Engineered extracellular vesicles carrying let-7a-5p for alleviating inflammation in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV-let-7a-5p) derived from transfected Wharton's jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI. METHODS: A cellular nanoporation (CNP) method was used to induce the production and release of EV-let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV-let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-ß)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV-let-7a-5p in a rat model of hyperoxia-induced ALI. RESULTS: The CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV-let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-ß-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV-let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV-let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function. CONCLUSION: This study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p-enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.

Detecting circulating microbial cell-free DNA by next-generation sequencing in patients with Mycobacterium avium complex-lung disease: A pilot study.

Objectives: Determining a diagnosis for non-Tuberculous mycobacterium (NTM)-lung disease (LD) remains difficult. The value of circulating cell-free DNA (cfDNA) secreted from microbes has been established in the detection of pathogens in septic patients. However, it is unknown whether NTM-derived cfDNA is detectable in plasma from patients with NTM-LD and whether this is associated with the disease status of NTM-LD, especially in patients with Mycobacterium avium complex (MAC)-LD. Materials and Methods: In this pilot study, from 2018 to 2019, we enrolled adult patients with MAC-LD at Taipei Veterans General Hospital in Taiwan for the detection of circulating cfDNA. We performed cfDNA extraction from plasma, next-generation sequencing (NGS) for nonhuman cfDNA, and sequence matching to a microbial database and then assessed the association between pathogen cfDNA and MAC-LD. Results: Two (40%) plasma samples from MAC-LD patients had detectable MAC-specific cfDNA, namely one instance of DNA polymerase III alpha subunit and one instance of ATP-binding cassette transporters permease. The plasma samples from the three other MAC-LD cases and the one tuberculosis control were negative for either NTM-derived cfDNA or tuberculosis-related cfDNA. In addition to MAC-specific cfDNA, Ralstonia solanacearum, Staphylococcus aureus, and Pasteurella multocida were the most observed bacteria in our patients. The two patients with MAC-cfDNA positivity yielded higher radiographic scores (P = 0.076) and presented a higher number of nonhuman reads than those without MAC-cfDNA positivity (P = 0.083). Conclusion: Using NGS method, we demonstrated MAC-cfDNA was detectable in patients with MAC-LD. Further large-scale research is warranted to assess the clinical value of detecting MAC-specific cfDNA in MAC-LD patients.

Clinical utility of immunohistochemical subtyping in patients with small cell lung cancer.

OBJECTIVES: Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy. MATERIALS AND METHODS: Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR-mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed. RESULTS: ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) CONCLUSIONS: This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC.

Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.

PURPOSE: ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. METHODS: We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. RESULTS: A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). CONCLUSION: The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

Characteristics, treatment patterns, and clinical outcomes in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertions.

PURPOSE: Epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) are associated with poor prognosis and resistance to traditional therapies in patients with non-small cell lung cancer (NSCLC). We aimed to elucidate the characteristics and treatment patterns to improve outcomes among this population in Taiwan. METHODS: Patients with advanced or recurrent NSCLC harboring EGFR ex20ins from 2011 to 2021 were reviewed. The treatment groups were classified as platinum-based chemotherapy (PtC), EGFR tyrosine kinase inhibitor (TKI), and others. The response to therapy, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and factors associated with survival were analyzed. RESULTS: Among the 71 patients, most were never-smoking males with stage IVB adenocarcinoma. The most common first-line (1L) regimen was PtC, followed by TKI. The most common second-line (2L) regimen was TKI. The median PFS of 1L treatment was 5.03 months, and the median OS was 18.43 months. Compared with that of TKI, 1L PtC use was associated with a higher ORR (26.3% vs. 9.1%) and DCR (60.5% vs. 18.2%) and a longer PFS (5.37 vs. 3.13 months, p = 0.044). PFS was also significantly longer in the 2L PtC group than in the 2L TKI group (4.73 vs. 2.25 months, p = 0.047). No patients receiving an immune checkpoint inhibitor-based regimen exhibited a therapeutic response. CONCLUSION: This study demonstrated the heterogeneous clinical characteristics and treatment pattern of NSCLC patients with EGFR ex20ins, underscoring the need for more effective therapies for this distinct molecular subtype.

