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Objectives: The clinical significance of bacteremia in patients with complicated pleural infection is still uncertain. We aimed to examine the incidence and clinical significance of bacteremia in patients with complicated pleural infection. Methods: This retrospective study comprised of consecutive patients who received pleural drainage due to complicated parapneumonic effusion or empyema. The clinical, laboratory, and radiologic data and clinical outcome were compared between patients with and without bacteremia. Additionally, the factors associated with overall mortality were evaluated in these patients. Results: Of 341 patients included in the analysis, 25 (7â¯%) had a positive blood culture. Blood culture testing added 2â¯% identification of causative pathogen compared to pleural fluid culture alone. By multivariable analysis, radiologic features of cavitary lesion, a RAPID score≥5, and a positive microbial culture in pleural fluid were independently associated with bacteremia. Despite these clinical distinctions, there was ultimately no significant difference in in-hospital mortality between patients with and without bacteremia (3 vs. 4â¯%, p=1.0). The only factor significantly associated with overall mortality among patients with complicated pleural infections was a higher RAPID score [HR=1.96 (95â¯% CI=1.35-2.84)]. Conclusions: The rate of bacteremia in patients with complicated pleural infection was 7â¯%. Blood culture testing demonstrated limited diagnostic yield and had minimal impact on clinical outcomes compared to pleural fluid culture. Therefore, it seems that blood culture testing is more advantageous for specific patients with suspected pleural infection who have cavitary lesions or a RAPID score≥5.
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INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.
Subject(s)
Bronchiectasis , Disease Progression , Pectoralis Muscles , Tomography, X-Ray Computed , Humans , Male , Female , Bronchiectasis/mortality , Bronchiectasis/diagnostic imaging , Aged , Pectoralis Muscles/diagnostic imaging , Retrospective Studies , Middle Aged , Hospitalization , Sarcopenia/diagnostic imaging , Sarcopenia/mortality , Sarcopenia/diagnosis , PrognosisABSTRACT
BACKGROUND/AIMS: Epidermal growth factor receptor (EGFR) mutation is important in determining the treatment strategy for advanced lung cancer patients with malignant pleural effusion (MPE). Contrary to serum carcinoembryonic antigen (S-CEA) levels, the associations between pleural fluid CEA (PF-CEA) levels and EGFR mutation status as well as between PF-CEA levels and treatment efficacy have rarely been investigated in lung adenocarcinoma patients with MPE. METHODS: This retrospective study enrolled lung adenocarcinoma patients with MPE and available PF-CEA levels and EGFR mutation results. The patients were categorized based on PF-CEA levels: < 10 ng/mL, 10-100 ng/mL, 100-500 ng/mL, and ≥ 500 ng/mL. The association between PF-CEA levels and EGFR mutation status as well as their therapeutic impact on overall survival was compared among the four groups. RESULTS: This study included 188 patients. PF-CEA level was found to be an independent predictor of EGFR mutation but not S-CEA level. The EGFR mutation rates were higher as the PF-CEA levels increased, regardless of cytology results or sample types. Among EGFR-mutant lung adenocarcinoma patients receiving EGFR-tyrosine kinase inhibitor (TKI) treatment, those with high PF-CEA levels had significantly better survival outcomes than those with low PF-CEA levels. CONCLUSION: High PF-CEA levels were associated with high EGFR mutation rate and may lead to a favorable clinical outcome of EGFR-TKI treatment in EGFR-mutant lung adenocarcinoma patients with MPE. These findings highlight the importance of actively investigating EGFR mutation detection in patients with suspected MPE and elevated PF-CEA levels despite negative cytology results.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Pleural Effusion, Malignant , Pleural Effusion , Humans , Pleural Effusion, Malignant/diagnosis , Pleural Effusion, Malignant/etiology , Pleural Effusion, Malignant/therapy , Carcinoembryonic Antigen/genetics , Carcinoembryonic Antigen/therapeutic use , Retrospective Studies , Protein Kinase Inhibitors/therapeutic use , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Lung Neoplasms/drug therapy , ErbB Receptors/genetics , Pleural Effusion/chemically induced , Pleural Effusion/diagnosis , Pleural Effusion/drug therapy , MutationABSTRACT
