Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

Regulated cell death in cancer: from pathogenesis to treatment.

ABSTRACT: Regulated cell death (RCD), including apoptosis, pyroptosis, necroptosis, and ferroptosis, is regulated by a series of evolutionarily conserved pathways, and is required for development and tissue homeostasis. Based on previous genetic and biochemical explorations of cell death subroutines, the characteristics of each are generally considered distinctive. However, recent in-depth studies noted the presence of crosstalk between the different forms of RCD; hence, the concept of PANoptosis appeared. Cancer, a complex genetic disease, is characterized by stepwise deregulation of cell apoptosis and proliferation, with significant morbidity and mortality globally. At present, studies on the different RCD pathways, as well as the intricate relationships between different cell death subroutines, mainly focus on infectious diseases, and their roles in cancer remain unclear. As cancers are characterized by dysregulated cell death and inflammatory responses, most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells. In this review, we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression. The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised. We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds, immune checkpoint inhibitors, and nanoparticles. Together, these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.

A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection.

BACKGROUND: Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. RESEARCH QUESTION: Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection? STUDY DESIGN AND METHODS: This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29. RESULTS: The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. INTERPRETATION: TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection. TRIAL REGISTRATION: ClinicalTrials.gov; No. NCT03715322; URL: www. CLINICALTRIALS: gov.

Coexistence of Lung Squamous Cell Carcinoma and Pulmonary Tuberculosis Within a Single Lesion: A Case Report.

Pulmonary tuberculosis (TB) and lung cancer are both common diseases with poor prognosis and high mortality worldwide. The coexistence of the two diseases has rarely been reported while their relationship has been noted. Here we describe a patient diagnosed with both TB and squamous cell carcinoma in a single lesion. The patient had a cough for four months and polypnea for two months, with a smoking history of over 40 years. Chest computed tomography (CT) showed a lobular mass in the right hilar region, which was diagnosed as TB by transbronchial lung biopsy. The symptoms and CT findings indicated the possibility of lung cancer. So, the patient underwent a further lung biopsy at the periphery of the mass, which was confirmed as squamous cell carcinoma. This case illuminated that when the mass with cancer-like morphologic features and location instead of typical TB, even the initial pathological result shows TB, coexistence of the diseases should be considered.

Comparison of Different Clinical Prognostic Scores in Patients with Pulmonary Embolism and Active Cancer.

OBJECTIVE: This article aimed to validate and compare the prognostic performance of generic scores (Pulmonary Embolism Severity Index [PESI] and Hestia) and cancer-specific pulmonary embolism (PE)/venous thromboembolism (VTE) scales (Registro Informatizado de la Enfermedad TromboEmbólica [RIETE], POMPE-C, and modified Ottawa) in PE patients with active cancer. METHODS: A retrospective study was conducted among 460 patients with PE and active cancer. The primary outcome was 30-day overall mortality. Secondary outcomes were 30-day PE-related death and overall adverse outcomes. The prognostic accuracy of clinical scores was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Within 30 days, 18.0% of patients died, 2.0% suffered major bleeding, and 0.2% presented recurrence of VTE. All scales showed a high area under the ROC curve (AUC) for predicting 30-day overall mortality except modified Ottawa (0.74 [0.70-0.78] for PESI, Hestia, and RIETE; 0.78 (0.74-0.81) for POMPE-C; 0.64 (0.59-0.68) for modified Ottawa]. PESI divided the least patients (9.1%) into low risk, followed by modified Ottawa (17.0%). Hestia stratified the most patients (65.4%) as low risk. But overall mortality of low-risk patients based on these three scales is high (>5%). RIETE and POMPE-C both classified 30.9% of patients as low risk, and low-risk patients stratified by these two scales presented a low overall mortality (1.4 and 3.5%). Similar predictive performance was found for 30-day PE-related death and overall adverse outcomes in these scores. CONCLUSION: Cancer-specific PE prognostic scores (RIETE and POMPE-C) performed better than generic scales (PESI and Hestia) and a cancer-specific VTE prognostic scale (modified Ottawa) in identifying low-risk PE patients with active cancer who may be suitable for outpatient treatment.

Comparison between the Khorana prediction score and Caprini risk assessment models for assessing the risk of venous thromboembolism in hospitalized patients with cancer: a retrospective case control study.

