The association between sleep duration and lung cancer: a meta-analysis.

PURPOSE: The link between sleep duration and lung cancer risk has been suggested by some epidemiological studies. This meta-analysis was performed to further understand this relationship. METHODS: MEDLINE and EMBASE entries up to December 2022 were searched for eligible publications. A random effects model was used to calculate pooled relative risks (RRs) with 95% confidence intervals (95% CIs). Publication bias was estimated using Begg's and Egger's regression asymmetry test. RESULTS: The meta-analysis included 11 studies (including 10 cohort studies and 1 case-control study). The pooled adjusted RRs were 1.13 (95% CI: 1.03-1.24) for short sleep duration and 1.21 (95% CI: 1.07-1.37) for long sleep duration. CONCLUSION: The findings of this meta-analysis suggested that both short and long sleep duration are associated with an increase in lung cancer risk. These findings need to be corroborated through large-scale prospective studies.

Elevated ADAR expression is significantly linked to shorter overall survival and immune infiltration in patients with lung adenocarcinoma.

To date, few studies have investigated whether the RNA-editing enzymes adenosine deaminases acting on RNA (ADARs) influence RNA functioning in lung adenocarcinoma (LUAD). To investigate the role of ADAR in lung cancer, we leveraged the advantages of The Cancer Genome Atlas (TCGA) database, from which we obtained transcriptome data and clinical information from 539 patients with LUAD. First, we compared ARAR expression levels in LUAD tissues with those in normal lung tissues using paired and unpaired analyses. Next, we evaluated the influence of ADARs on multiple prognostic indicators, including overall survival at 1, 3 and 5 years, as well as disease-specific survival and progression-free interval, in patients with LUAD. We also used Kaplan-Meier survival curves to estimate overall survival and Cox regression analysis to assess covariates associated with prognosis. A nomogram was constructed to validate the impact of the ADARs and clinicopathological factors on patient survival probabilities. The volcano plot and heat map revealed the differentially expressed genes associated with ADARs in LUAD. Finally, we examined ADAR expression versus immune cell infiltration in LUAD using Spearman's analysis. Using the Gene Expression Profiling Interactive Analysis (GEPIA2) database, we identified the top 100 genes most significantly correlated with ADAR expression, constructed a protein-protein interaction network and performed a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis on these genes. Our results demonstrate that ADARs are overexpressed in LUAD and correlated with poor patient prognosis. ADARs markedly increase the infiltration of T central memory, T helper 2 and T helper cells, while reducing the infiltration of immature dendritic, dendritic and mast cells. Most immune response markers, including T cells, tumor-associated macrophages, T cell exhaustion, mast cells, macrophages, monocytes and dendritic cells, are closely correlated with ADAR expression in LUAD.

HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small Cell Lung Cancer.

PURPOSE: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. EXPERIMENTAL DESIGN: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). RESULTS: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. CONCLUSIONS: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.

Efficacy, safety and pharmacokinetics of Unecritinib (TQ-B3101) for patients with ROS1 positive advanced non-small cell lung cancer: a Phase I/II Trial.

This phase I/II trial characterized the tolerability, safety, and antitumor activities of unecritinib, a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1, ALK, and c-MET, in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements. Eligible patients received unecritinib 100, 200, and 300 mg QD, and 200, 250, 300, and 350 mg BID in a 3 + 3 design during dose escalation and 300 and 350 mg BID during expansion. Phase II trial patients received unecritinib 300 mg BID in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) per independent review committee (IRC). Key secondary endpoints included intracranial ORR and safety. The ORR of 36 efficacy evaluable patients in the phase I trial was 63.9% (95% CI 46.2%, 79.2%). In the phase II trial, 111 eligible patients in the main study cohort received unecritinib. The ORR per IRC was 80.2% (95% CI 71.5%, 87.1%) and the median progression-free survival (PFS) per IRC was 16.5 months (95% CI 10.2, 27.0). Additionally, 46.9% of the patients who received recommended phase II dose of 300 mg BID experienced grade 3 or higher treatment-related adverse events. Treatment-related ocular disorders and neurotoxicity occurred in 28.1% and 34.4% of patients, respectively, but none was grade 3 or higher. Unecritinib is efficacious and safe for ROS1 inhibitor-naive patients with ROS1-positive advanced NSCLC, particularly patients with brain metastases at baseline, strongly supporting that unecritinib should become one of the standards of care for ROS1-positive NSCLC.ClinicalTrials.gov identifier: NCT03019276 and NCT03972189.

