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Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A side-by-side comparison of concordance of EFIRM and droplet digital PCR (ddPCR) for the detection of the two front-line actionable EFGR mutations was performed with paired plasma and saliva samples from 13 NSCLC patients. Deep sequencing analysis based on single-strand DNA library preparation was employed to determine the size distributions of EGFR L858R ctDNA in plasma and saliva samples. EFIRM detected both EGFR mutations with 100% sensitivity in both plasma and saliva samples, whereas ddPCR detected EGFR mutations with sensitivities of 84.6% and 15.4%, respectively. In saliva samples, the majority of EGFR L858R ctDNA fragments detected were

Introduction: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. Methods: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. Results: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35–1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12–0.85; p = 0.013). Conclusion: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs. [ABSTRACT FROM AUTHOR]

Differences in cellular radiosensitivity and the binding affinity of radiopharmaceuticals could directly affect the radiotherapeutic effects. In this study, we investigated the radionuclide (177Lu) induced radiosensitivity of serval non-small-cell lung cancer cells (NSCLCs) as well as the binding affinity of cetuximab to those cells. The apoptosis of NSCLCs caused by 177Lu was related to the DNA double-strand damage and was cell-type dependent. We also proved that the introduction of 177Lu to the antibody could enhance its cytotoxic effect on NSCLCs. The [177Lu]Lu-DOTA-cetuximab could accumulate in the HCC827 tumor xenografts with excellent stability according to in vivo SPECT/CT imaging and the biodistribution results. The [177Lu]Lu-DOTA-cetuximab showed high potential to be used for targeting diagnosis and radiotherapy in lung cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: The addition of bevacizumab or ramucirumab to systemic therapy for EGFR-mutated non-small-cell lung cancer (NSCLC) patients provides survival benefits. No study to date has compared the efficacy and safety of these two antiangiogenic therapies (AATs). This study enrolled patients with stage IIIB to IV EGFR-mutated NSCLC who were treated with first-line EGFR-TKIs between January 2014 and May 2022. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). Bevacizumab and ramucirumab did not differ in PFS (24.1 vs. 15.7 months, p = 0.454). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261) or between the two AATs (48.6 vs. 43.0 months, p = 0.924). The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. The effectiveness and safety of the two AATs were similar. The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar. [ABSTRACT FROM AUTHOR]

Background: The treatment options for epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR‐tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole‐brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. Methods: A total of 150 EGFR‐mutant NSCLC patients with BMs who received first‐ or second‐generation EGFR‐TKIs as first‐line treatment between January 2012 and October 2019 were included in this analysis. Results: After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung‐mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35–0.83), who received afatinib or erlotinib as first‐line treatment (HR: 0.521, 95% CI: 0.33–0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32–0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23–0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR‐TKI provided more OS benefits in patients with Lung‐mol GPA ≥3 compared with EGFR‐TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227). Conclusions: The study demonstrated that EGFR‐mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung‐mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status. [ABSTRACT FROM AUTHOR]

There is an urgent need to develop more specific targeted therapies for lung cancer treatment due to the its low survival rate. EGFR is a transmembrane tyrosine kinase protein that is overexpressed in lung cancer. Herein, a novel anti-EGFR antibody, 5A7, was modified with chelators for zirconium-89 (89Zr) and lutetium-177 (177Lu) labeling. The radiolabeled 5A7 could specifically bind to A549 tumor according to the in vitro and in vivo evaluation. Furthermore, the 177Lu labeled 5A7 antibody could inhibit tumor growth significantly in A549 bearing xenografts. The radiolabeled anti-EGFR 5A7 antibody has high potential to be used for PET imaging and radiotherapy. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (ADC) is the predominant histological type of lung cancer, and radiotherapy is one of the current therapeutic strategies for lung cancer treatment. Unfortunately, biological complexity and cancer heterogeneity contribute to radioresistance development. Karyopherin α2 (KPNA2) is a member of the importin α family that mediates the nucleocytoplasmic transport of cargo proteins. KPNA2 overexpression is observed across cancer tissues of diverse origins. However, the role of KPNA2 in lung cancer radioresistance is unclear. Herein, we demonstrated that high expression of KPNA2 is positively correlated with radioresistance and cancer stem cell (CSC) properties in lung ADC cells. Radioresistant cells exhibited nuclear accumulation of KPNA2 and its cargos (OCT4 and c‐MYC). Additionally, KPNA2 knockdown regulated CSC‐related gene expression in radioresistant cells. Next‐generation sequencing and bioinformatic analysis revealed that STAT1 activation and nuclear phospholipid scramblase 1 (PLSCR1) are involved in KPNA2‐mediated radioresistance. Endogenous PLSCR1 interacting with KPNA2 and PLSCR1 knockdown suppressed the radioresistance induced by KPNA2 expression. Both STAT1 and PLSCR1 were found to be positively correlated with dysregulated KPNA2 in radioresistant cells and ADC tissues. We further demonstrated a potential positive feedback loop between PLSCR1 and STAT1 in radioresistant cells, and this PLSCR1‐STAT1 loop modulates CSC characteristics. In addition, AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. Our results collectively support a mechanistic understanding of a novel role for KPNA2 in promoting radioresistance in lung ADC cells. [ABSTRACT FROM AUTHOR]