The data regarding pulmonary artery stump thrombosis (PAST) after lung cancer surgery are insufficient. The aim of the present study was to evaluate the incidence, clinical characteristics, and prognosis of PAST. We retrospectively investigated the incidence and clinical characteristics of PAST among patients who underwent lung resection for lung cancer at 2 institutions. We compared the clinical parameters between PAST and pulmonary embolism (PE) and examined the clinical course of patients with PAST. Of the 1885 patients, PAST was found in 36 patients (1.9%). Right lower lobectomy (nâ =â 13) and middle-lower bilobectomy (nâ =â 9) were the most common types of surgery. The median time interval from lung resection to the detection of PAST was 3.8 months. Immobilization and a history of cerebrovascular disease were not observed in the PAST group. Most of the patients with PAST (91.7%) were diagnosed incidentally, whereas many patients with PE (75.9%) were symptomatic at the time of diagnosis. During the follow-up, one patient (2.8%) had contralateral PE complications. However, no patients in the PAST group experienced pulmonary thromboembolism-related in-hospital death or adverse outcomes. There was no difference in the prognosis of patients with PAST according to the administration of anticoagulation. PAST was rarely detected in lung cancer patients on follow-up chest computed tomography after lung resection. Patients with PAST were asymptomatic in most cases and had relatively favorable clinical outcomes. However, these patients are at risk of contralateral PE, despite its rarity.
Subject(s)
Lung Neoplasms , Pulmonary Embolism , Venous Thrombosis , Humans , Retrospective Studies , Lung Neoplasms/surgery , Lung Neoplasms/complications , Pulmonary Artery/surgery , Hospital Mortality , Tertiary Care Centers , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Venous Thrombosis/etiology , Lung , Pulmonary Embolism/epidemiology , Pulmonary Embolism/etiology , Pulmonary Embolism/diagnosisABSTRACT
INTRODUCTION: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. RESULTS: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). CONCLUSION: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/surgery , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/genetics , Lipid Metabolism/genetics , Genotype , Polymorphism, Single Nucleotide , PrognosisABSTRACT
BACKGROUND: Neurogenic differentiation 1 (NeuroD1) is a representative small cell lung cancer (SCLC) transcription regulator involved in the carcinogenesis and behavior of SCLC. Histone modifications play an important role in transcription, and H3 lysine 4 trimethylation (H3K4me3) is primarily associated with promoter regions. METHODS: We investigated the association between single nucleotide polymorphisms (SNPs) in NeuroD1 and H3K4me3 coincident regions, selected using ChIP sequencing (ChIP-seq), and the clinical outcomes of 261 patients with SCLC. RESULTS: Among 230 SNPs, two were significantly associated with both the chemotherapy response and overall survival (OS) of patients with SCLC. RNF145 rs2043268A>G was associated with worse chemotherapy response and OS (under a recessive model, adjusted odds ratio [aOR], 0.50, 95% confidence interval [CI], 0.26-0.94, P = 0.031, and adjusted hazard ratio [aHR], 1.88, 95% CI, 1.38-2.57, P < 0.001). CINP rs762105A>G was also associated with worse chemotherapy response and OS (under a dominant model, aOR, 0.47, 95% CI, 0.23-0.99, P = 0.046, and aHR, 2.03, 95% CI, 1.47-2.82, P < 0.001). ChIP-quantitative polymerase chain reaction and luciferase assay confirmed that the two SNPs were located in the active promoter regions and influenced the promoter activity of each gene. CONCLUSION: To summarize, among SNPs selected using ChIP-seq in promoter regions with high peaks in both NeuroD1 and H3K4me3, RNF145 rs2043268A>G and CINP rs762105A>G were associated with clinical outcomes in patients with SCLC and also affected the promoter activity of each gene.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Histones/genetics , Histones/metabolism , Histones/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Promoter Regions, Genetic , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/geneticsABSTRACT
BACKGROUND: Stenotrophomonas maltophilia has been increasingly recognized as an opportunistic pathogen associated with high morbidity and mortality. Data on the prognostic factors associated with S. maltophilia pneumonia in patients admitted to intensive care unit (ICU) are lacking. METHODS: We conducted a retrospective analysis of data from 117 patients with S. maltophilia pneumonia admitted to the ICUs of two tertiary referral hospitals in South Korea between January 2011 and December 2022. To assess risk factors associated with in-hospital mortality, multivariable logistic regression analyses were performed. RESULTS: The median age of the study population was 71 years. Ventilator-associated pneumonia was 76.1% of cases, and the median length of ICU stay before the first isolation of S. maltophilia was 15 days. The overall in-hospital mortality rate was 82.1%, and factors independently associated with mortality were age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.09; P=0.046), Sequential Organ Failure Assessment (SOFA) score (OR, 1.21; 95%; CI, 1.02-1.43; P=0.025), corticosteroid use (OR, 4.19; 95% CI, 1.26-13.91; P=0.019), and polymicrobial infection (OR, 95% CI 0.07-0.69). However, the impact of appropriate antibiotic therapy on mortality was insignificant. In a subgroup of patients who received appropriate antibiotic therapy (n=58), antibiotic treatment modality-related variables, including combination or empirical therapy, also showed no significant association with survival. CONCLUSIONS: Patients with S. maltophilia pneumonia in ICU have high mortality rates. Older age, higher SOFA score, and corticosteroid use were independently associated with increased in-hospital mortality, whereas polymicrobial infection was associated with lower mortality. The effect of appropriate antibiotic therapy on prognosis was insignificant.
