Immunotherapy efficacy predictive tool for lung adenocarcinoma based on neural network.

Background: Remarkably, the anti-cancer efficacy of immunotherapy in lung adenocarcinoma (LUAD) has been demonstrated. However, predicting the beneficiaries of this expensive treatment is still a challenge. Materials and methods: A group of patients (N = 250) diagnosed with LUAD and receiving immunotherapy were retrospectively studied. They were randomly divided into a training dataset (80%) and a test dataset (20%). The training dataset was utilized to train neural network models to predict patients' objective response rate (ORR), disease control rate (DCR), responders (progression-free survival time > 6 months), and overall survival (OS) possibility, which were validated by both the training and test datasets and packaged into a tool later. Results: In the training dataset, the tool scored 0.9016 area under the receiver operating characteristic (AUC) curve on ORR judgment, 0.8570 on DCR, and 0.8395 on responder prediction. In the test dataset, the tool scored 0.8173 AUC on ORR, 0.8244 on DCR, and 0.8214 on responder determination. As for OS prediction, the tool scored 0.6627 AUC in the training dataset and 0.6357 in the test dataset. Conclusions: This immunotherapy efficacy predictive tool for LUAD patients based on neural networks could predict their ORR, DCR, and responder well.

BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation.

Introduction: Inflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown. Methods: The animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction. Results and conclusions: We show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1ß levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1ß production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation.

Assessing the efficacy of immunotherapy in lung squamous carcinoma using artificial intelligence neural network.

Background: At present, immunotherapy is a very promising treatment method for lung cancer patients, while the factors affecting response are still controversial. It is crucial to predict the efficacy of lung squamous carcinoma patients who received immunotherapy. Methods: In our retrospective study, we enrolled lung squamous carcinoma patients who received immunotherapy at Beijing Chest Hospital from January 2017 to November 2021. All patients were grouped into two cohorts randomly, the training cohort (80% of the total) and the test cohort (20% of the total). The training cohort was used to build neural network models to assess the efficacy and outcome of immunotherapy in lung squamous carcinoma based on clinical information. The main outcome was the disease control rate (DCR), and then the secondary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: A total of 289 patients were included in this study. The DCR model had area under the receiver operating characteristic curve (AUC) value of 0.9526 (95%CI, 0.9088-0.9879) in internal validation and 0.9491 (95%CI, 0.8704-1.0000) in external validation. The ORR model had AUC of 0.8030 (95%CI, 0.7437-0.8545) in internal validation and 0.7040 (95%CI, 0.5457-0.8379) in external validation. The PFS model had AUC of 0.8531 (95%CI, 0.8024-0.8975) in internal validation and 0.7602 (95%CI, 0.6236-0.8733) in external validation. The OS model had AUC of 0.8006 (95%CI, 0.7995-0.8017) in internal validation and 0.7382 (95%CI, 0.7366-0.7398) in external validation. Conclusions: The neural network models show benefits in the efficacy evaluation of immunotherapy to lung squamous carcinoma patients, especially the DCR and ORR models. In our retrospective study, we found that neoadjuvant and adjuvant immunotherapy may bring greater efficacy benefits to patients.

Application of ddPCR in detection of the status and abundance of EGFR T790M mutation in the plasma samples of non-small cell lung cancer patients.

Background/Objective: The third-generation epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitor (TKIs), such as osimertinib, designed for targeting the acquired drug-resistant mutation of EGFR T790M, was approved as the first-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC). Thus, detection of the EGFR T790M mutation for NSCLC is crucial. However, tissue samples are often difficult to obtain, especially in patients at advanced stages. This study assessed the performances of droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) in detecting EGFR T790M status and abundance in the plasma ctDNA samples of patients with NSCLC. We also explored the association between T790M status and abundance and the response to third-generation EGFR-TKIs. Methods: A total of 201 plasma samples with matched tissues, 821 plasma samples, and 56 patients who received third-generation EGFR-TKIs with response evaluation were included in this study. ddPCR and NGS were used to detect the mutation status and abundance of T790M in the tissues and/or blood samples. Results: The results showed that the sensitivity and the specificity of EGFR T790M mutation status detected by ddPCR in plasma samples were 81.82% and 91.85%, respectively, compared with the tissue samples, with a consistency coefficient of 0.740. Among the 821 plasma samples, the positive rates of EGFR T790M detected by ddPCR and NGS were 34.2% (281/821) and 22.5% (185/821), respectively. With NGS results as the reference, the sensitivity and the specificity of ddPCR were 100% and 84.91%, respectively, and the consistency coefficient of the two methods was 0.717. In addition, we found that a higher EGFR T790M abundance was linked to a higher treatment response rate to the third-generation EGFR-TKIs regardless of the classification of the median value of 0.43% (P = 0.016) or average value of 3.16% (P = 0.010). Conclusion: Taking these data together, this study reveals that ddPCR is an alternatively potent method for the detection of EGFR T790M in the plasma samples of NSCLC patients.