We investigated the effects of cigarette smoke extract (CSE) on lung fibroblasts and found that the invasiveness of lung cancer cells was facilitated by the conditioned medium from CSE‐treated fibroblasts. CSE induced autophagy in fibroblasts and increased the expression of autophagy‐related proteins, including optineurin and Ras‐related protein Rab1B. Afterward, the fibroblasts produced high levels of interleukin‐8 (IL‐8), which promoted cancer cell invasion. The inhibition of either optineurin or Rab1B abrogated a rise in microtubule‐associated protein 1 light chain 3 β and a decrease in p62 protein, as well as the production of IL‐8, in CSE‐treated fibroblasts. A three‐dimensional invasion assay using cancer cell spheroids revealed that the invasion of cancer cells alone and the fibroblast‐led cancer cell invasion were both enhanced by the conditioned media from CSE‐treated fibroblasts. These results suggest that cigarette smoke may induce autophagy and IL‐8 secretion in lung fibroblasts and modify the microenvironment to favor invasion of lung cancer cells. What's new? Autophagy in stromal cells may play an important role in cancer progression and therapy. Besides interactions between cancer cells and cancer‐associated fibroblasts, external stimulation could alter stromal autophagy in the tumor microenvironment. Here, the authors found that cigarette smoke extract induced autophagy in fibroblasts and increased the expression of autophagy‐related proteins. The fibroblasts produced high levels of IL‐8, which promoted cancer cell invasion. Using a 3D cellular spheroid culture, the authors also observed enhanced fibroblast‐led cancer cell invasion. Cigarette smoke may induce autophagy and IL‐8 secretion in lung fibroblasts and modify the microenvironment to favor invasion of lung cancer cells. [ABSTRACT FROM AUTHOR]

Background: Programmed death‐ligand 1 (PD‐L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD‐L1 expression plays a role in anaplastic lymphoma kinase (ALK)‐positive lung ADC is unknown. We aimed to evaluate the impact of PD‐L1 in patients with ALK‐positive lung ADC receiving crizotinib. Materials and Methods: PD‐L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase‐polymerase chain reaction was used for ALK variant detection, and immunofluorescence‐based multiplex staining was applied for exploring immune cells in tumor microenvironments. Results: A total of 78 patients with ALK‐positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild‐type tumors, PD‐L1 expression was lower in ALK‐positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD‐L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression‐free survival (PFS) was better in tumors with negative PD‐L1 expression (ORR/PFS in PD‐L1 0% vs. 1%–49% vs. 50%–100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p =.007/.022). The multivariate Cox proportional hazards model revealed that PD‐L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160–0.650, p =.002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD‐L1 expression. Conclusion: Positive PD‐L1 expression was associated with unfavorable clinical outcomes in patients with ALK‐positive lung ADC receiving crizotinib. Implications for Practice: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small‐molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death‐ligand 1 (PD‐L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD‐L1 expression was also associated with worse response rate and shorter progression‐free survival of anaplastic lymphoma kinase (ALK)‐positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD‐L1 compared with long variants (V1, V2, and V6). Testing PD‐L1 before initiating crizotinib for ALK‐positive lung cancer could be a simple method to provide important prognostic information. This article focuses on the effect of PD‐L1 on ALK‐positive lung adenocarcinoma and examines the association of pretreatment tumor PD‐L1 and clinical outcomes of patients receiving the first approved ALK inhibitor, crizotinib. [ABSTRACT FROM AUTHOR]

Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression. Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments. A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1–49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250–0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1–49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses. Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients. • Pre-treatment PD-L1 can predict TKI response in EGFR mutant lung adenocarcinoma (ADC). • Pre-treatment PD-L1 can predict acquired T790M in EGFR mutant lung ADC after TKI therapy. • PD-L1 negatively correlated with B cells, macrophages, and regulatory T cells in EGFR mutant ADC. • Abundant tumour-infiltrating B cell is associated with good TKI response in EGFR mutant ADC. • Pre-treatment PD-L1 may help select the most appropriate regimen for EGFR mutant ADC. [ABSTRACT FROM AUTHOR]

