Heterogeneous components of lung adenocarcinomas confer distinct EGFR mutation and PD-L1 expression.

BACKGROUND: Lung adenocarcinoma (LAC) is composed of lepidic, papillary, mucinous, micropapillary and solid components in its parenchyma. Complex responses to therapeutics result from intratumoral heterogeneity. However, it remains confused that what components in a mixed LAC tumor are responsible to the heterogeneous EGFR mutation and PD-L1 expression. METHODS: We investigated EGFR status via laser microdissection to capture spatially separated cancer cell subpopulations and digital droplet PCR to determine the abundance of EGFR sensitizing mutation and naïve T790M. Whilst, PD-L1 expression level via tumor proportion score (TPS) was evaluated by Ventana immunohistochemistry using SP263 antibody. PD-L1 expression levels were tiered in < 1, 1-49% and > =50% groups. RESULTS: EGFR mutation harbored in 154 (59%) of 261 LAC patients and more frequently occurred in papillary, lepidic and micropapillary constituents. Higher levels of PD-L1 were found in LACs at stage III and IV (68.3%) versus those at stage I and II (31.7%) (P = 0.04). Solid predominant LACs (41.3%) expressed PD-L1 with TPS > =50%, versus mucinous and lepidic LACs (P < 0.01). LACs with solid constituents also had more positive proportion of PD-L1 protein. Cut-offs < 1, 1-49% or > =50% were associated with patients' progression-free survival and longer in the < 1% group (22.9 month, 95% CI 17.6-28.2) (P < 0.05). LACs consisting of two constituents with PD-L1 TPS < 1% had a better prognosis than the groups with single component and more than two components (P < 0.05). Eighteen LACs (6.9%) had concomitantly deletion in exon 19 or L858R and naïve T790M mutation. The abundance of T790M varied diversely with sensitizing mutation. PD-L1 expression was not concordant in same components and usually negative in the EGFR-mutated constituents. Heterogeneous PD-L1 expression occurred in the vicinity of stromal tissues. 58.8, 29.4 and 11.8% in ALK positive LACs (N = 17) were found PD-L1 expression via cutoffs of < 1, 1-49% and > =50%, respectively (P > 0.05). CONCLUSION: Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns. Heterogeneous PD-L1 expression in higher level usually occurred in solid component both in EGFR mutated and EGFR wild-typed LACs. EGFR mutated LACs heterogeneously had sensitizing and resistant mutation and was accompanied with PD-L1 expression, but discordant among histological constituents. Immune checkpoint inhibitor combined with third generation EGFR tyrosine kinase inhibitor should be more effective to these LACs.

Analysis of Cytokine Levers in Pleural Effusions of Tuberculous Pleurisy and Tuberculous Empyema.

The aim is to examine whether the interleukin-1ß (IL-1ß), IL-2, IL-6, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type-1 (PAI-1), and tissue plasminogen activator (t-PA) levels were different in pleural effusions of tuberculous pleurisy and tuberculous empyema. IL-1ß, IL-2, IL-6, TNF-α, PAI-1, and t-PA levels in pleural fluids of 40 patients with tuberculous pleurisy and 38 patients with tuberculous empyema were measured. The levels of IL-1ß, PAI-1, and t-PA in the pleural effusions were different between tuberculous pleurisy and tuberculous empyema; it could be helpful to differentiate the two diseases. The levels of PAI-1, IL-1ß were higher and t-PA, IL-6 were lower in pleural effusions of the patients with tuberculous empyema and who must undergo operation than the patients who could be treated with closed drainage and anti-TB chemotheraphy. These indications may be helpful to evaluate whether the patient needs the operation.

Sarcopenia is associated with short- and long-term mortality in patients with acute-on-chronic liver failure.

