Alternation of psychological resilience may moderate mentalization toward mental health conditions from macro- and microstructure aspects.

OBJECTIVE: We aim to investigate the interplay between mentalization, brain microstructure, and psychological resilience as potential protective factors against mental illness. METHOD: Four hundred and twenty-six participants (mean age 40.12±16.95; 202 males, 224 females), without psychiatric or neurological history, completed assessments: Dissociative Process Scale (DPS), Peace of Mind (PoM), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Resilience Scale for Adults (RSA), and Magnetic Resonance Imaging (MRI) structures with selected regions of interest, and Diffusion Tensor Imaging (DTI) maps from various tracts in the right hemisphere and connection to the frontal areas, including anterior thalamic radiation (ATR), Cingulum (hippocampus) (CH), Corticospinal tract (CST), Superior longitudinal fasciculus (SLF), Inferior fronto-occipital fasciculus (IFOF), and Uncinate fasciculus (UF) were analyzed. RESULTS: Two clusters, representing hypomentalization (HypoM) and hypermentalization (HyperM), were identified based on DPS, CPSS, and RFQ responses. One-way ANOVA showed no significant age or gender differences between clusters. The HypoM group exhibited lower PoM scores, higher BDI and BAI scores, and lower RSA scores (ps< 0.05). Structural brain metric comparison showed significant differences in GMV in the right caudal middle frontal gyrus (rcMFG), right superior frontal gyrus (rsFG), and right frontal pole (rFP) between groups. In addition, the HyperM individuals with a higher risk of depression and a higher ratio of intrapersonal to interpersonal factors of resilience were found with reduced GMV on the rcMFG. Additionally, analyses of DTI metrics revealed significant differences between two groups in rATR and rSLF in terms of fractional anisotropy (FA) values; rATR, rCST, rUF, rSLF, rCH and rIFOF in terms of mean diffusivity (MD) values, and radial diffusivity (RD) (corrected p = 0.05). Moreover, the positive correlation between different domains of resilience and white matter (WM) integrity implied further enhancement of intrapersonal or interpersonal resilience factors that are different for people with different mentalization. CONCLUSIONS: The findings underscore the importance of considering both intrapersonal and interpersonal factors in understanding the interactions between psychological resilience and mental health conditions relevant to brain mechanisms.

Consensus of the Taiwanese dermatological association and Taiwan Lung Cancer Society on the prevention and management of tyrosine kinase inhibitor-related skin toxicities in patients with non-small cell lung cancer: An updated version incorporating Taiwanese treatment experience.

The 2023 consensus from the Taiwanese Dermatological Association (TDA) and Taiwan Lung Cancer Society (TLCS) addresses the management of tyrosine kinase inhibitor (TKI)-induced skin toxicities in non-small cell lung cancer (NSCLC). Providing a comprehensive overview, the consensus reflects recent advances in understanding causes and developmental processes of TKI-related skin toxicities. Aimed at guiding clinicians in Taiwan, the consensus integrates new treatment perspectives while incorporating experiences from local dermatology experts. Recommendations underwent a voting process, achieving consensus when 75% or more of experts agreed, leading to their inclusion. Approved by over 90% of participants, the recommended treatment algorithms for major skin toxicities offer valuable insights for clinicians managing TKI-associated effects in NSCLC patients.

Afatinib treatment in a large real-world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P < .001) and OS (HR 2.56 [95% CI, 1.37-4.75]; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; P = .016), and type-I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; P = 4.3 × 10-5 ). Tendencies of higher CNS and lower systemic progression were observed in type-II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18-4.89]; P = .016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01-0.48]; P = .021) were independent predictors of secondary T790M. Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

Postauricular Incision Versus Conventional Transcervical Incision in Second Branchial Cleft Cyst Excision: A Systematic Review and Meta-Analysis.