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Objective: This study aimed to (1) identify the changes of 5 domains of family caregiver (FC) burden, overall burden, and its subtrajectories when caring for newly diagnosed advanced lung cancer patients during the first 6 months following cancer diagnosis; and (2) identify the FC-related and patient-related factors most associated with the overall FC burden and each of its subtrajectories.Methods: A total of 150 newly diagnosed advanced lung cancer patient-FC dyads were recruited from a Taiwanese medical center. The overall FC burden was evaluated 4 times: before treatment, and 1, 3, and 6 months after treatment. The potential subtrajectory of the caregiver burden was investigated by latent class growth analysis. The FC-related and patient-related factors having the greatest effect on the overall FC burden and its subtrajectories over time were identified by generalized estimating equations.Results: The highest level of burden domain was "Impact on daily schedule" over time. Generally, most of the FC reported a moderate level of overall burden over the investigation period. Three subtrajectories of the overall FC burden over time (% caregivers) were identified: high burden (34.7%), moderate burden (56.0%), and low burden (9.3%), respectively. The self-efficacy of FC was the strongest factor related to the changes of the FC's burden and burden in each subtrajectory.Conclusion: The results support the existing and different types of subtrajectories of the FC's burden. Health care professionals should provide care based on those differences. Further research to test interventions which integrate those important factors related to FC's burden, particularly FC's self-efficacy, is strongly suggested. [ABSTRACT FROM AUTHOR]

Reactivation of hepatitis B virus (HBV) is a documented risk during cytotoxic chemotherapy in patients with lung cancer. Cases of HBV reactivation in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment have been reported; however, the incidence of HBV reactivation in patients treated with EGFR TKIs has not yet been reported. We enrolled 171 patients who were diagnosed as having NSCLC from 2011 through 2017 and who also had positive hepatitis B surface antigen (HBsAg). All patients had received EGFR TKIs as anticancer treatment for at least 2 weeks during their treatment course. Reactivation of HBV is defined as one of the following: an increase in HBV DNA by at least 10-fold compared to baseline or an absolute increase to >10ˆ5 IU/mL with abnormal liver function. The median duration of EGFR TKI treatment was 10.5 months (95% confidence interval: 8.2–12.8). Sixteen (9.36%) patients met the criteria of HBV reactivation during EGFR TKI treatment, with an annual incidence of 7.86%. HBV reactivation occurred during erlotinib treatment in 6 patients, followed by 5 patients with gefitinib treatments, 3 patients with osimertinib treatment and 2 with afatinib treatment. No independent risk factor for HBV reactivation was identified. NSCLC patients receiving EGFR TKI treatment may have a clinically meaningful risk of HBV reactivation during the treatment period. Thus, monitoring liver function, HBV viral load and serology of HBV (i.e., HBeAg and anti-HBc) during EGFR TKI therapy is recommended for NSCLC patients with positive HBsAg. • NSCLC patients have a clinically meaningful risk of HBV reactivation during EGFR TKI treatment. • No independent risk factors were identified for HBV reactivation during EGFR TKI treatment. • HBV screening and monitoring liver function are recommended for NSCLC patients before and during EGFR TKI treatment. [ABSTRACT FROM AUTHOR]

Epithelial‐to‐mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E‐cadherin promoter‐luciferase reporter vectors. NIMA‐related kinase‐4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion‐related proteins such as E‐cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E‐cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4‐knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis. [ABSTRACT FROM AUTHOR]

Abstract: An increasing number of studies have demonstrated that micro‐ribonucleic acids (miRNAs) are important tumor suppressors during carcinogenesis. However, the function of miRNA‐541 (miR‐541) in malignancies, especially lung cancer, has not been widely reported. In this study, miR‐541 expression was significantly decreased in squamous cell lung carcinoma (SCLC) cancerous tissue and SCLC cell lines. To analyze miR‐541 function in SCLC, we overexpressed miR‐541 in SCLC cell lines (SK‐MES‐1 and H226). According to the CCK8, wound scratch, and transwell invasion assay results, miR‐541 overexpression significantly inhibited SCLC cell proliferation, migration, and invasion ability. Next, using RT‐PCR, Western blotting, immunocytochemistry, and luciferase assays, HMGA2 was identified, for the first time, as a direct regulatory target of miR‐541 in SK‐MES‐1 and H226 cells. Furthermore, upregulating HMGA2 expression significantly alleviated the suppressive effects of miR‐541 on SK‐MES‐1 and H226 cell proliferation, migration, and invasion. In summary, our study revealed that miR‐541 inhibited SCLC proliferation and invasion by directly targeting HMGA2. [ABSTRACT FROM AUTHOR]

