Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
Summary
Background
Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated.
Objectives
We compared ...autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non‐severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs).
Methods
Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)‐8 (100 ng/mL). Autophagy (light chain 3‐II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin‐1, and IL‐8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil‐derived neurotoxin (EDN).
Results
Untreated and IL‐8‐treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL‐8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL‐8‐induced NET production levels negatively were correlated with FEV1/FVC (r = −0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin‐1, and IL‐8 production from AECs. Higher levels of NET‐induced ECP and EDN were released from PBEs in SA compared with NSA groups.
Conclusions and Clinical Relevance
Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.
(
) promoter methylation status in primary and recurrent glioblastoma may change during treatment. The purpose of this study was to correlate
promoter methylation status changes with DWI and DSC PWI ...features in patients with recurrent glioblastoma after standard treatment.
Between January 2008 and November 2016, forty patients with histologically confirmed recurrent glioblastoma were enrolled. Patients were divided into 3 groups according to the
promoter methylation status for the initial and recurrent tumors: 2 groups whose
promoter methylation status remained, group methylated (
= 13) or group unmethylated (
= 18), and 1 group whose
promoter methylation status changed from methylated to unmethylated (
= 9). Normalized ADC and normalized relative CBV values were obtained from both the enhancing and nonenhancing regions, from which histogram parameters were calculated. The ANOVA and the Kruskal-Wallis test followed by post hoc tests were performed to compare histogram parameters among the 3 groups. The
test and Mann-Whitney
test were used to compare parameters between group methylated and group methylated to unmethylated. Receiver operating characteristic curve analysis was used to measure the predictive performance of the normalized relative CBV values between the 2 groups.
Group methylated to unmethylated showed significantly higher means and 90th and 95th percentiles of the cumulative normalized relative CBV values of the nonenhancing region of the initial tumor than group methylated and group unmethylated (all
< .05). The mean normalized relative CBV value of the nonenhancing region of the initial tumor was the best predictor of methylation status change (
< .001), with a sensitivity of 77.78% and specificity of 92.31% at a cutoff value of 2.594.
promoter methylation status might change in recurrent glioblastoma after standard treatment. The normalized relative CBV values of the nonenhancing region at the first preoperative MR imaging were higher in the
promoter methylation change group from methylation to unmethylation in recurrent glioblastoma.
Recently, Lee et al reported a new grading system for the lumbar spinal foraminal stenosis. They considered the type of stenosis, the amount of fat obliteration, and the presence of nerve root ...compression. Our aim was to evaluate whether a new MR imaging grading system correlated with symptoms and neurologic signs and could replace the previous grading system.
We examined 91 patients (M/F = 49:42; mean age, 50 years) who visited our institution and underwent MR imaging of the L-spine and were evaluated by 2 musculoskeletal radiologists. The presence and grade of lumbar foraminal stenosis at the maximal narrowing point was assessed according to the new grading system suggested by Lee et al (Lee system) and the Wildermuth grading system (Wildermuth system). Results were correlated with clinical manifestations and neurologic physical examination. Statistical analysis was performed by using κ statistics, categoric regression analysis, and nonparametric correlation analysis (Spearman correlation).
Interobserver agreement in the grading of foraminal stenosis between the 2 readers was substantially correlated (κ of Lee system = 0.767, κ of Wildermuth system = 0.734). The Rs for reader 1 and reader 2 between the Lee system and the Wildermuth system were 0.880 and 0.885, between Lee system and PNM were 0.715 and 0.604, and between the Wildermuth system and PNM were 0.800 and 0.680. For patients younger than 50 years of age, the R between the Lee and Wildermuth systems was higher than that for patients 50 years or older, but the Rs between the grading system and PNM were lower in the younger group than in the older group. The Rs of the Wildermuth system with PNM were higher in the older group than in the younger group; the differences between the Rs of the Lee system with PNM and the Wildermuth system with PNM were higher in the older group (0.016 young versus 0.130 old and 0.008 versus 0.107).
Interobserver agreement of the Lee system was slightly higher than the Wildermuth system and substantially correlated. Both systems are good for evaluation of lumbar spinal foraminal stenosis, but the Lee system showed slightly better interobserver agreement and good clinical correlation in the younger group of patients.
Background
Surfactant protein D (SPD) is a member of the collectin family that lines the airway epithelial cells with host defense. However, the role of SPD in the pathogenesis of aspirin‐exacerbated ...respiratory disease (AERD) is still unclear.
Methods
The serum SPD level was measured in patients with AERD (n = 336), those with aspirin‐tolerant asthma (ATA, n = 442), and healthy controls (HC, n = 104). Polymorphisms of SFTPD in the study subjects were analyzed. The effect of LTE4 on SPD production through eosinophil infiltration was investigated in BALB/c mice. The protective function of SPD against eosinophils inducing inflammation and remodeling was assessed in vitro/vivo. The potential efficacy of nintedanib against airway remodeling through the production of SPD was evaluated.
Results
The serum SPD level was significantly lower (P < .001) in AERD compared with ATA patients, and negatively correlated with fall in FEV1 (%) after lysine‐aspirin bronchoprovocation test and/or the urinary LTE4 level. In addition, polymorphism of SFTPD at rs721917 was significantly different in the study subjects (odds ratio, 2.124; 95% confidence intervals, 1.310‐3.446; P = .002). LTE4‐exposed mice showed an increased eosinophil count with a decreased SPD level in bronchoalveolar lavage fluid. Eosinophils increased α‐smooth muscle actin expression in airway epithelial cells, which was attenuated by SPD treatment. Furthermore, nintedanib protected the airway epithelial cells against eosinophils by enhancing the production of SPD.
Conclusion
The decreased level of SPD in AERD was associated with airway inflammation/remodeling under the eosinophilic condition, suggesting that modulation of SPD may provide a potential benefit in AERD.
High level of leukotriene E4 induces eosinophil infiltration in the lungs, leading to the reduction of surfactant protein D in patients with AERD. Decreased level of surfactant protein D and increased number of eosinophils enhance airway inflammation/remodeling. Modulation of surfactant protein D may provide a potential benefit in airway epithelium against eosinophils.
The Reactor Experiment for Neutrino Oscillation (RENO) has been taking electron antineutrino (ν¯e) data from the reactors in Yonggwang, Korea, using two identical detectors since August 2011. Using ...roughly 500 live days of data through January 2013 we observe 290 775 (31 514) reactor ν¯e candidate events with 2.8% (4.9%) background in the near (far) detector. The observed visible positron spectra from the reactor ν¯e events in both detectors show a discrepancy around 5 MeV with regard to the prediction from the current reactor ν¯e model. Based on a far-to-near ratio measurement using the spectral and rate information, we have obtained sin22θ13=0.082±0.009(stat.)±0.006(syst.) and |Δmee2|=2.62−0.23+0.21(stat.)−0.13+0.12(syst.)×10−3 eV2.
Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. ...We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population. A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2'-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests. We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV₁), FEV₁/forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters. This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.
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