BACKGROUND: While sarcopenia is recognized as a predictor of mortality in cirrhosis, its influence on acute-on-chronic liver failure (ACLF) remains uncertain. Despite multiple studies examining the impact of sarcopenia on short-term mortality in patients with ACLF, the sample size of these studies was limited, and their outcomes were inconsistent. Therefore, this study aimed to explore the impact of sarcopenia on both short- and long-term mortality in patients with ACLF. METHODS: This retrospective cohort study included 414 patients with ACLF that were treated between January 2016 and September 2022. Sarcopenia was diagnosed based on the measurement of the skeletal muscle index at the third lumbar vertebra (L3-SMI). Subsequently, the patients were divided into sarcopenia and non-sarcopenia groups. We analysed the basic clinical data of the two groups. Multivariate Cox proportional analysis was used to analyse short-term (28 days) and long-term (1 year and overall) mortality rates. RESULTS: A total of 414 patients were included, with a mean age of 52.88 ± 13.41 years. Among them, 318 (76.8%) were male, and 239 (57.7%) had sarcopenia. A total of 280 (67.6%) patients died during the study period. Among them, 153 patients died within 28 days (37%) and 209 patients died within 1 year (50.5%). We found that the 28-day, 1-year and overall mortality rates in the sarcopenia group were significantly higher than those in the non-sarcopenia group (37% vs. 22.3%, P < 0.01; 50.5% vs. 34.9%, P < 0.01; and 67.6% vs. 53.1%, P < 0.01, respectively). Multivariate Cox regression analysis revealed that sarcopenia was significantly associated with increased mortality. The hazard ratios for sarcopenia were 2.05 (95% confidence interval [CI] 1.41-3.00, P < 0.01) for 28-day mortality, 1.81 (95% CI 1.29-2.54, P < 0.01) for 1-year mortality and 1.82 (95% CI 1.30-2.55, P < 0.01) for overall mortality. In addition, muscle density and international normalized ratio were associated with short- and long-term mortality. CONCLUSIONS: Sarcopenia is associated with both short- and long-term mortality in patients with ACLF. Therefore, regular monitoring for sarcopenia is important for these patients.

A 2.5-cm single-port video-assisted thoracoscopic surgery for stage III tuberculous empyema: a case report.

BACKGROUND: Stage III tuberculous empyema is a common disease of tuberculosis. Traditionally, it has been treated by thoracotomy or video-assisted thoracoscopic surgery with two to four incisions. But conventional surgery has large trauma, large bleeding volume and long recovery time. To our knowledge it is the first report of surgery for stage III tuberculous empyema with a mini single-port approach. CASE PRESENTATION: A 23-year-old woman admitted to our hospital with complaints of intermittent chest pain for half a year. We got the diagnosis of stage III tuberculous empyema after medical treatment. Considering that the patient was young and unmarried, we decided to perform minimally invasive pleural decortication through a 2.5 cm single port. The operation time was 240 min, and blood loss was 100 ml. The patient recovered well and postoperative pain was mild. CONCLUSION: This case demonstrates that single-port VATS with a smaller incision for the Stage III tuberculous empyema should be considered in well selected patients.

Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis.

Akt, a downstream mediator of phosphatidylinositol 3-kinase (PI3K), is a signal transduction protein that plays a central role in tumorigenesis. The tumor suppressor gene PTEN negatively regulates the PI3K/Akt signaling pathway. However, the roles of Akt and PTEN function in patients with non-small cell lung cancer (NSCLC) is not well established. To clarify roles of expression of phosphorylated Akt (p-Akt) and loss of PTEN expression in biological behavior and prognosis of NSCLC. Immunohistochemical staining was used to determine the expression of p-Akt and PTEN in 20 cases of normal lung tissues and 102 cases patients with NSCLC. All patients with NSCLC were followed from 3 to 60 months. The positive incidence of p-Akt expression and loss incidence of PTEN expression in NSCLC were 41.2% (42/102) and 46.1% (47/102), while negative of p-Akt expression (0%, 0/20) and positive of PTEN expression (100%, 20/20) in normal lung tissues. Overexpression of p-Akt and loss of PTEN expression were correlated to poor differentiation, lymph node involvement, distant metastasis and late stages. A significant negative correlation was observed between expression of p-Akt and PTEN (r = -0.425, P < 0.001). Patients with p-Akt positive expression (42/102) and loss of PTEN expression (47/102) showed significantly worse 5 years survival rate and median survival time than relevant those with p-Akt negative expression (14.29% versus 33.33%, 14 months versus 32 months, Log-rank test X(2) = 14.24, P < 0.001) and PTEN positive expression (10.64% versus 38.18%, 15 months versus 40 months, Log-rank test X(2) = 21.06, P < 0.001). A univariate analysis revealed that smoking, tumor size, lymph node involvement, distant metastasis, stage, p-Akt and loss of PTEN expression were significant correlative factors with prognosis. The result of multivariate Cox analysis showed that smoking, stage and loss of PTEN expression were independent prognosticators. p-Akt is overexpressed and accompanied by the loss of PTEN in clinical specimens of NSCLC. Both p-Akt and PTEN are concerned with invasion and metastasis of NSCLC. Loss of PTEN expression is an independent poor prognostic factor for patients with NSCLC.