OBJECTIVES: This study aimed to evaluate the optimal risk assessment model (RAM) to stratify the risk of venous thromboembolism (VTE) in hospitalized patients with cancer. We examined and compared the VTE predictive ability of the Khorana score (KS) and the Caprini RAM in hospitalized cancer patients. METHODS: We performed a retrospective case-control study among hospitalized cancer patients admitted to a comprehensive hospital in China from January 2015 to December 2016. A total of 221 cases were confirmed to have VTE during hospitalization and 221 controls were selected randomly. The Caprini RAM and KS were implemented and the individual scores of each risk factor were summed to generate a cumulative risk score. Meanwhile, the sensitivity, specificity, areas under curve of the receiver operating characteristic curve and calibration of these 2 models were analysed. RESULTS: Significant differences were observed in risk factors between VTE and non-VTE hospitalized cancer patients and the VTE risk increased significantly with an increase in the cumulative KS or Caprini RAM score. A classification of 'high risk' according to KS and Caprini RAM was associated with 2.272-fold and 3.825-fold increases in VTE risk, respectively. However, the Caprini RAM could identify 82.4% of the VTE cases that required preventive anticoagulant therapy according to American College of Chest Physicians guidelines, whereas the KS could only identify 35.3% of the VTE cases. In addition, the areas under curve of Caprini RAM were significantly higher than those of the KS (0.705 ± 0.024 vs 0.581 ± 0.025, P < 0.001), with a best cut-off value of 5 score, which happened to be the cut-off value for high risk of VTE in Caprini RAM. Both Caprini RAM and KS showed an excellent calibration curve (0.612 vs 0.141, P > 0.05), but the risk of VTE events predicted by Caprini seemed closer to the observed risk of VTE events. CONCLUSIONS: The Caprini RAM was found to be more effective than the KS in identifying hospitalized patients with cancer at risk of VTE.

The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis.

BACKGROUND: Studies investigating the role of hyperoxia in critically ill patients have reported conflicting results. We did this analysis to reveal the effect of hyperoxia in the patients admitted to the intensive care unit (ICU). METHODS: Electronic databases were searched for all the studies exploring the role of hyperoxia in adult patients admitted to ICU. The primary outcome was mortality. Random-effect model was used for quantitative synthesis of the adjusted odds ratio (aOR). RESULTS: We identified 24 trials in our final analysis. Statistical heterogeneity was found between hyperoxia and normoxia groups in patients with mechanical ventilation (I2 = 92%, P < 0.01), cardiac arrest(I2 = 63%, P = 0.01), traumatic brain injury (I2 = 85%, P < 0.01) and post cardiac surgery (I2 = 80%, P = 0.03). Compared with normoxia, hyperoxia was associated with higher mortality in overall patients (OR 1.22, 95% CI 1.12~1.33), as well as in the subgroups of cardiac arrest (OR 1.30, 95% CI 1.08~1.57) and extracorporeal life support (ELS) (OR 1.44, 95% CI 1.03~2.02). CONCLUSIONS: Hyperoxia would lead to higher mortality in critically ill patients especially in the patients with cardiac arrest and ELS.

Expression of Toll-like receptor 4 in lungs of immune-suppressed rat with Acinetobacter baumannii infection.

Toll-like receptor 4 (TLR4) is involved in the regulation of host responses to Acinetobacter baumannii (A. baumannii). The aim of the present study was to examine the function of TLR4 in lung inflammation in immune-suppressed rats with A. baumannii infection. A total of 72 Sprague-Dawley male rats were randomly divided into the control, A. baumannii infection and immune-suppressed infection groups. The immune-suppressed infection group was treated with 100 mg/kg hydrocortisone by subcutaneous injection every other day for 2 weeks prior to A. baumannii infection. Lung tissue was obtained on the 3rd and 7th day after tracheal inoculation with A. baumannii. The expression of TLR4 in bronchial and alveolar epithelial cells, and alveolar macrophage was examined using immunohistochemistry. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid were detected using ELISA. The results showed that in the control group, the expression of TLR4 was upregulated in the bronchial and alveolar epithelial, and alveolar macrophages, and the levels of IL-6 and TNF-α were increased in the early phase of A. baumannii infection. On the 7th day, no significant difference in the levels of IL-6 and TNF-α was observed between the A. baumannii infection and control groups. Conversely, the expression of TLR4 was downregulated in the immune-suppressed group, and the levels of IL-6 and TNF-α were reduced on the 3rd day after infection. In the subsequent observation period, the expression of TLR4 was upregulated and the levels of IL-6 and TNF-α were increased. In conclusion, the results show a critical role of TLR4 in mediating effective immune response in the lung of rat with A. baumannii infection.