Role of nebulized colistin as a substitutive strategy against nosocomial pneumonia caused by CR-GNB in intensive care units: a retrospective cohort study.

BACKGROUND: Adverse reactions, especially nephrotoxicity, are great concerns of intravenous colistin treatment. The role of substitutive nebulized colistin in treating nosocomial pneumonia caused by carbapenem-resistant Gram-negative bacterial (CR-GNB) in critically ill patients remains unknown. METHODS: This retrospective study enrolled patients with nosocomial pneumonia caused by colistin-susceptible CRGNB in the intensive care unit (ICU) without intravenous colistin treatment. Patients were categorized based on whether substitutive nebulized colistin was used alongside other intravenous antibiotics. Clinical responses and mortality rates were compared between the two groups in the original and propensity score (PS)-matched cohorts. This study aimed to investigate the clinical effectiveness of substitutive nebulized colistin in treatment outcomes of nosocomial pneumonia caused by CR-GNB. The impact of dosing strategy of nebulized colistin was also explored. RESULTS: In total, 343 and 214 patients with and without substitutive nebulized colistin, respectively, were enrolled for analysis. In the PS-matched cohort, clinical failure rates on day 7 (22.6 vs. 42.6%, p = 0.001), day 14 (27.0 vs. 42.6%, p = 0.013), and day 28 (27.8 vs. 41.7%, p = 0.027) were significantly lower in patients with nebulized colistin. In multivariate analysis, nebulized colistin was an independent factor associated with lower day 14 clinical failure (Original cohort: adjusted odds ratio (aOR) 0.45, 95% confidence interval (CI) 0.30-0.67; PS-matched cohort: aOR 0.48, 95% CI 0.27-0.87). There were no differences in clinical failure rate and mortality rate between patients receiving high (> 6 MIU/day) and low (≤ 6 MIU/day) dose nebulized colistin in the PS-matched cohort. CONCLUSIONS: In ICU-admitted patients with nosocomial pneumonia caused by colistin-susceptible CRGNB, substitutive nebulized colistin was associated with better clinical outcomes.

Circulating mitochondrial cell-free DNA dynamics in patients with mycobacterial pulmonary infections: Potential for a novel biomarker of disease.

Objectives: Human mitochondrial cell-free DNA (Mt-cfDNA) may serve as a useful biomarker for infectious processes. We investigated Mt-cfDNA dynamics in patients with pulmonary mycobacterial infections to determine if this novel biomarker could be used to differentiate disease states and severity. Methods: Patients with pulmonary tuberculosis (PTB), latent tuberculosis infection (LTBI), and nontuberculous mycobacterial-lung disease (NTM-LD) were enrolled at a tertiary care hospital in Taiwan between June 2018 and August 2021. Human Mt-cfDNA and nuclear-cfDNA (Nu-cfDNA) copy numbers were estimated by quantitative polymerase chain reaction. Variables associated with PTB and 2-month sputum culture-positivity, indicating poor treatment response, were assessed using logistic regression. Results: Among 97 patients with PTB, 64 with LTBI, and 51 with NTM-LD, Mt-cfDNA levels were higher in patients with PTB than in LTBI (p=0.001) or NTM-LD (p=0.006). In the Mycobacterium tuberculosis-infected population, Mt-cfDNA levels were highest in smear-positive PTB patients, followed by smear-negative PTB (p<0.001), and were lowest in LTBI persons (p=0.009). A Mt-cfDNA, but not Nu-cfDNA, level higher than the median helped differentiate culture-positive PTB from culture-negative PTB and LTBI (adjusted OR 2.430 [95% CI 1.139-5.186], p=0.022) and differentiate PTB from NTM-LD (adjusted OR 4.007 [1.382-12.031], p=0.011). Mt-cfDNA levels decreased after 2 months of treatment in PTB patients (p=0.010). A cutoff Mt-cfDNA level greater than 62.62 x 106 copies/µL-plasma was associated with a 10-fold risk of 2-month culture-positivity (adjusted OR 9.691 [1.046-89.813], p=0.046). Conclusion: Elevated Mt-cfDNA levels were associated with PTB disease and failed sputum conversion at 2 months in PTB patients, and decreased after treatment.