Purpose: Limited research has focused on women with lung cancer (LC) although they are recognized as the most vulnerable to psychological distress. This study explored in-depth the psychological distress experienced by women with incurable LC and analyzed the coping strategies with which they manage that distress.Methods: A qualitative methodology with in-depth interviews was employed for 34 women with advanced or recurrent LC. An inductive data-driven thematic analysis was applied to analyze transcripts.Results: Psychological distress was an iterative process for the women. Four themes were identified: shock regarding the diagnosis, distress regarding cancer treatment and its side effects, the facing of a recurrent or progressive disease, and persistent struggle with the life-limiting disease. Various coping strategies applied by the women to manage psychological distress were grouped into four themes: relying upon social support, focusing on positive thoughts, avoidance-based strategies, and religious faith and acceptance.Conclusions: Women with incurable LC experienced substantial iterative psychological distress throughout the illness, regardless of length of illness at time of interview. They applied multiple forms of coping. The findings enrich the limited existing literature on this understudied population and provide direction for the future development of interventions to improve their psychological well-being. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice. Materials and Methods: We enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan. Results: The median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7-14.2) and 26.9 months (21.2-32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11-0.83], p = .02; 2.69 [1.60-4.51], p < .001; 1.92 [1.24-2.97], p = .003; 2.26 [1.34-3.82], p = .002; 3.38 [1.85-7.78], p < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83-1.93], p = .275 and 0.75 [0.48-1.19], p = .211, respectively). Conclusion: HCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS. [ABSTRACT FROM AUTHOR]

Objective This study aimed to (i) explore the prevalence and levels (severity) of anxiety and depression in family caregivers (FCs) of patients newly diagnosed with advanced lung cancer (stage IIIb or IV) before first treatment, and (ii) identify the factors related to FCs' anxiety and depression. Methods For this cross-sectional study, 106 patient-FC dyads were recruited from a medical center in northern Taiwan. FCs' anxiety and depression were measured using the self-report Hospital Anxiety and Depression Scale, and FCs' ability to manage patients' symptoms was assessed using the Self-Efficacy in Symptom Management Scale. FCs' risks for anxiety and depression were separately identified using two multivariate logistic regression models. Results This study found two major results. First, before patients' first treatment, 50.9% and 32.1% of FCs were at risk for anxiety and depression, respectively. FCs' overall mean anxiety and depression scores were 7.7 (SD = 4.7) and 6.1 (SD = 4.5), respectively. Second, both FCs' anxiety and depression were significantly related to four factors: caring for another sick family member, younger age, having pain problems, and lower self-efficacy in managing symptoms. Conclusion Family caregivers of patients newly diagnosed with advanced lung cancer had anxiety and depression before the patients' first treatment. We strongly suggest developing and testing interventions to reduce FCs' psychological distress and enhance their quality of life, thus ensuring better quality of patient care. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus an interaction between arsenite and cigarette smoking in lung carcinogenesis was suspected. In the present study, we investigated the interactions of a tobacco-specific carcinogen 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone, NNK) and arsenite on lung cell transformation. BEAS-2B, an immortalized human lung epithelial cell line, was selected to test the centrosomal abnormalities and colony formation by NNK and arsenite. We found that NNK, alone, could enhance BEAS-2B cell growth at 1–5 μM. Under NNK exposure, arsenite was able to increase centrosomal abnormality as compared with NNK or arsenite treatment alone. NNK treatment could also reduce arsenite-induced G2/M cell cycle arrest and apoptosis, these cellular effects were found to be correlated with p53 dysfunction. Increased anchorage-independent growth (colony formation) of BEAS-2B cells cotreated with NNK and arsenite was also observed in soft agar. Our present investigation demonstrated that NNK could provide a p53 compromised status. Arsenite would act specifically on this p53 compromised status to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenite under tobacco-specific carcinogen co-exposure. [Copyright &y& Elsevier]

Abstract: Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-α-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 μM) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-α and 5 μM sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction. [Copyright &y& Elsevier]