Surgical removal is the treatment of choice for second branchial cleft cysts (SBCCs), which are congenital anomalies. The conventional procedure is performed through a transcervical approach, which would lead to a visible scar in the anterior neck. Conversely, the postauricular approach could keep the scar in the hairline or retroauricular sulcus, rendering it almost invisible after the surgery. The purpose of this meta-analysis was to evaluate the differences between the postauricular and conventional transcervical approaches to SBCC excision. A systematic review was performed using PubMed, Embase, and the Cochrane Library to identify studies comparing outcomes of SBCC surgery via postauricular and conventional transcervical approaches. The data of interest were analyzed with Comprehensive Meta-Analysis software (version 3). The data of interest were analyzed by calculating the risk difference (RD), the standardized mean difference, and the mean difference (MD) with the 95% confidence interval (CI). Three studies were eligible for the final analysis. The pooled analysis demonstrated that the cosmetic satisfaction score was significantly higher with the postauricular approach (standardized mean difference, 2.12; 95% CI, 0.68-3.56). The operative duration was significantly longer with the postauricular approach than with the conventional transcervical approach (MD, 12.81; 95% CI, 2.39-23.23). The incidences of postoperative marginal mandibular nerve palsy (RD, 0.00; 95% CI, -0.09 to 0.09), bleeding complications (RD, -0.02; 95% CI, -0.09 to 0.05), salivary complications (RD, -0.00; 95% CI, -0.07 to 0.06), cyst size (MD, 0.02; 95% CI, -0.96-0.99), and length of hospital stay (MD, -2.50; CI, -7.30 to 2.30) were comparable between the 2 groups. The postauricular approach is feasible for use in SBCC excision and yields better cosmetic outcomes, a longer operative duration, and a similar rate of complications.

Circulating EGFR Mutations in Patients with Lung Adenocarcinoma by Circulating Tumor Cell Isolation Systems: A Concordance Study.

Background: We developed a hybrid platform using a negative combined with a positive selection strategy to capture circulating tumor cells (CTCs) and detect epidermal growth factor receptor (EGFR) mutations in patients with metastatic lung adenocarcinoma. Methods: Blood samples were collected from patients with pathology-proven treatment-naïve stage IV lung adenocarcinoma. Genomic DNA was extracted from CTCs collected for EGFR mutational tests. The second set of CTC-EGFR mutational tests were performed after three months of anti-cancer therapy. Results: A total of 80 samples collected from 28 patients enrolled between July 2016 and August 2018. Seventeen patients had EGFR mutations, including Exon 19 deletion (n = 11), L858R (n = 5), and de-novo T790 and L858R (n = 1). Concordance between tissue and CTCs before treatment was 88.2% in EGFR- mutant patients and 90.9% in non-mutant patients. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of EGFR mutation tests for CTCs were 89.3%, 88.2%, 90.9%, 93.8%, and 83.3%, respectively. Conclusions: CTCs captured by a hybrid platform using a negative and positive selection strategy may serve as a suitable and reliable source of lung cancer tumor DNA for detecting EGFR mutations, including T790M.

Feasibility and effectiveness of afatinib for poor performance status patients with EGFR-mutation-positive non-small-cell lung cancer: a retrospective cohort study.

BACKGROUND: Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in patients with poor performance status (PS ≥ 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS ≥ 2. METHODS: The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients' clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. RESULTS: Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control. CONCLUSION: Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Blood Cadmium Levels and Oxygen Desaturation during the 6-Minute Walk Test in Patients with Chronic Obstructive Pulmonary Disease.