Erianin: A Direct NLRP3 Inhibitor With Remarkable Anti-Inflammatory Activity.

Erianin (Eri) is the extract of Dendrobium chrysotoxum Lindl. The NLRP3 inflammasome is a multiprotein complex that plays key roles in a wide variety of chronic inflammation-driven human diseases. Nevertheless, little is known about the protection of Eri against NLRP3 inflammasome-related diseases. In this study, we demonstrated that Eri inhibited NLRP3 inflammasome activation in vitro and in vivo. Mechanistically, Eri directly interacted with NLRP3, leading to inhibition of NLRP3 inflammasome assembly. Eri associated with the Walker A motif in the NACHT domain and suppressed NLRP3 ATPase activity. In mouse models, Eri had therapeutic effects on peritonitis, gouty arthritis and type 2 diabetes, via NLRP3. More importantly, Eri was active ex vivo for synovial fluid cells and monocytes from patients with IAV infection and gout. Eri may serve as a potential novel therapeutic compound against NLRP3-driven diseases.

Dynamics of Detection of Anti-SARS-CoV-2 IgG/IgM and SARS-CoV-2 RNA in Respiratory Tract Specimens in 48 COVID-19 Patients.

BACKGROUND: The rapid spread of pneumonia caused by SARS-CoV-2 has seriously threatened people. In this study, we detected the expression of anti-SARS-CoV-2 IgG/IgM and respiratory tract SARS-CoV-2 RNA in patients with COVID-19 and explored the correlation and clinical significance between SARS-CoV-2 antibody and respiratory SARS-CoV-2 RNA. METHODS: From March 5, 2020 to April 28, 2020, 48 cases with COVID-19 diagnosed in Beijing Xiaotangshan Hospital were enrolled. SARS-CoV-2 RNAs were detected by real-time fluorescence RT-PCR method. Serum SARS-CoV-2 IgG/IgM antibodies were determined by colloidal gold immunochromatography. The statistical analysis was performed using chi-squared test. RESULTS: In all the patients, SARS-CoV-2 RNA among 270 upper respiratory tract (nasal or throat swabs) samples, 71 lower respiratory tract (sputum) samples, and anti-SARS-CoV-2 IgM/IgG antibodies in 123 serum samples were detected during the hospitalization period. The positive rate of anti-SARS-CoV-2 IgG was significantly higher than that of anti-SARS-CoV-2 IgM within the first week after symptom onset (p < 0.05). The positive rate of anti-SARS-CoV-2 IgG was also significantly higher than that of anti-SARS-CoV-2 IgM during day 8 - 30 after symptom onset (p < 0.01). The positive rate of SARS-CoV-2 RNA in the lower respiratory tract specimens (64.8%, 46/71) was significantly higher than that in the upper respiratory tract (46.7%, 126/270) (p < 0.05). The positive rate (100%, 4/4) of SARS-CoV-2 RNA detection in the lower respiratory tract specimens before IgG seroconversion was significantly higher than that of the positive rate (59.3%, 32/54) after IgG seroconversion (p < 0.01). The positive rate (72.2%, 57/79) of SARS-CoV-2 RNA detection in the upper respiratory tract specimens before IgG seroconversion was significantly higher than that of the positive rate (30.7%, 39/127) after IgG seroconversion (p < 0.01). CONCLUSIONS: Anti-SARS-CoV-2 IgG might be detected within the first week after symptom onset. The application of SARS-CoV-2 antibody (IgG/IgM) detection is important for the suspected cases of SARS-CoV-2 infection with negative SARS-CoV-2 RNA results. The positive rate of SARS-CoV-2 RNA detection in the lower respiratory tract specimens was significantly higher than that in the upper respiratory tract. Sputum detection is recommended for the detection of SARS-CoV-2 RNA. Using lower respiratory tract specimens may reduce the false negative PCR tests. The detection of SARS-CoV-2 RNA can be improved by investigating follow-up specimens over time.

