgeons-verified pediatric trauma centers.

BACKGROUND: Child abuse remains a national epidemic that has detrimental effects if unnoticed in the clinical setting. Extreme cases of child abuse, or nonaccidental trauma (NAT), have large financial burdens associated with them due to treatment costs and long-term effects of abuse. Clinicians who have additional training and experience with pediatric trauma are better equipped to detect signs of NAT and have more experience reporting it. This additional training and experience can be measured by using the American College of Surgeons (ACS) Pediatric Trauma verification. It is hypothesized that ACS-verified pediatric trauma centers (vPTCs) have an increased prevalence of NAT because of this additional experience and training relative to non-ACS vPTCs. METHODS: The National Trauma Data Bank, for the years 2007 to 2014, was utilized to compare the prevalence of NAT between ACS vPTCs relative to non-ACS vPTCs to produce both crude and Injury Severity Score adjusted prevalence ratio estimates. RESULTS: The majority of NAT cases across all hospitals were male (58.3%). The mean age of the NAT cases was 2.3 years with a mean Injury Severity Score (ISS) of 11.1. The most common payment method was Medicaid (64.4%). The prevalence of NAT was 1.82 (1.74-1.90) times higher among ACS vPTCs and 1.81 (1.73-1.90) after adjusting for ISS. CONCLUSIONS: The greater prevalence of NAT at vPTCs likely represents a more accurate measure of NAT among pediatric trauma patients, likely due to more experience and training of clinicians. LEVEL OF EVIDENCE: Prognostic/Epidemiological, Level II.

Two case reports of orofacial paraesthesia demonstrating the role of the general dental practitioner in identifying patients with intracranial tumours.

The following case reports describe the clinical features, diagnosis and management of two patients who presented to their general dental practitioner with a complaint of orofacial paraesthesia. After appropriate investigations, both patients were diagnosed as having benign intracranial tumours and were managed by a neurosurgeon. These cases illustrate the important role the general dental practitioner has in the early recognition of potentially life-threatening conditions.

The LightCycler: a microvolume multisample fluorimeter with rapid temperature control.

Experimental and commercial microvolume fluorimeters with rapid temperature control are described. Fluorescence optics adopted from flow cytometry were used to interrogate 1-10-microL samples in glass capillaries. Homogeneous temperature control and rapid change of sample temperatures (10 degrees C/s) were obtained by a circulating air vortex. A prototype 2-color, 32-sample version was constructed with a xenon arc for excitation, separate excitation and emission paths, and photomultiplier tubes for detection. The commercial LightCycler, a 3-color, 24-sample instrument, uses a blue light-emitting diode for excitation, paraxial epi-illumination through the capillary tip and photodiodes for detection. Applications include analyte quantification and nucleic acid melting curves with fluorescent dyes, enzyme assays with fluorescent substrates and techniques that use fluorescence resonance energy transfer. Microvolume capability allows analysis of very small or expensive samples. As an example of one application, rapid cycle DNA amplification was continuously monitored by three different fluorescence techniques, Which included using the double-stranded DNA dye SYBR Green I, a dual-labeled 5'-exonuclease hydrolysis probe, and adjacent fluorescein and Cy5z-labeled hybridization probes. Complete amplification and analysis requires only 10-15 min.