Simple Summary: ctDNA assay is a promising non-invasive method to detect genomic alterations associated with lung cancer. In this prospective study of 25 patients with EGFR-mutant lung adenocarcinoma receiving osimertinib, ctDNA progression predated radiographic progression by 118 days in 11 of 20 patients with disease progression. Saliva-based ctDNA analysis and plasma NGS detected additional patients with ctDNA progression preceding clinical progression, suggesting the potential complementary roles of different ctDNA detection methodologies. Baseline mutant ctDNA level predicted progression-free survival while tumor volume measurements by volumetric CT did not. Serial ctDNA analysis of plasma and saliva is a clinically useful tool to monitor response and resistance to osimertinib. Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic guidance in non-small cell lung cancer (NSCLC) patients with discordant anaplastic lymphoma kinase (ALK) fluorescent in situ hybridization (+) where immunohistochemistry (IHC) (−) results are challenging. Selected reaction monitoring (SRM) quantitative multiplexed proteomics could detect ALK protein in NSCLC samples with delayed fixation where a conventional IHC method failed. ALK protein detection by the SRM method was associated with good responses on ALK inhibitors. It also could detect various predictive proteins for conventional chemotherapy at the same time, and combined results were related to clinical outcomes in this population. The SRM may provide additional information for therapeutic decision making in NSCLC patients with ambiguous ALK test results. Therapeutic guidance in non-small cell lung cancer (NSCLC) tumors that are positive for anaplastic lymphoma kinase (ALK) fluorescent in situ hybridization (FISH), but negative for ALK immunohistochemistry, is still challenging. Parallel routine screening of 4588 NSCLC cases identified 22 discordant cases. We rechecked these samples using ALK antibodies and selected reaction monitoring (SRM) quantitative multiplexed proteomics screening multiple protein targets, including ALK and MET for the ALK tyrosine kinase inhibitor (TKI), and FR-alpha, hENT1, RRM1, TUBB3, ERCC1, and XRCC1 for chemotherapy. The presence of ALK (31.8%), MET (36.4%), FR-alpha (72.7%), hENT1 (18.2%), RRM1 (31.8%), TUBB3 (72.9%), ERCC1 (4.5%), and a low level of XRCC1 (54.4%) correlated with clinical outcomes. SRM was more sensitive than the ALK D5F3 assay. Among the eight cases receiving ALK TKI, four cases with ALK or MET detected by SRM had complete or partial responses, whereas four cases without ALK or MET showed progression. Twenty-seven treatment outcomes from 20 cases were assessed and cases expressing more than half of the specific predictive proteins were sensitive to matching therapeutic agents and showed longer progression-free survival than the other cases (p < 0.001). SRM showed a potential role in therapeutic decision making in NSCLC patients with ambiguous ALK test results. [ABSTRACT FROM AUTHOR]

The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to heterogeneous disease entity. The aim of this study was to evaluate the clinicopathologic features and prognostic factors of patients with completely resected stage IIIA-N2 NSCLC. We retrospectively evaluated 77 consecutive patients with pathologic stage IIIA-N2 NSCLC (AJCC eighth edition) who underwent surgical resection with curative intent in China Medical University Hospital between 2006 and 2014. Survival analysis was conducted, using the Kaplan–Meier method. Prognostic factors predicting overall survival (OS) and disease-free survival (DFS) were analyzed, using log-rank tests and multivariate Cox proportional hazards models. Of the 77 patients with pathologic stage IIIA-N2 NSCLC examined, 35 (45.5%) were diagnosed before surgery and 42 (54.5%) were diagnosed unexpectedly during surgery. The mean age of patients was 59 years, and the mean length of follow-up was 38.1 months. The overall one-, three-, and five-year OS rates were 91.9%, 61.3%, and 33.5%, respectively. Multivariate analysis showed that tumor size <3 cm (hazards ratio (HR): 0.373, p = 0.003) and video-assisted thoracoscopic surgery (VATS) approach (HR: 0.383, p = 0.014) were significant predictors for improved OS. For patients with surgically treated, pathologic stage IIIA-N2 NSCLC, tumor size <3 cm and the VATS approach seemed to be associated with better prognosis. [ABSTRACT FROM AUTHOR]