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.

miR-137 represses migration and cell motility by targeting COX-2 in non-small cell lung cancer.

Background: Lung cancer is a common malignant tumor, with, non-small cell lung cancer (NSCLC) accounting for about 80-85% of cases. This study investigated the expression of miR-137 in NSCLC tissues and cells and its effects on the migration and invasion of NSCLC cells and related mechanisms. Methods: We collected the neoplastic and paracancerous tissues of NSCLC patients, detected the expression of miR-137 in NSCLC tissues and cell lines by real-time quantitative polymerase chain reaction (RT-qPCR), and analyzed the correlation between miR-137 expression and the clinicopathological features and survival of NSCLC. Following transfection with miR-137 mimic or inhibitor in NSCLC cell lines (A549 or H1299) to upregulate or downregulate the expression of miR-137, transwell assay was employed to detect the effects of miR-137 on migration or invasion. Online software was employed to predict and analyze the target gene of miR-137, and luciferase reporter gene system was adopted to validate it. The effects of miR-137 on the expressions of COX-2 and Epithelial-Mesenchymal Transition (EMT) related proteins were investigated by Western blot. Results: Compared to paracancerous tissues and BEAS-2B cells, the expressions of miR-137 in NSCLC tissues, A549 and H1299 cells were dramatically down-regulated (P<0.01). After transfection with miR-137 mimic or inhibitor in A549 and H1299 cells, the miR-137 expressions were markedly up-regulated or down-regulated (P<0.01), respectively. The number of migrating or invading cells was observably decreased or increased (P<0.01) after transfected with mimic or inhibitor, respectively, while relative luciferase activity was evidently decreased in cells co-transfected with miR-137 mimic and wild type recombined vector of 3'UTR of COX-2. While the expressions of COX-2 and E-cadherin were both substantially reduced in A549 cells treated with miR-137 mimic, that of vimentin was substantially raised. The expression of miR-137 correlated with smoking history, lymph node metastasis, and TNM clinical stage, and patients with high miR-137 expression had apparent longer survival. Conclusions: The expression of miR-137 was significantly down-regulated in NSCLC tissues and cells, and correlated with NSCLC progress. miR-137 suppressed the migration and invasion of NSCLC cells through regulating EMT relative proteins by targeting COX-2. miR-137 is expected to become a novel biomarker and therapeutic target of NSCLC.

AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations.

PURPOSE: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768). METHODS: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

CircRNA protein tyrosine phosphatase receptor type a suppresses proliferation and induces apoptosis of lung adenocarcinoma cells via regulation of microRNA-582-3p.

Circular RNAs (circRNAs) are associated with cancer progression. The present study aimed to examine the function of circRNA protein tyrosine phosphatase receptor type A (circRNA_PTPRA) in lung cancer cells and elucidate the underlying molecular mechanisms. The levels of circRNA_PTPRA and microRNA (miRNA/miR)-582-3p were measured in lung cancer tissue and cells using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation and apoptosis were evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. The expression of cyclin D1, caspase-3, and cleaved caspase-3 was assessed via western blotting. The sites of circRNA_PTPRA/miR-582-3p interaction were identified using StarBase, and validated using a dual-luciferase reporter assay. We observed that circRNA_PTPRA levels were remarkably decreased, and miR-582-3p expression was up-regulated in lung cancer tissues and cells. circRNA_PTPRA directly interacts with miR-582-3p and downregulates miR-582-3p expression in lung cancer cells. Moreover, an miR-582-3p inhibitor decreased lung cancer cell proliferation and promoted apoptosis. The overexpression of circRNA_PTPRA decreased cell proliferation and increased apoptotic cell numbers, whereas miR-582-3p overexpression reversed these effects. These findings demonstrate that the up-regulation of circRNA_PTPRA significantly reduces lung cancer cell proliferation and induces apoptosis by regulating miR-582-3p expression.

Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with poor prognosis and treatment options are scarce. Immunotherapy has shown robust clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with standard chemotherapy as a first-line treatment for ES-SCLC. METHODS: The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18-75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305. FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI 0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death). INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals.

On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial.

BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.

Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial.