The Effect of Abusive Supervision on Safety Behaviour: A Moderated Mediation Model.

Leadership behavior has an impact on the behavior of employees. Previous studies have mainly studied the impact of positive leadership behaviors on employees' behaviors, but there is an absence of research on the impact of negative leadership behaviours (abusive supervision) on safety behaviours (including safety participation and safety compliance). In this study, 599 front-line employees in the petrochemical industry were selected as subjects. Abusive supervision, safety behaviour, safety motivation and a conscientiousness questionnaire were used as measurements to explore the relationship between abusive supervision and employee safety behaviors, and to further explore the roles of safety motivation, conscientiousness and the relationship between them. This study found that abusive supervision is negatively related to employee safety behaviours (safety compliance and safety participation); that safety motivation plays a mediating role in the relationship between abusive supervision and employees' safety behavior; and that conscientiousness moderates the role of safety motivation between the relationship of abusive supervision and employees' safety behaviour. With a higher level of conscientiousness, the indirect relationship between abusive supervision and employee safety behaviours is weaker. Finally, we discuss the theoretical and practical significance of these findings for abusive supervision and the management of safety behaviours.

Optimization of Optical Machine Structure by Backpropagation Neural Network Based on Particle Swarm Optimization and Bayesian Regularization Algorithms.

Fit of the highly nonlinear functional relationship between input variables and output response is important and challenging for the optical machine structure optimization design process. The backpropagation neural network method based on particle swarm optimization and Bayesian regularization algorithms (called BMPB) is proposed to solve this problem. A prediction model of the mass and first-order modal frequency of the supporting structure is developed using the supporting structure as an example. The first-order modal frequency is used as the constraint condition to optimize the lightweight design of the supporting structure's mass. Results show that the prediction model has more than 99% accuracy in predicting the mass and the first-order modal frequency of the supporting structure, and converges quickly in the supporting structure's mass-optimization process. The supporting structure results demonstrate the advantages of the method proposed in the article in terms of high accuracy and efficiency. The study in this paper provides an effective method for the optimized design of optical machine structures.

[Analysis of the Efficacy of Immunotherapy on the Posterior Lines 
of Advanced EGFR Mutant Patients with Non-small cell Lung Cancer].

BACKGROUND: Immune checkpoint inhibitor monotherapy is reported to have little effect in advanced non-small cell lung cancer (NSCLC) patients with driver oncogenes. However, recent studies have shown that some patients with driver genes are still benefit from combination immunotherapy after tyrosine kinase inhibitors (TKIs) drug resistance. The purpose of this study was to analyze the efficacy of posterior line immunotherapy in NSCLC patients with epidermal growth factor (EGFR) sensitive mutation, and to evaluate the value of immunotherapy in posterior line therapy in patients with advanced EGFR mutation. METHODS: A total of 27 patients with EGFR mutation diagnosed in Beijing Chest Hospital, Capital Medical University from June 2018 to November 2020 were collected. After the progress of targeted therapy, they had received programmed cell death protein 1 (PD-1) checkpoint inhibitor combined with chemotherapy and anti-angiogenic drug therapy. RESULTS: Of the 27 advanced NSCLC patients, 19 cases (70.4%) did not have T790M mutation. There were 8 cases (29.6%) with T790M point mutation. The total objective response rate (ORR) was 40.7%. Kaplan-Meier survival analysis showed that there was no statistically significant difference among different EGFR mutations (χ²=4.15, P=0.230). But progression-free survival (PFS) was significantly longer in patients without T790M mutation than in patients with T790M mutation (9.2 mon vs 3.3 mon, χ²=2.808, P=0.041), and the same trend was observed in patients with overall survival treated with the PD-1 inhibitor (12.2 mon vs 7.3 mon, χ²=3.22, P=0.062). ORR of patients without T790M was significantly better than that with T790M (52.63% vs 12.5%, P=0.045). CONCLUSIONS: Patients with EGFR mutation can benefit from later-line combined immunotherapy. The patients with T790M mutation in the population of EGFR mutation had the worst effect of immunotherapy in the later line. Therefore, the follow-up treatment and whole-course management of these patients need to explore better treatment strategies to improve the benefit.

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs.

