Molecules targeting programmed cell death 1 or its ligand programmed death ligand 1 (PD-L1) revolutionized the treatment of patients with NSCLC. The only approved biomarker for predicting treatment ...response is the PD-L1 tumor proportion score (TPS) determined by immunohistochemistry. According to International Association for the Study of Lung Cancer recommendations, specimens that include fewer than 100 tumor cells or are older than 3 years should not be used for PD-L1 testing and the reliability of cell blocks has yet to be validated.
This retrospective study included 1249 consecutive patients with NSCLC who were tested for PD-L1 (using the clone 22C3) between September 2016 and April 2017. The associations between the presence of suboptimal characteristics (specimens with <100 tumor cells, specimens older than 3 years, or cell blocks) and PD-L1 TPS were examined by using a multinomial logistic regression.
Specimens from 35.5% of the patients had at least one suboptimal characteristic. For patients with a PD-L1 TPS of higher than 50%, there was a significantly higher probability that they had a specimen with more than 100 tumor cells (OR = 1.97, p = 0.008) and a more recent block (within 30 days versus after >3 years) (OR = 2.46, p = 0.023). There was no statistical difference in PD-L1 TPS between cell blocks and tissue specimens (biopsy OR = 0.99 p = 0.996 and surgery OR = 0.73 p = 0.302).
Our results suggest that specimens containing fewer than 100 tumor cells or older than 3 years may lead to an underestimation of PD-L1 status. Our findings also provide support for the use of cell blocks for PD-L1 testing, although further research is needed.
Following recent findings linking the human gut microbiota to gastrointestinal cancer and its treatment, the plausible relationship between lung microbiota and pulmonary cancer is explored. This ...study aims at characterizing the intratumoral and adjacent healthy tissue microbiota by applying a 16S rRNA gene amplicon sequencing protocol to tissue samples of 29 non-small cancer patients. Emphasis was put on contaminant management and a comprehensive comparison of bacterial composition between cancerous and healthy adjacent tissues of lung adenocarcinoma and squamous cell carcinoma is provided. A variable degree of similarity between the two tissues of a same patient was observed. Each patient seems to possess its own bacterial signature. The two types of cancer tissue do not have a distinct bacterial profile that is shared by every patient. In addition, enteric, potentially pathogenic and pro-inflammatory bacteria were more frequently found in cancer than healthy tissue. This work brings insights into the dynamic of bacterial communities in lung cancer and provides prospective data for more targeted studies.
Rationale:Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification loads than men for the same AS hemodynamic ...severity.Objective:We, thus, aimed to assess sex differences in aortic valve fibrocalcific remodeling.Methods and Results:One hundred and twenty-five patients underwent Doppler echocardiography and multidetector computed tomography within 3 months before aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed, and fibrosis degree was determined. Sixty-four men and 39 women were frequency matched for age, body mass index, hypertension, renal disease, diabetes mellitus, and AS severity. Mean age (75±9 years), mean gradient (41±18 mm Hg), and indexed aortic valve area (0.41±0.12 cm2/m2) were similar between men and women (all P≥0.18). Median aortic valve calcification (1973 1124–3490 Agatston units) and mean valve weight (2.36±0.99 g) were lower in women compared with men (both P<0.0001). Aortic valve calcification density correlated better with valve weight in men (r2=0.57; P<0.0001) than in women (r2=0.26; P=0.0008). After adjustment for age, body mass index, aortic valve calcification density, and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (P=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (P=0.01), and Masson trichrome staining revealed a greater proportion of dense connective tissue (P=0.02) in women compared with men.Conclusions:In this series of patients with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared with men. These findings suggest that the pathophysiology of AS and thus potential targets for drug development may be different according to sex.
Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in ...PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH.
We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals.
RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.
Meta-analyses suggest that yogurt consumption reduces type 2 diabetes incidence in humans, but the molecular basis of these observations remains unknown. Here we show that dietary yogurt intake ...preserves whole-body glucose homeostasis and prevents hepatic insulin resistance and liver steatosis in a dietary mouse model of obesity-linked type 2 diabetes. Fecal microbiota transplantation studies reveal that these effects are partly linked to the gut microbiota. We further show that yogurt intake impacts the hepatic metabolome, notably maintaining the levels of branched chain hydroxy acids (BCHA) which correlate with improved metabolic parameters. These metabolites are generated upon milk fermentation and concentrated in yogurt. Remarkably, diet-induced obesity reduces plasma and tissue BCHA levels, and this is partly prevented by dietary yogurt intake. We further show that BCHA improve insulin action on glucose metabolism in liver and muscle cells, identifying BCHA as cell-autonomous metabolic regulators and potential mediators of yogurt's health effects.
