Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor,pexidartinib

Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0–8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) μg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2–4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL). Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.     

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Objectives

Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC.

Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment

Objective

The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women.

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

Cancer Chemotherapy and Pharmacology - Zanubrutinib (BGB-3111) is a potent Bruton’s tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown...     

Total Knee Arthroplasty Is Safe and Successful in Patients With Klippel-Trénaunay Syndrome

Background

Klippel-Trénaunay syndrome (KTS) is a severe vascular malformation that can lead to hypertrophic osteoarthritis. Total knee arthroplasty (TKA) performed in extremities affected with KTS is challenging given the high-risk vascular considerations and occasionally poor bone quality.