PURPOSE: Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear. METHODS: From 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed. RESULTS: In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms. CONCLUSIONS: Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

[Evaluation of Response to Immune Checkpoint Inhibitor Monotherapy or 
Combination with Chemotherapy for Patients with Advanced Non-small Cell Lung Cancer and High PD-L1 Expression].

BACKGROUND: Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been widely used in the treatment of lung cancer. There are controversies in clinical practice for patients with advanced non-small cell lung cancer (NSCLC) and high programmed cell death-ligand 1 (PD-L1) expression receiving ICIs monotherapy or combination chemotherapy. METHODS: This study retrospectively analyzed the clinical data of 49 patients with advanced NSCLC and high PD-L1 expression. Immunohistochemistry was performed with 22C3 antibody, and the expression level of PD-L1 was evaluated according to tumor proportion score (TPS). Objective response rate (ORR) and progression free survival (PFS) were compared by groups of different clinical characteristics. RESULTS: ORR of monotherapy and combination therapy group was 47.1% (8/17) and 43.8% (14/32), respectively, without statistical difference (P=0.825). The median PFS of monotherapy and combination therapy group was 8.0 months and 6.8 months, respectively, without statistical difference (P=0.502). Statistical analysis of predictors of immunotherapy for the patients showed first-line immunotherapy had better ORR than subsequent immunotherapy (12/19, 63.2% vs 10/30, 33.3%, P=0.041), however no difference in PFS. And there were no differences in ORR or PFS among groups of age, gender, smoking status, performance status (PS), pathological type, tumor size and tumor-node-metastasis (TNM) stage. CONCLUSIONS: The therapeutic effect is similar between ICIs monotherapy and combination chemotherapy for patients with advanced NSCLC and high PD-L1 expression. ORR of first-line immunotherapy was better in patients with advanced NSCLC and high PD-L1 expression. The optimal treatment for this population remains further prospective clinical studies.

[A Real-world Study on the Assessment of Pathological Characteristics and Targeted Therapeutic Effect of Non-small Cell Lung Cancer Patients with Positive Driving Genes and High PD-L1 Expression].

BACKGROUND: Targeted therapy for patients with driver genes positive and immunotherapy for patients with driver gene-negative but high programmed death ligand 1 (PD-L1) expression are the standards of first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). The treatment options for patients with driver gene positive and high PD-L1 expression are still worth exploring. METHODS: The characteristics of 315 patients with NSCLC were identified to analyze the clinicopathological characteristics of patients with driver gene positive and high PD-L1 expression, and the efficacy of targeted therapy. RESULTS: Among the 315 patients, the total positive rate of driver genes was 62.2%, and the high PD-L1 expression rate (≥50.0%) was 11.2%. The proportion of patients with driver gene positive and high PD-L1 expression was 10.7%. PD-L1 was highly expressed in patients with epidermal growth factor receptor (EGFR) mutation, KRAS mutation, ALK fusion, BRAF mutation, and MET 14 exon skip mutation, the proportions were 7.8% (11/141), 18.2% (4/22), and 23.1%, (3/13), 50.0% (2/4) and 100.0% (1/1) respectively. EGFR mutation positive with PD-L1 high expression was mainly in patients with stage IV lung adenocarcinoma. KRAS mutation positive with PD-L1 high expression was mainly in patients with a history of smoking. Among them, two patients were followed in detail for targeted therapy, who with ALK fusion-positive and PD-L1 high expression (90.0%), EGFR L858R mutation and PD-L1 high expression (70.0%) respectively. The total OS of the patients was 5 months, 2 months. CONCLUSIONS: The high PD-L1 expression rate in NSCLC patients with different driver gene mutations was variable, which maybe correlated with distinct clinicopathological characteristics. Patients with sensitive mutations and high PD-L1 expression may be less benefit from targeted therapy and have poor prognosis.

Job Insecurity and Safety Behaviour: The Mediating Role of Insomnia and Work Engagement.

From the perspective of resource conservation theory, this study selected 568 enterprise employees as subjects and conducted data collection using a random sampling method to explore the relationship between job insecurity and safe behaviours as well as the role of insomnia and job engagement in this relationship. The results show that (1) job insecurity is negatively correlated with safety behaviour, (2) insomnia mediates the relationship between job insecurity and safety behaviour, (3) work engagement plays a mediating role in the relationship between job insecurity and safety behaviour, and (4) insomnia and work engagement play a serial mediating role in the relationship between job insecurity and safety behaviour.

