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Background and Objective: Checkpoint inhibitor pneumonitis (CIP), caused by the anti‐programmed cell death‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high‐mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. Methods: Blood samples, prospectively stored before anti‐PD‐1/PD‐L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non‐small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti‐PD‐1/PD‐L1 therapy. Results: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut‐off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut‐off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. Conclusion: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients. CIP incidence in the patients with high levels of serum HMGB1 (≥ 11.24 ng/ml) was significantly and reproducibly higher than in those with its low levels (< 11.24 ng/ml) in patients with NSCLC. Our results suggest that HMGB1 may be a potential blood marker for the prediction of CIP. [ABSTRACT FROM AUTHOR]

Background and objective: High‐mobility group box 1 (HMGB1) is a known mediator of acute lung injury through the acceleration of pro‐inflammatory –signalling. Previous studies showed that HMGB1 is increased in the lung and circulation of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE‐IPF). This study investigated the predictive value of circulatory HMGB1 for disease progression and prognosis of IPF in the stable phase and AE phase. Methods: In total, 76 patients with stable IPF, 17 patients with AE‐IPF, 37 patients with chronic obstructive pulmonary disease (COPD) and 74 healthy controls were included. Serum HMGB1 levels were compared among the four groups and the associations of HMGB1 levels with the onset of AE and prognosis were evaluated in patients with stable IPF. The prognostic value of HMGB1 was determined in AE‐IPF. Results: Serum HMGB1 levels in patients with stable IPF were significantly higher than those in healthy controls, and in patients with AE‐IPF they were even higher than the levels in either of these groups (6.26 ± 5.27, 3.42 ± 2.69 and 19.20 ± 16.76 ng/mL, respectively). There was no significant difference in serum HMGB1 levels between stable IPF patients and COPD patients. Higher levels of HMGB1 were associated with earlier onset of AE in stable IPF patients and with shorter survival in AE‐IPF patients (P = 0.030 and 0.001, respectively). Conclusion: Higher levels of serum HMGB1 predict earlier onset of AE in stable IPF patients and shorter survival in AE‐IPF patients, indicating that HMGB1 is associated with acute deterioration of the disease. This study showed that elevated levels of serum high‐mobility group box 1, a mediator of acute lung injury through the acceleration of pro‐inflammatory signalling, predicts earlier onset of acute exacerbation (AE) in patients with stable idiopathic pulmonary fibrosis and shorter survival in patients with AE. See relatedEditorial [ABSTRACT FROM AUTHOR]