Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men -an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose-and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-b-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-b-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women -a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.Propofol (2,6-diisopropylphenol) has become a widely used intravenous sedative agent for induction and maintenance of anaesthesia due to its rapid onset, relatively short emergence time and favourable safety profile. However, extensive interindividual variability in pharmacokinetic and pharmacodynamic parameters has previously been reported [1][2][3]. The biotransformation of propofol is a multipathway process: UDP-glucuronosyltransferase 1A9 (UGT1A9) is the main enzyme that catalyses the glucuronidation of propofol to propofol glucuronide (PG) [4]. Cytochrome P-450 enzyme 2B6 (CYP2B6) and to a lesser extent CYP2C9 are responsible for the hydroxylation of propofol to its hydroxylated metabolites. The major hydroxylated metabolite 4-hydroxypropofol (OHP) is subsequently metabolized to 4-hydroxypropofol-1-O-b-Dglucuronide (Q1G) and 4-hydroxypropofol-4-O-b-D-glucuronide (Q4G) [5]. Up to 90% of propofol is eliminated via the urine in the form of its glucuronidated metabolites [5,6], suggesting a crucial role of UGTs in its clearance.Single-nucleotide polymorphisms (SNPs) in UGT1A9 and CYP2B6 might contribute to the inter-individual variability in the formation rate of propofol metabolites. Age, weight, height and lean body mass have also been reported to play a relevant role in propofol clearance [7][8][9][10]. Furthermore, growing evidence suggests that sex is an independent factor that influences the rate of recovery from general anaesthesia [11]. A faster recovery has been reported in women after the administration of inhaled agents [11] or intravenous propofol [12], and faster decrease plasma propofol levels were reported in women than in men [1]. Currently, it is...

BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of theGZMBgene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation ofGZMBrs8192917 was assessed. Patients with homozygous and heterozygous variants ofGZMBrs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation ofGZMBwas associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828).

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Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.