Background and Objectives: chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and a history of exposure to noxious stimuli. Cigarette smoking is the most important causal factor for developing COPD. Cadmium, a minor metallic element, is one of the main inorganic components in tobacco smoke. Inhaled cadmium was associated with a decline in lung function, gas exchange impairment, and the development of obstructive lung disease. Patients with COPD who had oxygen desaturation during the 6-min walk test (6MWT) had a significantly worse prognosis than non-desaturation in COPD patients. Nonetheless, few studies have addressed the influence of blood cadmium levels on exercise-induced oxygen desaturation in COPD patients. Our objective was to assess the potential impact of blood cadmium levels on oxygen desaturation during the 6MWT among COPD patients. Materials and Methods: we performed a retrospective analysis of patients with COPD who were examined for blood cadmium levels in a tertiary care referral center in Taiwan, between March 2020 and May 2021. The 6-min walk test was performed. Normal control subjects who had no evidence of COPD were also enrolled. Results: a total of 73 COPD patients were analyzed and stratified into the high-blood cadmium group (13 patients) and low-blood cadmium group (60 patients). A total of 50 normal control subjects without a diagnosis of COPD were enrolled. The high-blood cadmium group had a significantly higher extent of desaturation than the low-blood cadmium group. The frequency of desaturation during 6MWT revealed a stepwise-increasing trend with an increase in blood cadmium levels. A multivariable logistic regression model revealed that blood cadmium levels were independently associated with desaturation during the 6MWT (odds ratio 12.849 [95% CI 1.168-141.329]; p = 0.037). Conclusions: our findings indicate that blood cadmium levels, within the normal range, were significantly associated with desaturation during 6MWT in patients with COPD.

Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: final analysis of the GioTag study.

Aim: Final overall survival (OS) and time on treatment analysis of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib. Patients & methods: Patients (n = 203) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months before data entry. Primary outcome was time on treatment; OS analysis was exploratory. Results: Median time on treatment with afatinib and osimertinib was 27.7 months (90% CI: 26.7-29.9). Median OS was 37.6 months (90% CI: 35.5-41.3); median OS was 41.6 and 44.8 months in Del19-positive patients and Asian patients, respectively. Conclusion: In real-world clinical practice, sequential afatinib and osimertinib was associated with encouraging outcomes in patients with EGFR mutation-positive NSCLC, especially in Del19-positive patients and Asian patients. Clinical Trial Registration: NCT03370770 (ClinicalTrials.gov).

Common mental disorders in Taiwanese consumers of commercial low-dose computed tomography lung cancer screening: Comparison with a nationally representative sample.

BACKGROUND/PURPOSE: We examined the prevalence of probable common mental disorders (CMDs) in commercial low-dose computed tomography (LDCT) lung cancer screening consumers relative to the general population and to determine the correlates of probable CMDs among screening participants. METHODS: Commercial LDCT lung cancer screening consumers (N = 1323) were compared with a nationally representative sample from the Taiwan Social Change Survey (TSCS) (N = 2034). Respondents scoring ≥3 on the Chinese Health Questionnaire were classified as having a probable CMD. Logistic regression was used to investigate differences between the two groups and correlates of probable CMDs among LDCT lung cancer screening participants. RESULTS: The prevalence of probable CMDs was higher among LDCT lung cancer screening participants (25.47%) than among TSCS adults (21.56%). Compared with the TSCS sample, the screening participants had a higher probability of CMDs (OR = 1.40, 95% CI = 1.13-1.73), higher education levels (OR = 7.95, 95% CI = 6.00-10.53), and a history of drinking (OR = 11.85, 95% CI = 9.45-14.85) or betel-quid use (OR = 5.43, 95% CI = 3.98-7.42) but were less likely to smoke (OR = 0.52, 95% CI = 0.40-0.68). Among the screening participants, being female (OR = 1.37, 95% CI = 1.02-1.84) and a current smoker (OR = 1.74, 1.19-2.54) and living near ≥2 smoking family members (OR = 2.30, 95% CI 1.57-3.38) were associated with an increased likelihood of having CMDs. CONCLUSION: Commercial LDCT lung cancer screening users may have a positive association with probable CMDs compared to the general population. Screening programs should consider including criteria and providing psychoeducation to improve the physical and mental outcomes of participants. CLINICAL TRIAL REGISTRATION: Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) do not require registration.

Prognostic impact of combining whole-body PET/CT and brain PET/MR in patients with lung adenocarcinoma and brain metastases.

PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP. CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life.

Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: updated analysis of the observational GioTag study.