The evaluation of a new multidimensional job insecurity measure in a Chinese context.

This study examines the psychometric properties of a new multidimensional job insecurity measure (JIM) by O'Neill and Sevastos in a Chinese context. Overall, the results corroborate the construct validity, reliability and criterion-related validity of the JIM. Based on the results of the exploratory factor analysis, the new scale has 15 items and three items were removed from the dimensions of job loss and job change because of differences in culture and understanding between Chinese and Western employees. Additionally, the relationship between job insecurity and theoretically viable antecedents (three different types of conflicts) and outcomes (i.e., job satisfaction and counterproductive work behaviour) were also examined, and the results show that the three conflicts are effective predictors of job insecurity and job insecurity is predictor of outcomes variables. All findings show that this new JIM is more parsimonious and more effective in assessing job insecurity in the Chinese context.

HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four different subtypes of HER2 exon 20 insertions were identified, including a rare subtype G778_S779insCPG never reported before with a partial response (PR) to pyrotinib and progression-free survival (PFS) of 12.8 months. Our findings reveal that HER2 exon 20 insertion mutations were detected in a small subset of lung adenocarcinomas. Given the different drug sensitivities, determining the mutation subtype by next-generation sequencing at the time of diagnosis might make sense.

Prognostic Significance of Serum miR-22, miR-125b, and miR-15b in Non-Small Cell Lung Cancer Patients.

BACKGROUND: Studies have shown that miRNA (miR) can be stably detected in serum, and aberrant expression of various miRNAs has shown diagnostic value in non-small cell lung cancer (NSCLC) patients. However, the role of miRNA in the context of prognosis has not been extensively investigated. Our previous study reported that miR-22, miR-125b, and miR-15b in serum had potential for use as tumor markers for auxiliary diagnosing of NSCLC. Therefore, the objective of this study was to detect the levels of miR-22, miR-125b, and miR-15b in serum from NSCLC patients and explore the potential prognostic significance of the three selected miRNAs. METHODS: The relative expression of miR-22, miR-125b, and miR-15b in 74 patients with advanced NSCLC in pre- and post-chemotherapy were detected by real-time quantitative polymerase chain reaction. RESULTS: Serum level of miR-125b significantly decreased after chemotherapy (p < 0.05) and the levels of miR-15b significantly increased (p < 0.01), while there was no change in the level of serum miR-22 (Z = 0.716, p > 0.05). Compared with pre-chemotherapy, serum miR-125b expression in advanced NSCLC patients of responders (CR + PR) were significantly decreased post-chemotherapy (p < 0.05); serum miR-15b expression in advanced NSCLC patients of responders (CR + PR) were increased (p < 0.01). The chemotherapy sensitivity of advanced NSCLC patients with high expression of miR-125b was lower than that of NSCLC patients with low expression (p < 0.05). The chemotherapy sensitivity of advanced NSCLC patients with high expression of miR-15b was higher than that of NSCLC patients with low expression (p < 0.05). High levels of serum miR-125b and low levels of serum miR-15b were related to poor overall survival (p < 0.05). CONCLUSIONS: The serum levels of miR-125b and miR-15b in advanced NSCLC patients were changed pre- and post-chemotherapy and these changes were associated with chemotherapeutic response. Serum miR-125b and miR-15b have certain potential clinical value for chemotherapeutic response in advanced NSCLC. The serum levels of miR-125b and miR-15b in patients with advanced NSCLC before treatment may be used to estimate the overall survival.

PD-L1+ aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients.

Sustained angiogenesis and increased PD-L1 expression on endothelial and carcinoma cells contribute toward fostering an immunosuppressive microenvironment suitable for tumor growth. PD-L1+ CTCs were reported to associate with poor prognosis in NSCLC patients. However, whether or not aneuploid circulating tumor endothelial cells (CTECs) express PD-L1, then serve as a surrogate biomarker to evaluate immunotherapy efficacy remains unknown. In this study, a novel SE-iFISH strategy was established to comprehensively quantify and characterize a full spectrum of aneuploid CTCs and CTECs in advanced NSCLC patients subjected to second-line anti-PD-1 (nivolumab) immunotherapy. In situ co-detection of diverse subtypes of aneuploid CTCs and CTECs expressing PD-L1 and Vimentin was performed. The present clinical study demonstrated that significant amounts of PD-L1+ aneuploid CTCs and CTECs could be detected in histopathologic hPD-L1- patients. In contrast to decreased PD-L1+ CTCs, the number of multiploid PD-L1+ CTECs (≥tetrasomy 8) undergoing post-therapeutic karyotype shifting increased in patients along with tumor progression following anti-PD-1 treatment. Progressive disease (PD) lung cancer patients possessing multiploid PD-L1+ CTECs had a significantly shorter PFS compared to those without PD-L1+ CTECs. In carcinoma patients, aneuploid CTCs and CTECs may exhibit a functional interplay with respect to tumor angiogenesis, progression, metastasis, and response to immunotherapy.