INTRODUCTION: Camrelizumab, a humanized immunoglobulin G4-κ monoclonal antibody against programmed cell death protein 1, has exhibited antitumor activity and tolerability across various tumors, including lung cancers. We conducted this double-blind, randomized phase 3 trial to investigate the efficacy and safety of camrelizumab or placebo plus chemotherapy as first-line treatment for patients with advanced squamous NSCLC. The predictive value of circulating tumor DNA (ctDNA) dynamics was also analyzed. METHODS: CameL-sq, a double-blind, randomized phase 3 trial (NCT03668496), was conducted in 53 centers in the People's Republic of China. A total of 389 patients with stage IIIB-IV squamous NSCLC were randomized (1:1) to receive 4 to 6 cycles of carboplatin plus paclitaxel with camrelizumab or placebo (every 3 wk), followed by maintenance therapy with camrelizumab or placebo. Peripheral blood ctDNA samples were collected at baseline and the time after two cycles of treatment. RESULTS: Of 389 eligible patients, 193 patients allocated camrelizumab plus chemotherapy and 196 patients allocated placebo plus chemotherapy were included in the efficacy and safety analysis. The results revealed significantly prolonged progression-free survival (median, 8.5 vs. 4.9 mo; p <0.0001) and overall survival (median, not reached vs. 14.5 mo; p <0.0001) with camrelizumab-chemotherapy versus placebo-chemotherapy. No unexpected treatment immune-related adverse events were observed in both groups. Biomarker analysis revealed that ctDNA clearance after two cycles of treatment was independently associated with dramatically longer progression-free survival (p <0.0001) and overall survival (p <0.0001) in camrelizumab plus chemotherapy group. CONCLUSIONS: Our findings support camrelizumab plus chemotherapy as a first-line treatment option in advanced squamous NSCLC. On-treatment ctDNA dynamics exhibited the potency to predict the efficacy of camrelizumab plus chemotherapy.

Efficacy of Aumolertinib (HS-10296) in Patients With Advanced EGFR T790M+ NSCLC: Updated Post-National Medical Products Administration Approval Results From the APOLLO Registrational Trial.

INTRODUCTION: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. METHODS: Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. RESULTS: A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. CONCLUSIONS: Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

The prognostic value of longitudinal circulating tumor DNA profiling during osimertinib treatment.

BACKGROUND: Serial profiling of circulating tumor DNA (ctDNA) could reflect dynamic molecular changes in response to treatment and potentially predict impending disease progression (PD). Herein, we investigated the molecular factors and dynamic changes in ctDNA that can serve as predictors of survival outcomes of patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) who received osimertinib therapy after progression from prior EGFR inhibitor regimen. METHODS: Capture-based targeted sequencing was performed on the baseline and longitudinal plasma samples collected from 72 and 57 patients, respectively, using a 168-gene panel. RESULTS: Analysis revealed that inferior overall survival (OS) was correlated with various baseline molecular features including high allelic fraction (AF) of EGFR sensitizing mutations (P=0.045), high maximum AF (maxAF, P=0.060), or harboring concurrent genomic alterations such as copy number amplification (CNA) in EGFR (P=0.026) or in other genes (P=0.026), and genes involved in the cell cycle (P=0.004) or TP53 signaling pathway (P=0.032). Moreover, ctDNA clearance at first follow-up after 6 weeks of osimertinib therapy was correlated with significantly longer progression-free survival (PFS) (P=0.022) and OS (P=0.009). Molecular PD, reflected by the emergence of new mutation or increased AF of existing mutations, was detected at an average lead time of 2.5 months prior to radiological PD. Patients with molecular PD were more likely to harbor CNA (P=0.035) and TP53 mutations (P=0.023). CONCLUSIONS: Molecular factors derived from serial ctDNA profiling can serve as predictive and prognostic markers, which could allow early detection of PD, preceding imaging modalities by 2.5 months.

Simultaneous in situ detection of protein expression of multiple tumor markers of circulating tumor cells and heteroploid of chromosome 8 in primary lung cancer.