The serious ambient fine particulate matter (PM 2·5) pollution issue in China has received great attention in the past 10 years and it is one of key risk factors for developing lung cancer. Studies have investigated the effect of PM 2·5 associated with regional transport and internal migration on lung cancer mortality and morbidity. However, evidence for a forecast of PM 2·5 -induced lung cancer across China is scarce. We aimed to predict the spatial distribution of lung cancer morbidity and mortality in China due to exposure to PM 2·5 concentration. For this modelling study, we used the lung cancer morbidity and mortality data (2006–14) from Chinese cancer registrations. The annual concentrations (1998–2016) of global surface PM 2·5 (0·01° by 0·01° spatial resolution) were also collected. A spatial autocorrelation method was used to investigate spatial clusters of lung cancer on a county-level in China. Ridge regression (RR), partial least squares regression (PLSR), model tree (MT), regression tree (RT), and the combined forecasting model (CFM) were alternative methods used to predict the lung cancer morbidity and mortality. A kriging interpolation method was used to obtain the spatial distribution of lung cancer mortality and morbidity in 2015 and 2016. The lung cancer morbidity increased from 49·70 per 100 000 population (2006) to 59·03 per 100 000 population (2014), and the lung cancer morbidity increased from 44·15 per 100 000 population to 47·23 per 100 000 population. Spatial autocorrelation analysis indicated that the morbidity and mortality of lung cancer and PM 2·5 concentration were significantly spatially autocorrelated for each year in China (spatial correlation 0·26–0·42 for morbidity and 0·25–0·44 for mortality; p<0·0001). Results from kriging method suggested a similar spatial distribution in morbidity and mortality of lung cancer associated with PM 2·5 in 2015 and 2016, and high morbidity and mortality of lung cancer areas were mainly located in central-east coast areas. The occurrence of severe PM 2·5 pollution was not localised only in a county or city, but was a regional-level problem. Key findings from this study showed a large regional scale of lung cancer morbidity and mortality has occurred in China due to PM 2·5 pollution. It is necessary to strengthen regional collaborative pollution management among the high PM 2·5 concentration regions. None. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) of plasma cell-free DNA identifies driver mutations in advanced non-small cell lung cancer (NSCLC) and may complement routine molecular evaluation. The utility of liquid NGS at the start of tumour workup is undetermined. This is a randomised study of patients with suspected advanced NSCLC. All patients received blood liquid NGS testing at their first clinic visit and underwent standard histological diagnosis and tissue genotyping, encompassing polymerase chain reaction based methods for EGFR mutation, immunohistochemical (IHC) staining for ALK fusion and BRAF V600E mutation, and an IHC screening followed by confirmation using fluorescence in situ hybridization confirmation for ROS1 fusion. They were then randomly assigned to receive NGS results either after tissue genotyping (Group A) or as soon as possible after histological diagnosis of advanced NSCLC (Group B). The study measured time to start of systemic treatment as the primary endpoint and secondary endpoints included biomarker discovery rate, objective response rate (ORR), and progression-free survival (PFS). This study enroled 180 patients with suspected advanced NSCLC, randomised into two groups. 63 patients in Group A and 59 in Group B with advanced NSCLC were confirmed as advanced NSCLC and analysed. Most had adenocarcinoma (Group A: 77.8%, Group B: 79.7%). The prevalence of EGFR mutations in the two groups was similar (Group A: 57.1%; Group B: 56.6%). Other driver alterations were rare. The median time to treatment was shorter in Group B (20 days) than in Group A (28 days). ORR and PFS did not differ between groups significantly. Liquid NGS had high concordance with tissue testing and identified driver mutations in 42.6% (20/47) of tissue-negative cases. Performing liquid NGS at the initial clinic visit for suspected advanced NSCLC identifies more patients suitable for targeted therapies and shortens time to the start of treatment. • Liquid NGS finds treatable mutations in over 60% of East Asian NSCLC patients. • Upfront liquid NGS shortens the time to treatment by 8 days in advanced NSCLC. • Liquid NGS detects 42.6% of cases missed by four-gene tissue testing. [ABSTRACT FROM AUTHOR]

Karyopherin subunit alpha 2 (KPNA2, importin α1) is a nucleoplasmic protein responsible for the nuclear import of proteins with classical nuclear localization signals. Aberrant nuclear accumulation of KPNA2 has been observed in numerous cancer tissues. AMP-activated protein kinase (AMPK) is involved in the phosphorylation and acetylation of KPNA2 in enterocytes. However, the impact of these post-translational modifications on modulating the nucleocytoplasmic distribution of KPNA2 and its oncogenic role remain unclear. Unlike nuclear accumulation of wild-type KPNA2, which promoted lung cancer cell migration, KPNA2 Lys22 acetylation-mimicking mutations (K22Q and K22Q/S105A) prevented nuclear localization of KPNA2 and reduced the cell migration ability. Cytosolic KPNA2 K22Q interacted with and restricted the nuclear entry of E2F transcription factor 1 (E2F1), an oncogenic cargo protein of KPNA2, in lung cancer cells. Intriguingly, the AMPK activator EX229 promoted the nuclear export of KPNA2 S105A. However, the CBP/p300 inhibitor CCS-1477 abolished this phenomenon, suggesting that CBP/p300-mediated acetylation of KPNA2 promoted KPNA2 nuclear export in lung cancer cells. Collectively, our findings suggest that the CBP/p300 positively regulates KPNA2 acetylation, which enhances its cytosolic localization and suppresses its oncogenic activity in lung cancer. • Lys22 acetylation of KPNA2 enhances its cytoplasmic distribution. • Acetylation and phosphorylation contribute to the nucleocytoplasmic cycling of KPNA2. • KPNA2 mutants with Lys22 acetylation-mimetic attenuate lung cancer cell migration. • The AMPK-CBP/p300 axis regulates the acetylation of Lys22 in KPNA2. [ABSTRACT FROM AUTHOR]