Comparison of Lacrosse Non-Slip Elements and Cutting Balloons in Treating Calcified Coronary Lesions: a Retrospective, Single-Blind Randomized Controlled Study.

INTRODUCTION: The present study aimed to compare Lacrosse non-slip elements (NSE) and cutting balloons in treating calcified coronary lesions. METHODS: A retrospective analysis was performed in 79 patients, who were diagnosed with moderate to severe calcified coronary lesions by coronary angiography, and underwent interventional therapy from January to December 2017. Lacrosse NSEs were used in 41 patients, while cutting balloons were used in 38 patients. The basic clinical characteristics, angiographic images, perioperative parameters, operation durations, interventional complications and incidence of major adverse cardiovascular events were compared. RESULTS: There was no significant difference in age, gender and risk factors between the two groups (P > 0.05). Furthermore, there was no significant difference in operation duration, and perioperative and postoperative complications between the two groups (P > 0.05). CONCLUSION: Compared with cutting balloons, the Lacrosse NSE has a similar effect in treating moderate to severe calcified coronary lesions.

Nivolumab-induced Thyroid Dysfunctions in Patients with Previously Treated Non-small Cell Lung Cancer.

BACKGROUND: Nivolumab, a fully human IgG4 programmed cell death-1 checkpoint inhibitor, demonstrated its benefit of prolonged survival in advanced non-small cell lung cancer (NSCLC). However, nivolumab generated unique immune-related adverse events such as thyroid dysfunctions. Herein we assessed nivolumab-induced thyroid dysfunctions in patients with previously treated advanced NSCLC in our hospital. METHODS: The medical records of 11 patients with advanced NSCLC who were initiated with nivolumab treatment between June 28, 2018, and January 15, 2019, in our hospital were reviewed. Serological tests of thyroid-stimulating hormone and free tetraiodothyronine were measured at baseline and every 8 weeks. RESULTS: Three out of 11 patients developed new-onset hypothyroidism during the treatment, and two of three patients had transient hyperthyroidism first. Two patients were diagnosed with Grade 2 hypothyroidism and received levothyroxine therapy. The other one was Grade 1 hypothyroidism and asymptomatic. All these three patients continued nivolumab therapy. CONCLUSION: Nivolumab-induced thyroid dysfunctions in advanced NSCLC were mostly mild and controlled. Thyroid function needs to be monitored for early prediction and appropriate managements of thyroid dysfunctions.

PD-L1 Expression and Its Regulation in Lung Adenocarcinoma with ALK Translocation.

BACKGROUND: The mechanism of regulation of PD-L1 expression by ALK translocation remains unclear. We detected PD-L1 protein expression and its regulation in lung adenocarcinoma patients with EML4-ALK fusion gene. METHODS: PD-L1 and ALK expression at protein level in human lung adenocarcinoma cell lines and tumor tissue specimens was evaluated by immunohistochemistry analysis and Western blotting. The expression at DNA level and RNA level was indicated by quantitative real-time PCR analysis. The signal pathway was indicated at protein level by western blotting. RESULTS: The PD-L1 protein expression was higher in human lung adenocarcinoma cell lines with EML4-ALK fusion gene than that without this fusion gene. Induced expression of EML4-ALK in A549 cells significantly increased PD-L1 protein expression, whereas PD-L1 protein expression was downregulated after crizotinib and pembrolizumab successively. Significant positive correlations between PD-L1 and p-ERK, p-STAT3 or p-AKT expression were observed in ALK-translocated tumors. PD-L1 overexpression was significantly associated with shorter progressive survival and overall survival after crizotinib in ALK-translocated patients. CONCLUSIONS: We demonstrate that ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.