Aims: Overall survival (OS) and updated time to treatment failure (TTF) analysis of patients with EGFR mutation-positive (Del19, L858R) non-small-cell lung cancer who received sequential afatinib/osimertinib in the real-world GioTag study. Patients & methods: Patients had T790M-positive disease following first-line afatinib and received osimertinib treatment (n = 203). Primary outcome was TTF. The OS analysis was exploratory. Results: Median OS was 41.3 months (90% CI: 36.8-46.3) overall and 45.7 months (90% CI: 45.3-51.5) in patients with Del19-positive tumors (n = 149); 2-year survival was 80 and 82%, respectively. Updated median TTF with afatinib and osimertinib was 28.1 months (90% CI: 26.8-30.3). Conclusion: Sequential afatinib/osimertinib was associated with encouraging OS/TTF in patients with EGFR T790M-positive non-small-cell lung cancer, especially in patients with Del19-positive tumors. Trial registration number: NCT03370770.

Pharyngeal distensibility during expiration is an independent predictor of the severity of obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Pharyngeal distensibility and collapsibility reflect the passive properties of tissue in the airway, are an indicator of the ease with which an airway can be deformed and are related to the severity of obstructive sleep apnoea (OSA). During normal tidal respiration, the collapsibility of the pharynx during expiration is passive without confounding by neuromuscular activation that occurs during inspiration. We evaluated the distensibility and collapsibility of the upper airway in subjects with OSA during wakefulness using sophisticated dynamic computed tomography (CT) imaging. We hypothesized that the dynamic changes of the upper airway during expiration would be related to the severity of OSA. METHODS: Twenty-three patients with OSA and eight normal subjects underwent simultaneous measurement of respiratory flow and airway calibre using ultrafast CT. The change in pharyngeal cross-sectional area divided by the change in concomitant flow (as distensibility or collapsibility) was measured and compared across different severities of OSA. RESULTS: The slope of this relationship between delta area and delta flow during expiration was significantly higher in severe OSA when compared with normal controls and mild-moderate OSA. Differences in airway distensibility or collapsibility between severity groups were significant in expiration but not in inspiration. Distensibility or collapsibility contributed most to the apnoea-hypopnoea index in regression modelling. Age, gender, and body mass index (BMI) were not significant independent predictors. CONCLUSION: Our study demonstrates that airway distensibility during the expiratory phase of awake respiration is correlated with the severity of OSA.

Monocytic C-C chemokine receptor 5 expression increases in in vitro intermittent hypoxia condition and in severe obstructive sleep apnea patients.

PURPOSE: Obstructive sleep apnea (OSA) patients have higher risk of cardiovascular disease. C-C chemokine receptor 5 (CCR5), as an important receptor for monocyte recruitment and the initiation of atherosclerosis, was studied under intermittent hypoxia and in OSA patients. METHODS: The expression and function of CCR5 regulated by intermittent hypoxia in monocytic THP-1 cells were investigated in an in vitro intermittent hypoxia culture system. The expression levels of protein and mRNA were analyzed by western blot and RT/real-time PCR analysis. Cell adhesion assay and transwell filter migration assay were carried out to investigate the adhesion and chemotaxis of monocytes. In addition, the mRNA expression of CCR5 in monocytes isolated from peripheral blood of 72 adults was analyzed. RESULTS: Intermittent hypoxia upregulated the expression of CCR5 in THP-1 cells and enhanced the adhesion and chemotaxis of monocytes to vascular endothelial cells mediated by RANTES. The CCR5 expression induced by intermittent hypoxia was inhibited by inhibitor for p42/44 MAPK. Besides, the expression of CCR5 in monocytes increased along the AHI value especially in severe OSA patients that was statistically significant compared with mild and moderate OSA groups. CONCLUSIONS: This study demonstrated the increased monocytic CCR5 gene expression in patients with severe OSA. Intermittent hypoxia, the characteristic of OSA, induced monocytic CCR5 gene expression and the enhanced RANTES-mediated chemotaxis and adhesion through p42/44 MAPK signal pathways.

Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC).

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15-55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.

