Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, telangiectasia, and visceral vascular manifestations. Infectious and ischemic central nervous system (CNS) manifestations due to embolism through pulmonary arteriovenous malformations (PAVMs) represent the main causes of morbidity. To improve the phenotypic characterization of HHT with PAVM, we conducted a retrospective multicenter study of patients with HHT and at least 1 PAVM detected by chest computed tomography (CT) and/or pulmonary angiography, with particular attention to CNS and infectious manifestations. The study included 126 patients (47 men, 79 women), with a mean age of 43.1 +/- 17.4 years; 45 patients had a mutation of the ENG gene and 16 had a mutation of ACVRL1. PAVMs were diagnosed as a result of systematic screening procedures (29%), incidental imaging findings (15%), dyspnea (22%), or CNS symptoms (13%). The PAVMs were diagnosed at a mean age of 43 +/- 17 years, with a linear distribution of diagnosis between 20 and 75 years. Dyspnea on exertion was present in 56% of patients. Four patients had a hemothorax, including 1 during pregnancy. Fifty-three CNS events directly related to HHT (excluding migraine) were observed in 35% of patients: cerebral abscess (19.0%), ischemic cerebral stroke (9.5%), transient cerebral ischemic attack (6.3%), and cerebral hemorrhage (2.4%). The median age of onset was 33 years for cerebral abscesses (range, 11-66 yr), and 53.5 years for ischemic cerebral events (range, 2-72 yr). Migraine was reported in 16% of patients. The diagnoses of PAVM and HHT were made at the time of the cerebral abscess in 13 cases (54%). Forty-three percent of patients were hypoxemic at rest. Contrast echocardiography showed intrapulmonary right-to-left shunting in 87% of tested patients. PAVMs were seen on chest radiograph in 54% of patients, and on the CT scan in all patients. One hundred five patients (83%) underwent treatment of the PAVM, by percutaneous embolization (71%) and/or by surgical resection (23%). A high frequency of CNS and infectious complications was observed in this large series of patients with HHT-related PAVM. Physicians may not be sufficiently aware of the clinical manifestations of this orphan disorder. Patients diagnosed with HHT should be informed by physicians and patient associations of the risk of PAVM-related complications, and systematic screening for PAVM should be proposed, regardless of a patient's symptoms, familial history, or genetic considerations.