BACKGROUND: Previously published studies have shown that circulating tumor cells (CTC) play an important role in clinical staging, efficacy monitoring and prognostic evaluation of lung cancer. The aim of the present study was to investigate the significance of simultaneous in situ detection of multiple tumor marker protein expression and chromosome 8 aneuploid of CTC in the diagnosis and treatment of primary lung cancer. METHODS: We investigated the expression of cytokeratin 18 (CK18) and Vimentin on the surface of CTC and the aneuploidy of chromosome 8 in the peripheral blood of 24 patients with metastatic primary lung cancer, which were detected by subtraction enrichment (SE) and immunofluorescence in situ hybridization (iFISH). Their correlation with clinicopathological features, curative effect, and prognosis was analyzed. RESULTS: The positive rate of CTC was 95.83% (23/24). There was a certain correlation between the positive rate of CTC and smoking, and a correlation between the number of CTC and histopathological type. The number of monoploid, diploid, triploid, and polyploid CTC had no statistical correlation with progression-free survival (PFS) or overall survival (OS). However, a tetraploid CTC count of ≥2 was an unfavorable predictor of response; a tetraploid CTC count ≥1 was an unfavorable prognostic predictor of poor OS. The rate of CK18+ CTC in all 24 patients was 4.35% (1/23). Seven out of these 24 patients were also tested for Vimentin, and the rate of Vimentin+ CTC was 85.71% (6/7). Small-cell (≤5 µm) CTC was found in 6 of these 7 patients and accounted for 11.83% (11/93) of the total CTC. The tumor marker phenotype of small-cell CTC was CK18- and Vimentin+. In addition, circulating tumor microthrombi (CTM) were found in 2 of these 7 patients (28.57%). CONCLUSIONS: SE-iFISH has a high detection rate of CTC in the peripheral blood of patients with metastatic primary lung cancer, and it can identify small cell CTC. Tetraploid CTC count ≥2 can predict poor PFS in patients with advanced lung cancer. Tetraploid CTC count ≥1 could predict poor OS in patients with advanced lung cancer. CTM can predict poor prognosis in patients with lung cancer.

Clinical characteristics of asymptomatic carriers of novel coronavirus disease 2019: A multi-center study in Jiangsu Province.

Asymptomatic SARS-CoV-2-infected individuals are thought to play major roles in virus transmission. This study aimed to analyze the characteristics of asymptomatic carriers with COVID-19 to control the spread of the virus. We retrospectively investigated the clinical characteristics of 648 consecutive subjects who were enrolled in the study and were divided into asymptomatic carriers, mild cases, ordinary cases, severe or critical cases, and evaluated their impact on disease severity by means of Spearman correlation and multiple regression analyses. Receiver operating characteristic curve analysis was conducted to determine the optimum cutoff levels of laboratory findings for diagnostic predictors of asymptomatic carriers of COVID-19. In our study, a total of 648 subjects on admission with a mean age of 45.61 y including 345 males and 303 females were enrolled in our study. The leukocyte, lymphocyte, eosinophil, platelet, C-reactive protein, interleukin-6, CD3+, CD4+, and CD8 + T lymphocyte levels, and the erythrocyte sedimentation rate differed significantly among the groups (all p ≤ 0.05). Disease severity was negatively associated with the CD3+ (r = -0.340; p < 0.001), CD4+ (r = -0.290; p = 0.001) and CD8+ (r = -0.322; p < 0.001) T lymphocyte levels. The significant diagnostic predictors of asymptomatic carriers of COVID-19 included the blood cell, cytokine, and T lymphocyte subset levels. Inflammation and immune response may play important roles in disease progression. Hence, the laboratory parameters identified should be considered in clinical practice, which provide new insights into the identification of asymptomatic individuals and the prevention of virus transmission.

IMPDH2 promotes cell proliferation and epithelial-mesenchymal transition of non-small cell lung cancer by activating the Wnt/ß-catenin signaling pathway.

Inosine 5'-monophosphate dehydrogenase type II (IMPDH2) is an important enzyme involved in the biosynthesis of guanine nucleotides. Therefore, the present study aimed to investigate the potential and molecular mechanism of IMPDH2 in non-small cell lung cancer (NSCLC). Reverse transcription-quantitative PCR and immunohistochemistry were used to detect IMPDH2 expression levels in NSCLC tissues and cells. A Cell Counting Kit-8 assay, colony formation assay, flow cytometry, wound healing, Transwell assay, western blotting and immunofluorescence analyses were utilized to identify the effects of upregulated IMPDH2 levels on NSCLC cells. The expression levels of IMPDH2 have been discovered to be upregulated in several types of human cancer; however, the biological and clinical value of IMPDH2 in NSCLC remains unclear. The results of the present study revealed that the expression levels of IMPDH2 were significantly upregulated in NSCLC tissues. Furthermore, the genetic knockdown of IMPDH2 significantly hindered the proliferation, apoptosis, invasion, migration and epithelial-mesenchymal transition of NSCLC cells, whereas the overexpression of IMPDH2 achieved the opposite results. In addition, the results of the present study demonstrated that the inhibition of IMPDH2 inhibited the Wnt/ß-catenin signaling pathway by decreasing the expression levels of Wnt3a and ß-catenin, while increasing the expression levels of phosphorylated glycogen synthase kinase-3ß in NSCLC cells. These findings of the present study indicated that IMPDH2 may promote NSCLC progression by activating the Wnt/ß-catenin signaling pathway, which suggested that IMPDH2 may be a novel therapeutic target for patients with NSCLC.

Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer.

PURPOSE: The epithelial-to-mesenchymal transition (EMT) phenotype-based subsets of circulating tumor cells (CTCs) might be predictors of tumor progression. We evaluated the clinical properties of different phenotypic CTCs in patients with non-small cell lung cancer (NSCLC). Secondly, we explored the association between different phenotypic CTCs and the uptake of 18F-fluorodeoxyglucose (FDG) by the primary tumor on a positron emission tomographic (PET) scan. METHODS: Venous blood samples from 34 pathologically confirmed Stage IIB-IVB NSCLC patients were collected prospectively. CTCs were immunoassayed using a SE-i·FISH®CTC kit. We identified CTCs into cytokeratin positive (CK+) and cytokeratin negative (CK-) phenotypes. CTC classifications were correlated with the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Overall survival (OS) and progression-free survival (PFS) curves were produced using the Kaplan-Meier method. RESULTS: CTCs were detected in 91.2% of NSCLC patients. CTC counting was associated with TNM stage (P = 0.014) and distant metastasis (P = 0.007). The number of CK-CTCs was also positively associated with TNM stage (P = 0.022) and distant metastasis (P = 0.007). Both total CTC counting and CK-CTC counting did not show association with SUVmax value (P = 0.959, P = 0.903). Kaplan-Meier survival analysis demonstrated that patients with ≥ 7 CTCs had shorter OS (P = 0.003) and PFS (P = 0.001) relative to patients with < 7 CTCs). Notably, the number of CK-CTCs can act as independent risk factors for PFS (P = 0.044) and OS (P = 0.043) in NSCLC patients. However, SUVmax value was not associated with OS (P = 0.895) and PFS (P = 0.686). CONCLUSION: The CTC subpopulations could be useful evidence for testing metastasis and prognosis in NSCLC patients. The SUVmax value of the primary tumor was not related to prognosis in patients with NSCLC.

Clinical Characteristics and Predictors of Disease Progression in Severe Patients with COVID-19 Infection in Jiangsu Province, China: A Descriptive Study.

BACKGROUND: We studied patients with coronavirus disease 2019 (COVID-19) infected by severe acute respiratory syndrome coronavirus 2, a virus that originated in Wuhan, China, and is spreading over the country including Jiangsu Province. We studied the clinical characteristics and therapies of severe cases in Jiangsu Province. METHODS: A multicenter retrospective cohort study was conducted to analyze clinical, laboratory data and treatment of 60 severe cases with COVID-19 infection in Jiangsu Province between January 24, 2020 and April 20, 2020. The improvement and deterioration subgroups were compared to identify predictors of disease progression. RESULTS: A total of 653 infected cases with COVID-19 were reported in Jiangsu Province, of which 60 severe cases were included in this study. Up until April 20, 2020, the mortality of severe patients was 0%. The median age was 57 years. The average body mass index of these patients was 25 kg/m². White blood cell counts decreased in 45.0% of patients, lymphopenia in 63.3%, thrombocytopenia in 13.3% and procalcitonin levels in 88.3% of the patients were less than 0.5 ng/mL. There were no statistically significant differences in immunoglobulin therapy and GCs therapy between the improvement and deterioration subgroups. Logistic regression analysis identified higher levels of troponin T (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.00-1.08; P = 0.04), antiviral therapy with aerosol inhalation of interferon (OR: 6.33; 95% CI: 1.18-33.98; P = 0.03), and the application of non-invasive mechanical ventilation (OR: 1.99; 95%CI: 1.17-3.41; P = 0.01) as predictors of disease progression, whereas higher lymphocyte count (OR: 0.11; 95% CI: 0.02-0.57; P = 0.01) and early prone ventilation were associated with improvement (OR: 0.11; 95% CI: 0.01-0.98; P = 0.04). CONCLUSIONS: COVID-19 infection had a low mortality rate in Jiangsu Province, China. The higher levels of troponin T and lower lymphocyte count were predictors of disease progression. Early prone ventilation may be an effective treatment for severe cases.