Purpose/Objectives: To examine the changes in quality of life (QOL), symptoms, self-efficacy for coping with cancer, and factors related to those changes in patients with newly diagnosed advanced lung cancer.Design: Longitudinal and correlational.Setting: Oncology inpatient wards and outpatient departments of a medical center in northern Taiwan.Sample: 101 patients newly diagnosed with stage IIIB or IV lung cancer.Methods: Questionnaires were used to assess patients' QOL, symptoms, and self-efficacy before treatment and at one and three months following treatment. Factors related to the changes in global QOL and five functional dimensions were analyzed using six generalized estimating equation models.Main Research Variables: QOL, symptoms, and self-efficacy for coping with cancer.Findings: Patients reported moderate levels of global QOL, symptom severity, and self-efficacy for coping with cancer. They also reported high physical and cognitive functions, but relatively low role and social functions. Factors were significantly related to the most functional dimensions, including self-efficacy, fatigue, pain, sleep difficulties, and demographic- and disease-related factors. Self-efficacy was the most robust factor for predicting QOL.Conclusions: Patients with advanced lung cancer experience a compromised global QOL and relatively low social and role functioning during the first three months following cancer diagnosis. Levels of self-efficacy and symptoms significantly affected changes in QOL and functioning.Implications for Nursing: Applying a systematic assessment of changes in QOL and developing comprehensive interventions with self-efficacy training and symptom management are strongly recommended for clinical care to improve the QOL of patients with advanced lung cancer. [ABSTRACT FROM AUTHOR]

• Circulating tumor cells (CTCs) are frequently detected in advanced EGFR -mutated NSCLC. • Circulating cancer stem cell (CCSC) and tumor cell levels decreased after 12-week EGFR-TKI. • Levels of circulating cancer stem cell and tumor cells remained low at disease progression. • Pretreatment high CCSC and CTC levels may be associated with a trend towards poor outcomes. Circulating tumor cells (CTCs) are associated with tumor spread, whereas cancer stem cells may be related to drug resistance. However, few studies have analyzed the levels of circulating cancer stem cells (CCSCs) and CTCs in patients with advanced non-small cell lung cancer (NSCLC). Treatment-naïve patients with EGFR -mutated NSCLC who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy were recruited prospectively. The cell surface vimentin antibody was used for CTC detection and CD133 antibody for CCSC detection. CCSC and CTC levels were measured as cell count per 4 mL of blood, before treatment, after 2 and 12 weeks of treatment, and at disease progression. Data on clinical characteristics and outcomes were also collected. At diagnosis (n = 29), the median CCSC and CTC levels were 0 (interquartile range, 0–2) and 3 (2–9), respectively. After 12 weeks, the CCSC and CTC levels were lower than those at diagnosis (CCSC: 0 (0−0), p = 0.14; CTC: 1 (0–4), p = 0.048). At disease progression, the median CCSC and CTC levels were 0 (0–1) and 1 (0–2), respectively. Patients with higher CCSC and CTC levels at diagnosis had a numerically shorter progression-free survival. In patients with EGFR -mutated NSCLC, CCSC and CTC levels became lower after 12 weeks of EGFR-TKI therapy and remained low at disease progression. High pre-treatment CCSC and CTC levels may be associated with a trend towards poor treatment outcomes. [ABSTRACT FROM AUTHOR]

• A computer-aided diagnosis (CAD) system was proposed to diagnose the lung cancer in endobronchial ultrasound (EBUS) images. • In this study, a CAD system using the convolutional neural network (CNN) was proposed to automatically differentiate benign and malignant lesions for early detecting lung cancer. • The results of our CAD system show that the accuracy, sensitivity, specificity, and the area under ROC achieved 85.4%, 87.0%, 82.1%, and 0.8705, respectively. • Our study has demonstrated that CAD system based on the CNN architecture could provide an automatic method to differentiate benign and malignant lesions in patients with lung cancer. In the United States, lung cancer is the leading cause of cancer death. The survival rate could increase by early detection. In recent years, the endobronchial ultrasonography (EBUS) images have been utilized to differentiate between benign and malignant lesions and guide transbronchial needle aspiration because it is real-time, radiation-free and has better performance. However, the diagnosis depends on the subjective judgment from doctors. In some previous studies, which using the grayscale image textures of the EBUS images to classify the lung lesions but it belonged to semi-automated system which still need the experts to select a part of the lesion first. Therefore, the main purpose of this study was to achieve full automation assistance by using convolution neural network. First of all, the EBUS images resized to the input size of convolution neural network (CNN). And then, the training data were rotated and flipped. The parameters of the model trained with ImageNet previously were transferred to the CaffeNet used to classify the lung lesions. And then, the parameter of the CaffeNet was optimized by the EBUS training data. The features with 4096 dimension were extracted from the 7th fully connected layer and the support vector machine (SVM) was utilized to differentiate benign and malignant. This study was validated with 164 cases including 56 benign and 108 malignant. According to the experiment results, applying the classification by the features from the CNN with transfer learning had better performance than the conventional method with gray level co-occurrence matrix (GLCM) features. The accuracy, sensitivity, specificity, and the area under ROC achieved 85.4% (140/164), 87.0% (94/108), 82.1% (46/56), and 0.8705, respectively. From the experiment results, it has potential ability to diagnose EBUS images with CNN. [ABSTRACT FROM AUTHOR]