Assessment of Early Growth Response 1 in Tumor Suppression of Esophageal Squamous Cell Carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is associated with poor survival despite surgical resection, and its pathogenesis has been broadly investigated in the past decade. Early growth response 1 (EGR-1) could involve regulating tumor development in ESCC cells. Methods: An attempt was made to examine the molecular and cellular influence of EGR-1 in esophageal cancer cells by RNA extraction, real-time PCR (qRT-PCR), cell culture, small interfering RNA (siRNA) knockdown, western blot, migration assay, and cell viability assay. One hundred and forty-four samples of ESCC were collected from our hospital and analyzed. Significantly higher EGR-1 expression was noted in tumor-adjacent normal tissue compared with tumor lesions. Results: The univariate analysis showed no significant impacts of EGR-1 expression on patients' survival. However, after adjusting for the pathological stage, patients with EGR-1 expression > 68th percentile had lower risks of cancer-related death. Moreover, knockdown of EGR-1 significantly enhanced cell migration, invasion, and resistance to chemotherapeutic agents in two ESCC cell lines. Conclusions: EGR-1 plays a key role in tumor suppression involving tumor viability suppression and reflects the treatment effect of current chemotherapy for ESCC.

Next Generation Sequencing for Potential Regulated Genes and Micro-RNAs of Early Growth Response-1 in the Esophageal Squamous Cell Carcinoma.

Esophageal cancer has a poor prognosis due to its aggressiveness and low survival rate. In Ease Asia, esophageal squamous cell carcinoma (ESCC) outnumbers esophageal adenocarcinoma (EAC). The ESCC patients still have high mortality despite modern surgical resection and neoadjuvant treatment. Determining patient and outcome prognostic factors is critical in ESCC treatment. In esophageal cancer, early growth response-1 (Egr-1) is a tumor suppressor gene, but the mechanism and associated genes are unknown. The study utilizes RNA interference method, the platform of Next Generation Sequencing (NGS) and bioinformatics analysis to investigate the influences after the Egr-1 gene slicing on the ESCC cells. The heat maps of differentially expressed mRNA and microRNAs were analyzed using the algorithm, Burrows-Wheller Aligner. The study showed that the expression of 51 mRNA and 26 microRNAs have significant changes in ESCC cells after Egr-1 knockdown. The KEGG enrichment analysis linked Egr-1-regulated genes and microRNAs. Egr-1 interactions with these genes and microRNAs may be important in tumor progression. In conclusions, this study provided the transcriptome patterns and relating pathway analysis for Egr-1 knockdown in ESCC cells. The mRNA and microRNAs altered by Egr-1 gene silencing might provide key information in the treatment of ESCC.

Factors related to overweight and obese populations maintaining metabolic health.

Background: For people who are overweight or obese, maintaining a metabolically healthy status can decrease the risks of developing cardiovascular diseases and Type 2 diabetes. Despite this, only a limited amount of research has discussed the metabolically healthy overweight and obesity (MHOO) population in Asia and the factors associated with them maintaining their metabolic health. Methods: This study enrolled 195 MHOO participants from communities in northern Taiwan during 2009-2010 (baseline). Of the 195 participants, 89 completed the follow-up assessment after a median follow-up time of nine years. Body type was determined by body mass index (BMI, kg/m2). We defined overweight as a BMI ≥ 24 kg/m2 and <27 kg/m2 and defined obese as a BMI ≥ 27 kg/m2. Metabolic health was defined as the absence of cardiometabolic diseases and the presence of ≤1 of the cardiometabolic risk factors, namely hypertension, hyperglycemia, hypertriglyceridemia, and low serum high-density lipoprotein cholesterol. Metabolic health, BMI, and other covariates were evaluated at both baseline and follow-up. Generalized estimating equations (GEE) models were used to analyze the factors associated with maintenance of metabolic health during the follow-up period. Results: At baseline, the mean age of the study participants was 47.4 (SD 5.3) years and 46 (51.7%) of the participants were women. There were 51 (57.3%) individuals who maintained their metabolic health status at the time of the nine-year follow-up. The detrimental factors pertaining to metabolic health included older age, longer duration until follow-up, BMI ≥ 27 kg/m2, and increase in waist circumference. No significant relationships were observed between sociodemographic factors and lifestyle factors, such as sex, level of education, cigarette smoking, alcohol consumption, and physical activity, and sustained metabolic health among MHOO individuals. Conclusions: To maintain metabolic health and prevent negative changes in health status, control of bodyweight and waist circumference should remain a priority for MHOO individuals even when there are no metabolic disorders present.

PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis.

The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.

Does size affect the prognosis of resectable thymoma beyond the eighth edition TNM?

BACKGROUND: Thymoma is a type of rare mediastinal tumor whose clinical characteristics and indicators of prognosis are poorly understood. This single-institution retrospective study aimed to assess the predictive value of tumor, node, metastasis (TNM) staging incorporating tumor size in predicting the risk of thymoma recurrence after resection. METHODS: Four binary logistic regression models were developed. Models I and II included median tumor size and TNM stage, respectively. Model III included the above two variables. Model IV was model III containing these two variables and their interaction terms. All models were adjusted for WHO histological type, operational time, and adjuvant therapy. RESULTS: A total of 276 patients with a median age of 51.0, including 21 patients with thymoma recurrence, were included in this study. Models II or III showed a lower -2LogL and higher AUC (0.735 and 0.738 vs. 0.576) with significantly better discrimination than model I, and model III and model II shared similar discrimination. In model III, TNM stage was positively correlated with thymoma recurrence. The recurrence risk of patients with TNM stage IV was significantly higher than those with TNM stage I (OR of 11.03, p = 0.022). No significant correlation between the tumor size and recurrence risk (p = 0.779) and no interaction was found between medium tumor size and TNM stage in model IV. CONCLUSIONS: This study suggests that the prediction contribution of the TNM stage combined with tumor size is similar to the TNM stage alone for tumor recurrence in patients with thymoma after surgical resection.

3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway.

Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0-10-µM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA-mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan-Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA-transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA-transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role. • Short-term exposure of lung epithelial cells to 3-NBA can lead to ROS production and cell apoptosis. • Long-term chronic exposure to 3-NBA upregulates the levels of tumor-promoting genes such as EREG and IL-6. • Increased EREG expression in 3-NBA-transformed cells markedly contributes to tumorigenesis through PI3K/AKT and MEK/ERK activation and synergistically enhances the IL-6/STAT3 signaling pathway, which promotes tumorigenicity.

Do Metabolically Healthy People with Obesity Have a Lower Health-Related Quality of Life? A Prospective Cohort Study in Taiwan.

The association between metabolically healthy obesity (MHO) and health-related quality of life (HRQOL) has not been thoroughly evaluated. This study enrolled 906 adult participants aged 35-55 years between 2009 and 2010 in Northern Taiwan; 427 participants were followed up after eight years. Normal weight, overweight, and obesity were evaluated via body mass index. Metabolic health was defined as the absence of cardiometabolic diseases and having ≤1 metabolic risk factor. HRQOL was evaluated using the 36-Item Short Form Health Survey (SF-36), Taiwan version. Generalized linear mixed-effects models were used to analyze the repeated, measured data with adjustment for important covariates. Compared with metabolically healthy normal weight individuals, participants with metabolically unhealthy normal weight and obesity had a significantly poorer physical component summary score (ß (95% CI) = -2.17 (-3.38--0.97) and -2.29 (-3.70--0.87), respectively). There were no significant differences in physical and mental component summary scores among participants with metabolically healthy normal weight, overweight, and obesity. This study showed that metabolically healthy individuals with obesity and normal weight had similar HRQOL in physical and mental component summary scores. Maintaining metabolic health is an ongoing goal for people with obesity.

Changes in metabolic syndrome affect the health-related quality of life of community-dwelling adults.

