Capsule summary 55This article demonstrates that JAK inhibition represents a highly promising and well-tolerated 56 therapy for STING-associated vasculopathy, and which may also be relevant to the treatment 57 of other type I interferonopathies. 58 59Key words: Stimulator of Interferon genes, TMEM173, Janus kinase 1/2 inhibitor, type I 60 interferonopathy, interstitial lung disease, vasculopathy. 61 To the Editor: 62Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) 63 underlie a novel type I interferonopathy, 1 termed SAVI (STING-associated vasculopathy with 64 onset in infancy). 2,3 This disease is associated with high childhood morbidity and mortality. 65 STING is a central component of DNA sensing that leads to the induction of type I 66 interferons (IFN), which in turn drives the expression of IFN-stimulated genes (ISGs) through 67 the engagement of a common receptor and subsequent activation of Janus kinase 1 (JAK1) 68 and tyrosine kinase 2 (TYK2). 69We describe, for the first time, the use and efficacy of ruxolitinib, a selective oral JAK1/2 70 inhibitor, in three children with TMEM173-activating mutations over 6 to 18 months of 71 follow-up. The patients, aged between 5 and 12 years, exhibited the phenotypic variability 72 associated with TMEM173-activating mutations, 2,3,4 with lung disease and systemic 73 inflammation being the major features in P1 and P3, whilst in P2 skin involvement was most 74 prominent (Fig 1 and see Supplemental Text, Fig E3, and Table E1 in the Online Repository). 75There was minimal response to a broad spectrum of immunosuppressive therapies including 76 steroids, methotrexate and anti-CD20 monoclonal antibodies. 77 78An increased expression of ISGs, a so-called type I IFN signature, 5 was observed in all three 79 patients (see Fig E1, A in the Online Repository). Increased levels of STAT1 phosphorylation 80 were recorded in patient T lymphocytes (P1, P2, P3), T cultured lymphoblasts (P1) and 81 primary fibroblasts (P3) compared to controls (see Fig E2, A in the Online Repository). Liu et 82 al. demonstrated that, in vitro, three JAK1 inhibitors (ruxolitinib, tofacitinib and baricitinib) 83 were able to block the constitutive phosphorylation of STAT1 in lymphocytes from 84 TMEM173-mutated patients, 2 and we saw that exposure to ruxolitinib inhibited the 85 constitutive phosphorylation of STAT1 and decreased the expression of IL-6 and 3 ISGs 86 tested in T lymphoblasts from P1 (see Fig E2, B, C in the Online Repository). Considering the 87 severity of the phenotype and the poor response to conventional immunosuppressive 88 therapies, we hypothesized that JAK1 inhibition would block IFN signaling in the context of 89 activating mutations in TMEM173. 90 91We observed a marked positive effect on all aspects of the phenotype in all three treated 92 children. There was a general improvement in patient-reported well-being, a reduction of 93 febrile episodes, an almost complete resolution of the associated cutaneous lesions and a 94 major impr...

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

A simple and rapid ultra-high-performance liquid chromatography (UHPLC) method using UV detection was developed for the simultaneous determination of eight ␤-lactam antibiotics in human plasma, including four penicillins, amoxicillin (AMX), cloxacillin (CLX), oxacillin (OXA), and piperacillin (PIP), and four cephalosporins, cefazolin (CFZ), cefepime (FEP), cefotaxime (CTX), and ceftazidime (CAZ). One hundred-microliter samples were spiked with thiopental as an internal standard, and proteins were precipitated by acetonitrile containing 0.1% formic acid. Separation was achieved on a pentafluorophenyl (PFP) column with a mobile phase composed of phosphoric acid (10 mM) and acetonitrile in gradient elution mode at a flow rate of 500 l/min. Detection was performed at 230 nm for AMX, CLX, OXA, and PIP and 260 nm for CFZ, FEP, CTX, and CAZ. The total analysis time did not exceed 13 min. The method was found to be linear at concentrations ranging from 2 to 100 mg/liter for each compound, and all validation parameters fulfilled international requirements. Between-and within-run accuracy errors ranged from ؊5.2% to 11.4%, and precision was lower than 14.2%. This simple method requires small-volume samples and can easily be implemented in most clinical laboratories to promote the therapeutic drug monitoring of ␤-lactam antibiotics. The simultaneous determination of several antibiotics considerably reduces the time to results for clinicians, which may improve treatment efficiency, especially in critically ill patients.

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small–cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman’s rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02–3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78–36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46–27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.