Tumour markers in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is the most common pulmonary extra-articular manifestations of rheumatoid arthritis (RA), but the pathogenesis of RA-ILD is unknown. The purpose of this study was to investigate the tumour markers levels in patients of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to explore the diagnostic value of serum tumour markers for RA-ILD. METHODS: Twenty-eight patients with RA-ILD and 83 patients with RA only were included. Serum levels of tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 15-3, CA125, and CA19-9 were measured. RESULTS: Tumour markers CA15-3, CA125 and CA19-9 were increased in RA-ILD patients compared with RA without ILD patients. Logistic regression analysis revealed that older age (OR=1.06, 95% CI=[1.02-1.11]) and higher CA125 (OR=1.03, 95% CI=[1.01-1.05]) related to the increased risk of RA-ILD. ROC curve analysis showed the relationship between CA125 and RA-ILD was moderate (area under ROC curve (AUC)=0.78, 95% CI=[0.68-0.88]). In addition, CA125 levels above the normal reference (<35 U/ml) raised the risk of RA-ILD (OR=6.00, 95% CI=[2.37-15.16]). CONCLUSIONS: RA patient with older age and elevated tumour markers especially CA125 levels should be evaluated to check whether there is a potential of ILD.

Pulmonary Paragonimiasis Mimicking Tuberculous Pleuritis: A Case Report.

Pulmonary paragonimiasis is a food-borne zoonosis with a wide variety of radiologic findings, which sometimes can be confused with tuberculosis and carcinoma. Therefore, differential diagnosis is always warranted. A 43-year-old male farmer, with productive cough, blood-tinged sputum and chest pain, as well as patchy consolidation and pleural effusions in chest computer tomography, was misdiagnosed of community-acquired pneumonia and tuberculosis. Complete blood cell count, sputum smear and culture, chest computer tomography, thoracoscopy, and biopsy. The diagnosis of pulmonary paragonimiasis was established due to the finding of Charcot-Leyden crystals in the pleural necrosis, and antibodies against Paragonimus westermani in enzyme-linked immunosorbent assay. Paragonimiasis should be considered as a possibility in the differential diagnosis of tuberculosis. Thoracoscopy is an effective and valuable technology that can help make an accurate diagnosis.

Plasma miRNAs might be promising biomarkers of chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: We previously showed that microRNAs (miRNAs) in plasma are potential biomarkers for cigarette smoking-related lung fibrosis. Here, we want to find out promising miRNAs for early detection of chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS: Plasma miRNAs profiling was performed in COPD patients, asthma patients, and matched healthy controls. There was a >2-fold changes for all signature miRNAs between the COPD and control samples, with P values of < 0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs, was also carried out. We found seven miRNAs were special expression in the COPD patients. Furthermore, changes of miR-145-5p, miR-338-3p and miR-3620-3p were consistent with the classification of new ABCD classification of COPD. Targeted gene promising proved those miRNAs acted in inflammatory mediators, regulation of proliferation and differentiation, oxidative stress and so on. CONCLUSIONS: These results suggested that plasma miRNAs could be potential specific biomarker for early detection COPD.

Clinical features of rheumatoid arthritis-associated interstitial lung disease.

Interstitial lung disease (ILD) is the most common extra-articular manifestations of rheumatoid arthritis (RA) in the lung. This study aimed to identify clinical features of RA-associated ILD (RA-ILD). Patients with RA were retrospectively enrolled and sub-classified as RA-ILD or RA without ILD based on high-resolution computed tomography imaging. Pulmonary function testing parameters and levels of RA-related biomarkers, tumour markers, and acute-phase proteins were compared between the two groups. Logistic regression model was used to assess the strength of association between RA-ILD and clinical features of interest. Receiver operating characteristic analysis was performed to assess potential predictive value of clinical features for detecting RA-ILD. Comparison analysis indicated that the percentage of predicted value of total lung capacity, inspiratory capacity, and diffusion capacity of the lung for carbon monoxide (DLCO) were reduced in patients with RA-ILD. Tumour markers CA15-3 and CA125 were increased in patients with RA-ILD. Logistic regression analysis revealed that decreased DLCO was related to the increased likelihood of RA-ILD (OR = 0.94, 95%CI = [0.91, 0.98]). The cut-off point at 52.95 percent of predicted value could sensitively discriminate RA patients with or without ILD. Our study suggested that DLCO value could be a useful tool for detecting ILD in patients with RA.

Transcriptomic profiling of peripheral blood CD4⁺ T-cells in asthmatics with and without depression.