[Expression of FHIT gene in precancerous lesions and primary lung cancer tissues].

BACKGROUND: Fragile histidine triad (FHIT) gene, a candidate tumor suppressor gene, is recently identified at chromosome 3p14.2, spanning the FRA3B common fragile site. Abnormalities in expression of FHIT gene have been reported in a variety of human tumours including lung cancer. The aim of this study is to investigate the expression of FHIT gene in precancerous lesions and primary lung cancer and to analyze the role of FHIT gene in lung tumorigenesis. METHODS: FHIT protein expression was detected in 298 cases of formalin fixed paraffin-embedded human samples by immunohistochemistry, including 51 precancerous lesions, 161 lung cancer samples, 30 normal lung tissue samples, 23 pulmonary benign lesion tissues and 33 metastatic lymph nodes. RESULTS: All the normal lung tissues and pulmonary benign lesions showed positive FHIT protein expression, while the negative rate of FHIT protein expression in precancerous lesions, lung cancer tissues and metastatic lymph nodes was 54.9%, 59.0% and 78.8% respectively. Negative rate of FHIT protein in metastatic lymph nodes, lung cancer tissues and precancerous lesions was significantly higher than that in normal lung tissues and pulmonary benign lesions (P < 0.001). The expression of FHIT gene was closely related to histological classification, cell differentiation, pTNM stages and lymph node metastasis in lung cancer (P < 0.05). A marked reduction of FHIT protein expression was observed in patients with smoking history than that in patients without smoking history (P < 0.01). Furthermore, FHIT protein expression level in lung cancer was associated with survival of patients (P < 0.01). CONCLUSIONS: These results suggest that FHIT protein expression may occur at early stage of lung carcinogenesis and be associated with the oncogenesis and progression of cancer. The correlation between cigarette smoking and FHIT expression suggests a role of FHIT in the initiation of smoking-related lung tumorigenesis.

Consolidation chwemotherapy after concurrent chemoradiotherapy vs. chemoradiotherapy alone for locally advanced unresectable stage III non-small-cell lung cancer: A meta-analysis.

Concurrent chemoradiotherapy (CCRT) has been considered to be the standard of care for locally advanced unresectable stage III non-small-cell lung cancer (LA-NSCLC). Whether consolidation chemotherapy (CCT) following CCRT is able to further improve the clinical outcome remains unclear. We therefore undertook a meta-analysis to compare the two regimens for LA-NSCLC. A literature search was performed through PubMed, Embase, Cochrane Library and Chinese Biology Medicine, from their inception to November, 2015. Irrelevant studies were excluded using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Our primary endpoint was overall survival (OS), which was defined as the time from randomisation until death from any cause; the secondary endpoint was progression-free survival (PFS). All analyses were by intention-to-treat. Five phase III randomized controlled trials with 958 patients were included in the present meta-analysis. The results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Compared with CCRT, CCT after CCRT was not associated with statistically significant differences in OS (OR=1.24; 95% CI: 0.89-1.72; P=0.21) or PFS (OR=1.16; 95% CI: 0.74-1.83; P=0.53), but increased the risk of toxicity, including infection (P=0.02), pneumonitis (P=0.003) and treatment-related death (P=0.04). There were no significant differences in terms of benefit according to particular patient characteristics, such as age, gender, performance status, tumor histology or clinical stage. Thus, the present study failed to support the use of CCT after CCRT over CCRT alone, as there was no significant OS and PFS benefit for LA-NSCLC patients, but the use of CCT after CCRT resulted in increased toxicity.

Association between NADPH oxidase (NOX) and lung cancer: a systematic review and meta-analysis.