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High-level MET amplification (METamp) is a primary driver in â¼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Pyrimidines , Liquid BiopsyABSTRACT
Background: Patients with bronchiectasis commonly experience disease exacerbations, which cause significant morbidity and mortality. However, data regarding the clinical features of bronchiectasis patients hospitalized with hemoptysis are scarce. Methods: We retrospectively collected the data of patients with bronchiectasis-associated hospitalization at a tertiary referral center in Korea, and classified them into the hemoptysis and infective exacerbation (IE) groups. The presence of hemoptysis was defined as a volume of expectorated blood larger than 10 mL per 24 hours. The clinical, radiological, and laboratory parameters were compared between the two groups. Results: Patients were classified into the hemoptysis [267 (54.5%)] and IE [223 (45.5%)] groups. Among the 44 patients of the hemoptysis group, 37 (84.1%) presented with hemoptysis than with IE at the recurrent episode. The hemoptysis group had a significantly lower 30-day mortality than that of the IE group. Previous pulmonary tuberculosis (TB), mycetoma, and bronchial artery hypertrophy were independently associated with the hemoptysis group. In contrast, male sex, poor performance status, colonization of Pseudomonas aeruginosa, ≥3 involved lobes, cystic bronchiectasis, and emphysema were inversely associated with the hemoptysis group. The absence of hemoptysis was one of the independent predictors of 30-day mortality in patients with bronchiectasis-associated hospitalization. Conclusions: In Korea, bronchiectasis patients hospitalized with hemoptysis exhibit a distinct phenotype, and are more likely to have previous pulmonary TB, mycetoma, and bronchial artery hypertrophy. Hemoptysis is associated with a lower risk of short-term mortality compared to IE in bronchiectasis-associated hospitalization.
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BACKGROUND: Necroptosis is a regulated inflammatory cell death which plays a significant role in cancer development and progression. In this study, we evaluated whether genetic variants in key regulators of necroptosis may affect survival outcome of non-small cell lung cancer (NSCLC) patients after surgical resection. METHODS: A total of 674 patients who underwent curative surgery were included. Fifteen genetic variants in key regulators of necroptosis (RIPK1, RIPK3, and MLKL) were selected. The association of these variants with survival outcomes was evaluated. RESULTS: Two variants, RIPK1 rs17548629C > T and MLKL rs877375G > C, were associated with better overall survival and disease-free survival in multivariate analyses. When the patients were divided according to histology, the associations were significant only in adenocarcinoma, but not in squamous cell carcinoma. RIPK1 rs17548629 C-to-T change was associated with significantly increased luciferase activity by modulating the binding of miR-642a. Promoter assays showed a significantly increased promoter activity in MLKL rs877375C allele compared to G allele. Consistently, the mRNA expression level of RIPK1 and MLKL showed significant positive correlation with RIPK1 rs17548629C-to-T and MLKL rs877375G-to-C changes. CONCLUSION: Two genetic variants in key regulators in necroptosis, RIPK1 rs17548629C > T and MLKL rs877375G > C, may be used as biomarkers to predict survival outcomes in surgically resected NSCLC patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Protein Kinases/genetics , Protein Kinases/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/surgery , Necroptosis/genetics , Lung Neoplasms/genetics , Lung Neoplasms/surgery , PrognosisABSTRACT
Non-expandable lung (NEL) often occurs during pleural fluid drainage in patients with malignant pleural effusion (MPE). However, data regarding the predictors and prognostic impact of NEL on primary lung cancer patients with MPE receiving pleural fluid drainage, compared to malignant pleural mesothelioma (MPM), are limited. This study was aimed to investigate the clinical characteristics of lung cancer patients with MPE developing NEL following ultrasonography (USG)-guided percutaneous catheter drainage (PCD) and compare the clinical outcomes between those with and without NEL. Clinical, laboratory, pleural fluid, and radiologic data and survival outcomes of lung cancer patients with MPE undergoing USG-guided PCD were retrospectively