BACKGROUND: Cumulative studies have shown that asthma is associated with depression but the underlying mechanisms are poorly understood. This study aimed to determine whether asthma with depression is characterized by unique pathophysiological pathways by analyzing the global gene expression patterns of CD4(+) T-cells from asthmatics with or without depression. MATERIALS AND METHODS: Four groups of subjects (non-depressive asthmatics, depressive asthmatics, depression patients, and healthy controls) consisting of 6 participants in each group were studied. Peripheral CD4(+) T-cells were isolated and the global transcriptomic profiles were defined by using the Agilent SurePrint G3 Human GE 8x60K microarray. The differences in transcriptomic profiles between asthma with or without depression, depression patients and healthy controls were examined. Pathway enrichment analyses of differentially expressed genes were performed using the Ingenuity Pathway Analysis. Selected genes were verified and correlated to the clinical characteristics. RESULTS: A total of 1448 differentially expressed transcripts were identified in any of the non-depressive asthma vs. healthy control, depressive asthma vs. healthy control, or depression vs. healthy control comparisons after correction for multiple comparisons. Among these, 156 were demonstrated as differentially expressed genes only in depressive asthma vs. healthy control. Twenty significant biological pathways were identified and were involved in inflammation, metabolism, immunity, tumor and cell cycle. Increased expression of phosphoinositide-3-kinase, regulatory subunit 1 (alpha) was confirmed in depressive asthmatics and it was inversely correlated with lung function (FEV1/FVC%). CONCLUSIONS: Asthmatics with depression exhibit unique pathophysiological pathways and this result may provide clues for specific molecular mechanisms underlying asthma with depression.

A preliminary study towards downregulation of murine bone marrow eosinophilopoiesis mediated by small molecule inhibition of interleukin-5 receptor alpha gene in vitro.

BACKGROUND: Bone marrow eosinophilopoiesis induced by IL-5 makes a major contribution to eosinophilic airway inflammation in asthma. Bone marrow CD(34)(+) cells expressing IL-5Ralpha may be eosinophil progenitors. However, research on the effect of blocking IL-5Ralpha expression on bone marrow eosinophilopoiesis has seldom been reported. OBJECTIVE: To explore the effect of inhibiting IL-5Ralpha expression with IL-5Ralpha short hairpin RNA-expressing vector on murine bone marrow eosinophilopoiesisin vitro. METHODS: We constructed 4 kinds of plasmid vectors that could express small molecule inhibition, short hairpin RNA, which targeted IL-5Ralpha (P-IL-5Ralpha), and selected an effective one by transfecting B lymphoma cells in vitro. We also constructed an adenovirus vector which was inserted into an effective template sequence (Ad-IL-5Ralpha). The bone marrow cells were obtained from healthy Balb/c mice, and cultured and transfected by Ad-IL-5Ralpha in vitro. The expression of IL-5Ralpha and the count of newly produced eosinophils were detected in the cultured bone marrow cells. RESULTS: We found that P-IL-5Ralpha-3 targeted at the sequence of CAG CTG CCT GGT TCG TCT T markedly suppressed the IL-5Ralpha expression in the B lymphoma cellsin vitro. Ad-IL-5Ralpha could suppress the IL-5Ralpha expression of murine bone marrow cellsin vitro and it could also significantly decrease the IL-5-induced eosinophilia in the cultured bone marrow cells. CONCLUSION: These results indicate that the blocking of IL-5Ralpha expression by small molecule inhibition can help to effectively decrease murine bone marrow eosinophilopoiesis, and that bone marrow may be used as a critical target organ in the diseases involved in eosinophilia, such as asthma.

Effect of interleukin-5 receptor-alpha short hairpin RNA-expressing vector on bone marrow eosinophilopoiesis in asthmatic mice.

Bone marrow eosinophilopoiesis induced by interleukin (IL)-5 is a major contributor to eosinophilic airway inflammation in asthma. However,research on the use of IL-5 receptor alpha (IL-5Ralpha) as the target has seldom been reported. This study was undertaken to explore the effects of inhibition of IL-5Ralpha expression through an IL-5Ralpha short hairpin RNA-expressing vector on bone marrow eosinophilopoiesis and airway inflammation in an asthmatic mouse model. An effective plasmid vector was selected that could express short hairpin RNA targeted at IL-5Ralpha (P-IL-5Ralpha). An adenovirus vector (Ad) was then constructed that was inserted in an effective template sequence (Ad-IL-5Ralpha). An animal model of asthma was established by sensitizing and challenging Balb/c mice with ovalbumin. Animals were treated intravenously with Ad-IL-5Ra and changes in bone marrow eosinophilopoiesis and airway inflammation were detected in asthmatic mice. Investigators found that P-IL-5Ra-3 targeted at the sequence of CAG CTG CCT GGT TCG TCT T markedly suppressed IL-5Ralpha expression in B lymphoma cells in vitro. In addition, Ad-IL-5Ralpha could suppress IL-5Ralpha expression in murine bone marrow cells in vitro and in vivo, and it could significantly decrease IL-5-induced eosinophilia in cultured bone marrow cells. Additional studies indicated that intravenously injected Ad-IL-5Ralpha not only selectively reduced the number of eosinophils in the bone marrow, peripheral blood, and bronchoalveolar lavage fluid, it also relieved airway inflammation in asthmatic mice. Results reported here show that blocking of IL-5Ralpha expression through RNA interference can enhance effective treatment of asthma, and that bone marrow can be used as a key targeted organ in the treatment of asthmatic mice.