AMPK α1 Downregulates ROS Levels Through Regulating Trx Leading to Dysfunction of Apoptosis in Non-Small Cell Lung Cancer.

PURPOSE: AMP-activated protein kinase α1 (AMPK α1) associates closely with cancers. However, the relationship between AMPK α1 and non-small cell lung cancer (NSCLC) is not fully understood. In this study, we aim to explore the role and mechanism of AMPK α1 in NSCLC initiation and progression. MATERIALS AND METHODS: A total of 165 clinical NSCLC specimens were included in the formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays. The expression levels of AMPK α1 and thioredoxin (Trx) in NSCLC cancer tissues and adjacent non-tumor lung tissues were measured through using immunohistochemistry. MTT assay was used to detect cell proliferation. Intracellular ROS levels were measured by using H2DCFDA reagent. Lentiviruses including LV-PRKAA1-RNAi, LV-PRKAA1 and a negative LV-control were used to infect A549 cells to modulate AMPK α1 expression in vitro. Immunoblotting was used to determine the modulation relationship between AMPK α1 and Trx. Log rank test and Kaplan-Meier survival analysis were performed to evaluate the significances of AMPK α1 and Trx expression levels on NSCLC patients' prognoses. RESULTS: AMPK α1 was highly expressed in NSCLC cancer tissues and correlated with poor prognosis in patients with NSCLC. In A549 cells, overexpression of AMPK α1 promoted proliferation, suppressed ROS levels and inhibited apoptosis. Moreover, inhibition of AMPK α1 expression achieved the opposite effects. Trx was significantly overexpressed in NSCLC cancer tissues; furthermore, Trx expressed much more in cytoplasm when compared with cell nucleus. Trx expression levels were positively correlated with AMPK α1 expression levels in NSCLC tissues. AMPK α1 could regulate Trx in A549 cells. No significant correlations were observed between Trx expression variances and prognoses in NSCLC patients. Combination of AMPK α1 and Trx had no advantage in predicting prognoses of NSCLC patients. CONCLUSION: These results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of Trx expression, and thus represents a potential treatment target in patients with NSCLC.

Rare cause of repeated pulmonary embolism: a case of primary pleural squamous cell carcinoma and literature review.

BACKGROUND: Malignant tumors are risk factors for a pulmonary embolism (PE), and a PE caused by a tumor is not uncommon. Primary pleural squamous cell carcinoma (PPSCC) is a rare malignancy; thus, a related PE is extremely rare. CASE PRESENTATION: A previously healthy 49-year-old female patient was admitted to Northern Jiangsu People's Hospital owing to chest tightness, cough, and breathing difficulty that persisted for 3 days. Following admission, a computed tomography (CT) pulmonary angiography revealed an embolism in the main pulmonary artery, upper and lower pulmonary artery branch. The patient was treated with alteplase, warfarin, and antibiotics. Over the following year, she experienced recurrent chest pain and tightness and breathing difficulty, with multiple CT pulmonary angiography revealing thrombosis in the right and left main pulmonary artery. No abnormalities were observed in surrogate markers of autoimmune diseases, tumor antigen testing, or ultrasonography; thus, the cause of recurrent PE was not identified. Subsequently, a positron emission tomography-computed tomography (PET-CT) examination revealed diffuse heterogeneous thickening of the right pleura and substantially increased glucose metabolism. A CT-guided pleural biopsy was performed, and histopathological examination of the pleura eventually revealed a diagnosis of PPSCC. CONCLUSIONS: PPSCC is a rare tumor that lacks specific clinical manifestations and is difficult to detect with imaging techniques. The occurrence of PE as the primary manifesting symptom in a patient with PPSCC is extremely rare. Thus, malignant tumors should be considered in patients with no risk factors for PE and/or in those with recurrent PE. An immediate diagnosis and adequate intervention can be achieved with increased awareness of this diagnosis and subsequent related examinations.