reviewed and compared between those with and without NEL. Among 121 primary lung cancer patients with MPE undergoing PCD, NEL occurred in 25 (21%). Higher pleural fluid lactate dehydrogenase (LDH) levels and presence of endobronchial lesions were associated with development of NEL. The median time to catheter removal was significantly extended in those with NEL compared to those without (P = .014). NEL was significantly associated with poor survival outcome in lung cancer patients with MPE undergoing PCD, along with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), the presence of distant metastasis, higher serum C-reactive protein (CRP) levels, and not receiving chemotherapy. NEL developed in one-fifth of lung cancer patients undergoing PCD for MPE and was associated with high pleural fluid LDH levels and the presence of endobronchial lesions. NEL may negatively affect overall survival in lung cancer patients with MPE receiving PCD.
Subject(s)
Lung Neoplasms , Pleural Effusion, Malignant , Humans , Pleural Effusion, Malignant/diagnostic imaging , Pleural Effusion, Malignant/etiology , Pleural Effusion, Malignant/therapy , Retrospective Studies , Lung Neoplasms/complications , Cardiac Catheters , Drainage , LungABSTRACT
Limited data exist about the comparative immune cell population profile determined by cytometry by time-of-flight (CyTOF) analysis between active tuberculosis (TB) and latent TB infection (LTBI). In this study, we performed CyTOF analysis using peripheral blood mononuclear cells (PBMCs) to compare the differential immune cellular profile between active TB and LTBI. A total of 51 subjects (active TB [n = 34] and LTBI [n = 17]) were included. CyTOF analysis of 16 subjects (active TB [n = 8] and LTBI [n = 8]) identified a significantly higher Th17-like cell population in active TB than in LTBI. This finding was validated in the remaining 35 subjects (active TB [n = 26] and LTBI [n = 9]) using flow cytometry analysis, which consistently reveals a higher percentage of Th17 cell population in active TB (p = 0.032). The Th1/Th17 ratio represented good ability to discriminate between active TB and LTBI (AUC = 0.812). Among patients with active TB, the Th17 cell percentage was found to be lower in more advanced forms of the disease. Additionally, Th17 cell percentage positively correlated with the levels of IL-6 and neutrophil-lymphocyte ratio, respectively. In conclusion, CyTOF analysis of PBMCs showed a significantly higher percentage of Th17 cells in active TB although fairly similar immune cell populations between active TB and LTBI were observed.
Subject(s)
Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis , Humans , Latent Tuberculosis/diagnosis , Leukocytes, Mononuclear , Flow CytometryABSTRACT
BACKGROUND: Computed tomography (CT) is the mainstay imaging modality for suspected pleural malignancy. Tuberculous pleural effusion (TPE) can present with various pleural abnormalities. However, few studies have evaluated the different characteristics of pleural abnormalities on chest CT between TPE and malignant pleural effusion (MPE). METHODS: Pleural abnormalities on contrast-enhanced CT in 277 and 289 patients with confirmed TPE and MPE diagnoses, respectively, were retrospectively assessed and compared between the two groups. Discriminating factors and diagnostic performance for MPE were evaluated using multivariate analysis and receiver operating characteristic curves. RESULTS: Focal pleural thickening was present in 44 (16%) cases of TPEs and 202 (70%) of MPEs. Further characterization of focal pleural thickening showed that MPEs had a significantly greater number, larger maximal thickness, and more nodular contour form, compared to TPEs. On the other hand, diffuse and circumferential pleural thickening were significantly more common in TPEs. In multivariate analysis, independent predictors for MPE included focally thickened pleurae ≥7, maximum thickness ≥6 mm, nodular contour pattern, and the absence of diffuse pleural thickening. Out of all the individual or combined predictors for MPE, the presence of any one of the three sub-parameters of focal pleural thickening provided the best diagnostic yield with 66% sensitivity and 92% specificity. CONCLUSION: Although focal pleural thickening in TPE mimics that in MPE, the features of MPE are significantly different from those of TPE in terms of size, number, and contour. These different characteristics may help differentiate MPE from TPE in patients with suspected MPE.