BACKGROUND: Lung cancer is a leading cause of death worldwide. Considerable studies have reported that NADPH oxidase (NOX) expression or activity may play an important role in the tumorigenesis of lung cancer. However, the results are inconsistent. Thus, a systematic review and meta-analysis were conducted in this study. METHODS: A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges's g with 95% confidence intervals (95% CIs) or rate ratio with 95% CIs was adopted to assess the effect size. Fixed or random effect model was separately used based on the heterogeneity between the studies. RESULTS: A total of ten eligible studies were included in the current systematic review and overall meta-analysis showed that NOX/DUOX activity and mRNA were significantly in favor of lung cancer (Hedges's g =1.216, P=0.034). Suppression of NOX function by pharmacologic inhibitor or expression by siRNA resulted in significant inhibition of lung cancer cell invasion and migration in in vitro experiments (Hedges's g =2.422, P<0.001) and lung cancer formation in vivo studies (rate ratio =0.366, P=0.002). CONCLUSIONS: Findings of this systematic review indicate that NOX activity and expression is associated with tumorigenesis of lung cancer and inhibition of NOX function or mRNA expression significantly blocks lung cancer formation and invasion. Suppressing NOX up-regulation or interfering NOX function in tumor microenvironment may be one important approach to prevent oxidative-stress-related carcinogenesis in the lung.

Analysis of Pneumonectomy for Benign Disease: A Single Institution Retrospective Study on 59 Patients.

INTRODUCTION: Pneumonectomy is the only curative treatment for some benign diseases but the operation is a challenging procedure. Herein, we present our experiences of pneumonectomy for 59 patients. METHODS: The medical records of 59 patients who undergone pneumonectomy for benign lung diseases from 2008 to 2013 at the Division of Thoracic Surgery in Beijing Chest Hospital were retrospectively reviewed. RESULTS: There were 23 male and 36 female patients. Three procedures including pneumonectomy, pleuropneumonectomy and completion pneumonectomy were used. The operative time and intraoperative blood loss were statistically different in the patients who undergone different operations. The operative time of the patients with and without tuberculosis had no difference but the intraoperative blood loss was more in the patients with tuberculosis (P = 0.035). The operative type, age and operative blood loss were relevant with the morbidity, the P value were 0.024, 0.042 and 0.027 respectively. CONCLUSIONS: Pneumonectomy for patients with benign disease may be more difficult than for patients with lung cancer, mean while pleuropneumonectomy and completion pneumonectomy may be greater challenges. But with careful patient selection and operative technique, it is a satisfactory treatment method for benign lung disease. The morbidity is acceptable and associated with operative type, age and operative blood loss.

Application of hyperbranched rolling circle amplification for direct detection of mycobacterium tuberculosis in clinical sputum specimens.

BACKGROUND: Global tuberculosis (TB) control is encumbered by the lack of a rapid and simple detection method for diagnosis, especially in low-resource areas. An isothermal amplification method, hyperbranched rolling circle amplification (HRCA), was optimized to detect Mycobacterium tuberculosis (Mtb) in clinical sputum specimens. METHODS: A clinical validation study was performed to assess the diagnostic accuracy of HRCA. In order to analyze the detection limit of HRCA under optimal conditions, the method was initially used to detect purified H37Rv strain DNA and culture suspensions. Next, three strains of Mycobacterium tuberculosis complex (MTC) and eight strains of non-tuberculosis mycobacterium (NTM) were analyzed in order to evaluate specificity. Sputum specimens from 136 patients with diagnosed pulmonary TB, 38 lung cancer patients, and 34 healthy donors were tested by HRCA to validate the clinical application of HRCA for the rapid detection of Mtb. RESULTS: The detection limit of HRCA for purified H37Rv DNA and culture suspensions was 740 aM and 200cfu/ml, respectively. The results of all MTC strains were positive in contrast to the NTM specimens which were all negative. The detection sensitivity for the 136 sputum specimens from TB patients was 77.2% (105/136), which was slightly lower than that of quantitative real-time PCR(79.4%, 108/136) and culture (80.9%,110/136). The sensitivity of all three methods was statistically higher than smear microscopy (44.9%, 61/136). The overall specificity of HRCA was 98.6% (71/72) which was similar to that of quantitative real-time PCR (qRT-PCR) and smear/culture methods (100%, 72/72). CONCLUSIONS: Use of the HRCA assay for detection of Mtb within clinical sputum specimens was demonstrated to be highly sensitive and specific. Moreover, the performance of HRCA is simple and cost-effective compared with qRT-PCR and is less time consuming than culture. Therefore, HRCA is a promising TB diagnostic tool that can be used routinely in low-resource clinical settings.