The aim of bronchial thermoplasty is to improve asthma symptoms by reducing central airway smooth muscle mass. Up to now, the reduction of smooth muscle mass has been documented for only 1 group of ...10 patients who had 15% or more of their pretreatment total bronchial biopsy area occupied by smooth muscle.
To evaluate the effects of bronchial thermoplasty on airway smooth muscle mass and airway collagen deposition in adult patients with asthma, regardless of pretreatment smooth muscle area.
Seventeen patients with asthma underwent bronchial thermoplasty over the course of three visits. At Visit 1, bronchial biopsies were taken from the lower lobe that was not treated during this session. At Visit 2 (3-14 wk after the first visit), all 17 patients underwent biopsy of the lower lobe treated during the first procedure. At Visit 3 (7-22 wk after the first visit), nine patients agreed to undergo biopsy of the same lower lobe. Histological and immunohistochemical analyses were performed on the biopsy specimens.
Bronchial thermoplasty decreased airway smooth muscle from 12.9 ± 1.2% of the total biopsy surface at Visit 1 to 4.6 ± 0.8% at Visit 2 (P < 0.0001). For the nine patients who underwent a third biopsy, mean airway smooth muscle area was 5.3 ± 1.3% at Visit 3 (P = 0.0008 compared with baseline). Bronchial thermoplasty also decreased Type I collagen deposition underneath the basement membrane from 6.8 ± 0.3 μm at Visit 1 to 4.3 ± 0.2 μm at Visit 2 (P < 0.0001) and to 4.4 ± 0.4 μm for nine patients at Visit 3 (P < 0.0001 compared with baseline). Over the course of 1 year after treatment, the doses of inhaled corticosteroid, the number of severe exacerbations, and asthma control all improved (P ≤ 0.02).
For patients with severe asthma, bronchial thermoplasty reduced the smooth muscle mass of treated airway segments, regardless of the baseline level of muscle mass. Treatment also altered the deposition of collagen. At follow-up, bronchial thermoplasty improved asthma control; however, the limited number of subjects did not allow us to evaluate possible correlations between these improvements and the studied histological parameters. Further studies are needed to confirm these results and evaluate their persistence.
No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC).
We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC ...patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.
In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.
CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.
Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during ...influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.
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•PGE2 inhibits macrophage recruitment to the lungs during IAV infection•PGE2 inhibits type I IFN production and apoptosis in IAV-infected macrophages•PGE2 impairs macrophage antigen presentation and adaptive immunity against IAV•Pharmacological suppression of PGE2 protects against IAV infection
Summary The 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification of pulmonary adenocarcinoma recognizes the ...prognostic significance of different histologic patterns but does not address the issue of tumor grade. We previously developed an objective and prognostic grading system for pulmonary adenocarcinomas that is based on associating patterns with their metastatic potential. The best prognostic stratification was achieved by summing the grades of the 2 most predominant patterns (histologic score). Here, we extend this work by evaluating the prognostic importance of variant patterns of adenocarcinoma, which are not recognized by the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Pathologic specimens from 249 resected stage I adenocarcinomas were reviewed. The proportions of standard and nonstandard patterns (cribriform and fused glands) were recorded for each case. The associations between the presence of standard and nonstandard patterns, tumor histologic score, and disease-free survival were evaluated. Cribriform and fused gland patterns were observed in 15% and 29% of tumors, respectively. These nonstandard patterns each composed 10% to 100% of the entire tumors but were the predominant pattern in only 5% and 7% of tumors, respectively. The presence of complex glandular patterns was associated with solid pattern ( P < .001) and high histologic score ( P < .0001). Disease-free survival for tumors with predominant complex glandular patterns was similar to that for high-grade tumors ( P = .932) and was significantly worse than that for low- and intermediate-grade tumors ( P = .0025). Complex glandular patterns have a significant prognostic value and should be considered patterns of high-grade adenocarcinoma.
To the Editor: Bronchial thermoplasty (BT) has been shown to reduce airway mucosa smooth muscle mass, reticular basement membrane thickness (1-3), and epithelium nerve fibers (4). Because an ...improvement of bronchial epithelial integrity was reported after BT, suggesting that it induces an epithelium injury-repair cycle (5), we evaluated the effects of BT on airway cell regeneration and proliferation, and mucin MUC5AC and IL-13 expression. Because they showed a persisting expansion after BT, we evaluated their proliferation. ...in severe asthma, the bronchial epithelium could be considered as an important target of BT treatment.
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