Subject(s)
Pleural Effusion, Malignant , Pleural Effusion , Tuberculosis, Pleural , Humans , Pleural Effusion, Malignant/pathology , Retrospective Studies , Tuberculosis, Pleural/diagnostic imaging , Pleural Effusion/diagnosis , Tomography, X-Ray Computed , Diagnosis, DifferentialABSTRACT
BACKGROUND: Data regarding the clinical characteristics and treatment outcomes of patients with community-acquired pneumonia (CAP) and bronchiectasis (BE) are rare. This study aims to elucidate the clinical relevance of BE in patients with CAP. METHODS: Patients hospitalized with CAP in a single center were retrospectively analyzed and divided into significant BE (BE with ≥ 3 lobes or cystic BE on computed tomography) and control groups. Clinical and microbiological characteristics were compared between the two groups. RESULTS: In the final analysis, 2112 patients were included, and 104 (4.9%) had significant BE. The significant BE group exhibited a higher prevalence of sputum production, dyspnea, and complicated parapneumonic effusion or empyema than the control group. Pseudomonas aeruginosa was more frequently isolated in the significant BE group than in the control group, whereas Mycoplasma pneumoniae was less commonly identified. Length of hospital stay (LOS) was significantly longer in the significant BE group than the control group (12 [8-17] days vs. 9 [6-13] days, p < 0.001). In contrast, 30-day and in-hospital mortality rates did not significantly differ between the two groups. Furthermore, significant BE was an independent predictor of prolonged hospitalization in two models based on CURB-65 and pneumonia severity index. CONCLUSIONS: Significant BE occurred in approximately 5% of patients with CAP and was more likely to be associated with sputum, dyspnea, complicated parapneumonic effusion or empyema, and isolation of P. aeruginosa. Significant BE was an independent predictor of LOS in patients with CAP.
Subject(s)
Bronchiectasis , Community-Acquired Infections , Empyema , Pleural Effusion , Pneumonia , Humans , Retrospective Studies , Clinical Relevance , Pneumonia/complications , Pneumonia/epidemiology , Pneumonia/drug therapy , Pleural Effusion/drug therapy , Community-Acquired Infections/complications , Community-Acquired Infections/epidemiology , Community-Acquired Infections/drug therapy , Bronchiectasis/complications , Bronchiectasis/epidemiologyABSTRACT
BACKGROUND: Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small-cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. METHODS: In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. RESULTS: The SNP rs3806915C>A in semaphorin 6A (SEMA6A) gene was significantly associated with better chemotherapy response and OS (p = 0.04 and p = 0.04, respectively). The SNP rs11265375C>T in nescient helix-loop helix 1 (NHLH1) gene was also associated with better chemotherapy response and OS (p = 0.04 and p = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells (p = 4 × 10-6 ). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele (p = 0.001). CONCLUSION: These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/geneticsABSTRACT
BACKGROUND: Despite therapeutic advances, lung cancer prognosis remains poor. Loss of heterozygosity (LOH) in the 3p21 region is well documented in lung cancer, but the specific causative genes have not been identified. MATERIALS AND METHODS: Here, we aimed to examine the clinical impact of miR-135a, located in the 3p21 region, in lung cancer. miR-135a expression was assessed using quantitative real-time polymerase chain reaction. LOH was analyzed at microsatellite loci D3S1076 and D3S1478, and promoter methylation status was determined by pyrosequencing of resected samples of primary non-small-cell lung cancer (NSCLC). The regulation of telomerase reverse transcriptase (TERT) was evaluated in lung cancer cells H1299 by luciferase report assays after treatment with miR-135a mimics. RESULTS: miR-135a was significantly downregulated in squamous cell cancer (SCC) tumor tissues compared to normal tissues (p = 0.001). Low miR-135a expression was more frequent in patients with SCC (p = 2.9 × 10-4 ) and smokers (p = 0.01). LOH and hypermethylation were detected in 27.8% (37/133) and 17.3% (23/133) of the tumors, respectively. Overall, 36.8% (49/133) of the NSCLC cases harbored either miR-135a LOH or promoter hypermethylation. The frequencies of LOH and hypermethylation were significantly associated with SCCs (p = 2 × 10-4 ) and late-stage (p = 0.04), respectively. MiR-135a inhibited the relative luciferase activity of psiCHECK2-TERT-3'UTR. CONCLUSION: These results suggest that miR-135a may act as a tumor suppressor to play an important role in lung cancer carcinogenesis, which will provide a new insight into the translational value of miR-135a. Further large-scale studies are required to confirm these findings.