Objective Approximately 10%–15% patients with epidermal growth factor receptor ( EGFR ) mutations harbor non-classical mutations. However, the effects of EGFR-tyrosine kinases (TKIs), particularly second-generation EGFR-TKI (afatinib) compared to first-generation EGFR-TKIs (gefitinib/erlotinib), in patients with non-classical EGFR mutations remain unknown. Methods We conducted this retrospective study at the China Medical University Hospital (Taichung, Taiwan) from June 2011 to July 2016. Specimens from 1632 patients were tested for EGFR mutations. We surveyed the effectiveness of afatinib and gefitinib/erlotinib in stage IIIb-IV lung adenocarcinoma patients with non-classical EGFR mutations. Results Fifty-six patients with advanced-stage (stage IIIB-IV) lung adenocarcinoma with non-classical mutations and receiving EGFR-TKI treatment had completed follow-up and were further analyzed. Afatinib versus gefitinib/erlotinib showed that the objective response rates were 62.5% versus 50.0% ( p = 0.35). Median progression-free survival (PFS) of 11.0 versus 3.6 months ( p = 0.03), respectively, was observed for the 51 non-classical EGFR mutated (excluding 5 patients with exon 20 insertions) lung adenocarcinomas. Subset analysis showed that PFS curves of afatinib were more easily distinguished in non-classical EGFR mutations lacking a combination with a classical mutation (non-classical with classical complex mutations group: median PFS, 11.0 versus 8.2 months, p = 0.19; non-classical mutation alone or in combination with other non-classical mutations group: median PFS, 18.3 versus 2.8 months, p = 0.07). Conclusions Afatinib may be a first-choice EGFR-TKI for patients with advanced-stage lung adenocarcinomas harboring non-classical mutations. [ABSTRACT FROM AUTHOR]

Background Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR) mutations experiencing a response to EGFR -tyrosine kinase inhibitor (TKI) initially. We investigated EGFR -TKI retreatment in patients who had previously received EGFR -TKI followed by chemotherapy. Materials and methods This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR -TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment. Results In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4–92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR -TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR -TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR -TKI was 8.0 months (95% CI 7.3–8.2), and retreatment EGFR -TKI was 4.1 months (95% CI 2.7–4.6). The median OS since the start of the first-line EGFR -TKI therapy was 35.9 months (95% CI 28.8–50.9), and since the start of EGFR -TKI retreatment was 12.6 months (95% CI 10.4–20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR -TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR = 0.62, 95% CI 0.44-0.86; HR = 0.6, 95% CI 0.43–0.86), both p < 0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR = 0.51, 95% CI 0.30–0.86; HR = 0.52 (0.31–0.88), both p < 0.05). Conclusions EGFR -TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR- mutated NSCLC patients after failure of first-line EGFR -TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR -TKI and in females with the exon 21 mutation. [ABSTRACT FROM AUTHOR]

• Multi-functionalized hyaluronan (HA) derivatives containing asparagine-glycine-arginine (NGR) peptide, fluorescent probe and 177Lu radionuclide were successfully prepared. • HA derivative could synergically target tumors cells that overexpressing CD44 and CD13. • The fluorescent and radio-labeled HA derivative could accumulate in the tumors with abundant blood vessels ex vivo/in vivo. Hyaluronan (HA) is a negatively charged linear polysaccharide that can interact with cluster determinant 44 (CD44) overexpressed cancers. However, HA can also bind to excess substrates in the human body leading to the lower specificity of tumor targeting. Conjugation of other targeting group to HA could enhance the uptake by cancer cell comparing to that of native HA. In this study, we develop the multi-functionalized HA (177Lu-DOTA/Alexa647-HA100-N) for malignant tumor targeting. An asparagine-glycine-arginine (NGR) based peptide was selected for HA functionalization. The peptide is known to target CD13 receptor that is overexpressed in malignant tumors with abundant blood vessels, such as lung cancer. Furthermore, the fluorescent probe Alexa Fluor 647 for ex vivo / in vivo tracking and the radionuclide 177Lu for radioactive therapy were both labeled on the material. The functionalized HA could be bound by lung cancer cells and breast cancer cells. In vivo fluorescent imaging showed that the material could accumulate in the tumor site for more than 96 h. The 177Lu labeling of functionalized HA was stable for more 48 h at physiological conditions. The accumulation of 177Lu-DOTA/Alexa647-HA100-N in the tumor of lung cancer (NCI-H292) bearing mice was 1.91±0.97%ID/g, and it was about 17 times higher than the value in blood. Conclusion: The multimodality labeled functional HA was successfully prepared and could be fluorescent trackable ex vivo and in vivo. It showed high potential to be used for malignant cancer radiotherapy for its specific targeting property to tumors and radiotoxicity from the labeled 177Lu radionuclide. [Display omitted] [ABSTRACT FROM AUTHOR]