Metabolic syndrome (MetS) is associated with cardiovascular diseases, type 2 diabetes, chronic renal diseases, and all-cause mortality. Furthermore, MetS is associated with poor health-related quality of life (HRQOL). However, the impact of dynamic changes in MetS on changes in the HRQOL was not previously explored. This was an eight-year, prospective cohort study in which 906 middle-aged adults from Shipai, Taipei in northern Taiwan were enrolled during 2009-2010 (baseline). Of those sampled, 427 participants completed the follow-up investigation after 8 years. The HRQOL was measured using the Short Form Health Survey (SF-36). Other variables including age, sex, marital status, level of education, smoking, alcohol consumption, baseline body mass index, and changes in physical activity were adjusted. Compared with adults who never experienced MetS, adults with persistent MetS had a negative change in mental HRQOL (ß - 4.20, 95% CI - 7.54 to - 0.86, p = 0.01). The negative changes of persistent MetS on the HRQOL were in the domains of vitality and mental health (ß - 4.42, 95% CI - 8.10 to - 0.73 and ß - 3.47, 95% CI - 6.90 to - 0.04, respectively). Women and overweight adults were vulnerable to the detrimental effects of persistent MetS. For better HRQOL, more resources should be devoted to reversing MetS in public health.

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. METHODS: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed. RESULTS: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. CONCLUSIONS: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Multidisciplinary team discussion results in survival benefit for patients with stage III non-small-cell lung cancer.

BACKGROUND: The treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) discussion results in better patient survival. MATERIALS AND METHODS: MDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018. RESULTS: A total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (p<0.001), T staging (p = 0.009), performance status (p<0.001), and surgery (p = 0.016) to be significant prognostic factors. CONCLUSION: The results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC.

Physical activity and successful aging among middle-aged and older adults: a systematic review and meta-analysis of cohort studies.

BACKGROUND: We aimed to investigate the association between physical activity and successful aging among middle-aged and older adults and study how this association changes with age and time. RESULTS: The mean score of Newcastle-Ottawa Scale assessment was 8.0±0.8. Physically active middle-aged and older adults were more likely to age successfully than sedentary adults (OR=1.64, 95%CI: 1.40-1.94). The effect of physical activity was stronger in the younger group (OR=1.71, 95%CI: 1.41-2.08) than on the older group (OR=1.54, 95%CI: 1.13-2.08). However, the protective effect of physical activity reduced annually by approximately 3%. CONCLUSIONS: Physical activity promotes successful aging among middle-aged and older adults especially in the younger population. Being physically active at middle and old age is beneficial to successful aging. METHODS: We searched for the relevant studies in three online databases: Pubmed, Web of Science, and Embase. Fifteen community-based cohort studies were included. The Newcastle-Ottawa Scale assessment Form was used for quality assessment. Overall, 189,192 participants aged 43.9-79.0 years were analyzed. The odds ratio for successful aging of the most physically active group compared with sedentary group was analyzed. Subgroup analysis was conducted by age group. Univariate Meta-regression was performed according to follow-up years.

Efficacy of Paclitaxel plus TS1 against previously treated EGFR mutated non-small cell lung cancer.

BACKGROUND: Later line chemotherapy (≥2nd lines) such as Docetaxel or immunotherapy is frequently used. As the life expectancy of lung cancer patients is getting longer, we need to provide more treatment options. Other treatment options are not well documented except for Doxetaxel and immunotherapy. Therefore, the efficacy of paclitaxel plus TS1 (TTS1) is warranted. METHODS: We retrospectively reviewed the chart records of our non-small cell lung cancer patients who were treated between 2010 and 2013. Clinical characteristics, type of tumor, EGFR mutation status, and treatment response to first-line EGFR-TKI therapy and efficacy of TTS1, were collected. RESULTS: Twenty eight patients were enrolled in this study. No patients archived complete response and seven patients had partial response (ORR: 25%). The disease control rate was 60.7% (17/28). The progression free survival (PFS) was 4.0 months and overall survival (OS) was 15.8 months. Of them, 17 had EGFR mutations, eight EGFR wild type, and three were unknown EGFR status. After TTS1 treatment, patients with EGFR mutations had better PFS (4.9 months vs. 1.8 months) and OS (15.5 months vs. 7.2 months) compared with those of EGFR wild type. CONCLUSIONS: TTS1 are effective later line chemotherapy, especially in tumor EGFR mutated patients. Paclitaxel plus TS1 is another treatment of choice for NSCLC patients before a more effective treatment strategy is found.