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , MicroRNAs , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/genetics , Gene Expression Regulation, Neoplastic , Gene Silencing , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MicroRNAs/genetics , MicroRNAs/metabolismABSTRACT
BACKGROUND: Umeclidinium/vilanterol (UMEC/VI; ANORO ELLIPTA, GSK) is a commonly used dual bronchodilator. This study evaluated the safety and effectiveness of UMEC/VI in Korean patients with chronic obstructive pulmonary disease (COPD) over a 6-year period. METHODS: This was an open-label, multicentre, observational, post-marketing surveillance study. A total of 3,375 patients were enrolled consecutively in 52 hospitals, by 53 physicians, between July 2014 and July 2020. Patients who were administered UMEC/VI (fixed-dose 62.5 µg/25 µg) at least once and were monitored for safety and effectiveness were included in the analysis. Incidence and severity of adverse events (AEs) reported after administrating at least one dose of UMEC/VI were monitored, including unexpected adverse events (UAEs) and adverse drug reactions (ADRs). Effectiveness of UMEC/VI after 24 weeks of administration was also assessed using physician's evaluation (effective, ineffective/no change, worsening, indeterminable) and lung function improvement. RESULTS: Of 3,375 patients, 3,086 were included in the safety assessment group (mean age±standard deviation: 69.76±8.80 years; 85.9% male [n=2,652]; 73.1% aged ≥65 years [n=2,255]). The overall incidence of AEs was 28.8% (n=890), of which 2.2% (n=67) were ADRs. Serious AEs and UAEs were reported in 181 (5.9%) and 665 (21.6%) patients, respectively, and two patients (<0.1%) reported unexpected severe ADR. Of the 903/3,086 patients analysed for effectiveness, most (82.8%, n=748) showed overall disease improvement after UMEC/VI treatment. CONCLUSION: This study confirmed UMEC/VI administered to Korean patients according to the prescribing information was well-tolerated and can be considered an effective option for COPD treatment.
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OBJECTIVE: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. METHODS: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. RESULTS: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36-0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09-1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. CONCLUSION: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Pemetrexed/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Histone Code , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
This study was conducted to investigate the relationship between genetic variants in LKB1/AMPK/mTOR pathway and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. A total of 379 patients with NSCLC who underwent first-line paclitaxel-cisplatin chemotherapy was enrolled. The associations between 19 single nucleotide variants (SNVs) in the LKB1/AMPK/mTOR pathway and the chemotherapy response and overall survival (OS) were analyzed. Among the SNVs analyzed, AKT1 rs2494750G>C and TSC1 rs2809244C>A were associated with clinical outcomes after chemotherapy in multivariate analyses. The AKT1 rs2494750G>C was significantly associated with a better response to chemotherapy (adjusted odds ratio [aOR]: 1.92, 95% confidence interval [CI]: 1.02-3.62, p = 0.04). The TSC1 rs2809244C>A were significantly associated with better OS (adjusted hazard ratio [aHR]: 0.79, 95% CI: 0.62-0.99, p = 0.04). When stratified by tumor histology, AKT1 rs2494750G>C exhibited a significant association with the chemotherapy response only in adenocarcinoma and TSC1 rs2809244C>A was also significantly associated with OS only in adenocarcinoma. This result suggests that the AKT1 rs2494750G>C and TSC1 rs2809244 C>A may be useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.