Inhibition of yes-associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model.

Yes-associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030-BrM3(K-rasG12C mutation) and PC9-BrM3 (EGFRΔexon19 mutation) had a significantly decreased p-YAP(S127)/YAP ratio compared to parental H2030 (K-rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030-BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030-BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030-BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA-transfected H2030-BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030-BrM3 cell brain metastasis in a murine model.

Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma.

Although tumour PD-L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD-L1 axis in various cancers, the regulation of PD-L1 (CD274) expression is unclear. Yes-associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down-regulates PD-L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD-L1 protein expression compared to H290, MS-1 and H28 cells. In H2052 and 211H cells, PD-L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD-L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD-L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD-L1 enhancer region encompassing 2 putative YAP-TEAD-binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD-L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi-square). We conclude that PD-L1 is correlated with YAP expression, and inhibition of YAP down-regulates PD-L1 expression in human MPM. Further study of how YAP regulates PD-L1 in MPM is warranted.

Accuracy of Presurgical Functional MR Imaging for Language Mapping of Brain Tumors: A Systematic Review and Meta-Analysis.

Purpose To compare functional magnetic resonance (MR) imaging for language mapping (hereafter, language functional MR imaging) with direct cortical stimulation (DCS) in patients with brain tumors and to assess factors associated with its accuracy. Materials and Methods PubMed/MEDLINE and related databases were searched for research articles published between January 2000 and September 2016. Findings were pooled by using bivariate random-effects and hierarchic summary receiver operating characteristic curve models. Meta-regression and subgroup analyses were performed to evaluate whether publication year, functional MR imaging paradigm, magnetic field strength, statistical threshold, and analysis software affected classification accuracy. Results Ten articles with a total of 214 patients were included in the analysis. On a per-patient basis, the pooled sensitivity and specificity of functional MR imaging was 44% (95% confidence interval [CI]: 14%, 78%) and 80% (95% CI: 54%, 93%), respectively. On a per-tag basis (ie, each DCS stimulation site or "tag" was considered a separate data point across all patients), the pooled sensitivity and specificity were 67% (95% CI: 51%, 80%) and 55% (95% CI: 25%, 82%), respectively. The per-tag analysis showed significantly higher sensitivity for studies with shorter functional MR imaging session times (P = .03) and relaxed statistical threshold (P = .05). Significantly higher specificity was found when expressive language task (P = .02), longer functional MR imaging session times (P < .01), visual presentation of stimuli (P = .04), and stringent statistical threshold (P = .01) were used. Conclusion Results of this study showed moderate accuracy of language functional MR imaging when compared with intraoperative DCS, and the included studies displayed significant methodologic heterogeneity. © RSNA, 2017 Online supplemental material is available for this article.

Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study.

AIM: To assess outcomes in patients with EGFR mutation-positive (Del19, L858R) non-small-cell lung cancer receiving sequential afatinib and osimertinib in a real-world clinical setting. Materials & methods: In this retrospective, observational, multicenter study, patients (n = 204) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months prior to data entry. Primary outcome was time on treatment. RESULTS: Overall median time on treatment was 27.6 months (90% CI: 25.9-31.3), 30.3 months (90% CI: 27.6-44.5) in Del19-positive patients and 46.7 months (90% CI: 26.8-not reached) in Asians. The 2-year overall survival was 78.9%. CONCLUSION: In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M acquired resistance, and is a potentially attractive strategy, especially for Del19-positive tumors. TRIAL REGISTRATION NUMBER: NCT03370770.

Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.

Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-ß1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV-augmented bleomycin-induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild-type or Src-deficient were exposed to low tidal volume (VT ) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non-ventilated mice were used as control groups. Following bleomycin exposure in wild-type mice, high VT MV induced substantial increases in microvascular permeability, TGF-ß1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α-smooth muscle actin and decreased staining of E-cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src-deficient mice, dampened the MV-augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV-augmented EMT and pulmonary fibrosis after bleomycin-induced ALI, partly by inhibiting the Src pathway.