Search

Simple Summary: Carriers of germline BRCA1/2 pathogenic variants are at increased risk of developing BRCA-associated malignancies (breast, ovarian, prostate and pancreatic cancer), which are responsive to treatment with poly (adenosine phosphate-ribose) polymerase inhibitors (PARPi) and platinum-based chemotherapy (PBC). However, the role of BRCA mutations in tumor development and in the prediction of response to treatment in nonsmall cell lung cancer (NSCLC) remains unclear. In this study, we retrospectively analyzed a cohort of 26 patients with NSCLC harboring BRCA mutations treated at our center, demonstrating unique clinical features, including many nonsmokers and BRCA mutations. Importantly, patients with NSCLC and BRCA mutations demonstrate increased sensitivity to PBC and PARPi in comparison to patients with NSCLC and wild-type BRCA. The results suggest that BRCA mutations play some oncogenic role in NSCLC and warrant further prospective trials of treatment of NSCLC harboring BRCA mutations with PARPi. The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40–78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5–22), compared to 47.4% and 7 months (CI 95%, 5–9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17–0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi. [ABSTRACT FROM AUTHOR]

Background: DNA‐based next‐generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA‐based next‐generation sequencing has been proven to be valuable in detecting fusion and exon‐skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. Methods: The authors developed an RNA‐based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single‐nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin‐fixed, paraffin‐embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. Results: In analytical validation, the RNA panel achieved a limit of detection of 1.45–3.15 copies per nanogram for SNVs and 0.21–6.48 copies per nanogram for fusions. In 1253 formalin‐fixed, paraffin‐embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14‐skipping events, in which 14 fusions and six MET exon 14‐skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. Conclusions: Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing. RNA panel sequencing was capable of detecting multiple types of clinically actionable mutations with high accuracy. This simplified experimental method was proven in 1253 formalin‐fixed, paraffin‐embedded non–small cell lung cancer samples. [ABSTRACT FROM AUTHOR]

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non‐small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR‐driven and ALK‐driven diseases. This is a narrative review of the most relevant molecular alterations in non–small cell lung cancer beyond EGFR‐driven and ALK‐driven disease. The oncogenic role of these molecular aberrations and targeted therapy with emerging drugs in this setting are described. [ABSTRACT FROM AUTHOR]

Background: As the global population ages, the prevalence of early-stage nonsmall cell lung cancer (NSCLC) among octogenarians is rising. This demographic frequently presents with comorbid conditions, diminished cardiopulmonary function, and increased frailty, which elevate the risks associated with standard treatments. While lobectomy combined with lymph node dissection is still considered the gold standard for managing NSCLC, octogenarians are at significantly higher risk of perioperative mortality. Although wedge resection has been suggested as a less invasive option, previous research has insufficiently explored the influence of visceral pleural invasion (VPI) on postoperative outcomes. This study seeks to evaluate whether wedge resection can provide survival outcomes equivalent to those of anatomical resection in this high-risk population., Methods: We conducted a retrospective analysis using SEER data from 2010 to 2019, focusing on octogenarians diagnosed with stage I NSCLC and VPI. Propensity score matching, Kaplan-Meier survival analysis, log-rank testing, and Cox multivariate regression were employed to evaluate and compare the outcomes associated with two different surgical techniques., Results: We identified 523 octogenarians with stage I NSCLC and VPI, from a cohort of 1587 patients. In this study cohort, 372 (71.1%) patients received anatomical resection, while 151 (28.9%) patients underwent wedge resection. Following multivariable adjustment and propensity score matching, there were no statistically significant differences in lung cancer-specific survival (CSS; HR 0.99, 95% CI: 0.57-1.73) or overall survival (OS; HR 1.02, 95% CI: 0.68-1.53) observed between the two surgical groups. Additionally, multivariate Cox regression analysis indicated that the choice of surgical approach was not an independent prognostic factor for either CSS (HR 1.29, 95% CI: 0.62-2.69) or OS (HR 1.50, 95% CI: 0.68-1.62)., Conclusions: This study demonstrates that wedge resection is a viable surgical option for octogenarians with stage I NSCLC and VPI. Notably, the addition of lymph node dissection to wedge resection significantly enhances survival outcomes compared to wedge resection performed without lymph node dissection., (© 2025 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Few treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients. Methods: NSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan−Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors. Results: A total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy. Conclusions: Our results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed. [ABSTRACT FROM AUTHOR]

Background/aim: Significant advances have been achieved in immunotherapy for the treatment of lung cancer. It is known that tumor cells and cells in the tumor microenvironment express high amounts of programmed cell death ligand 1 (PD-L1). These PD-L1s interact with programmed cell death protein 1 (PD-1), causing immunosuppression. The aim of our study is to examine the correlation between the serum sPD-1 and sPD-L1 levels and clinicopathological characteristics in patients with nonsmall cell lung cancer. We also compared our results with the healthy population (control group). Materials and methods: Thirthy-seven nonsmall cell lung cancer (NSCLC) patients who were operated in our clinic were included in our study. The control group included fifteen healthy patients. The sPD-1 and sPD-L1 levels were measured in serum samples by using the ELISA method. Results: The preoperative sPD-1 and sPD-L1 levels were significantly higher in the study group compared to the control group (44.12 ± 22.25 pg/mL vs. 18.54 ± 6.56 pg/mL; p = 0.001 and 26.15 ± 18.03 pg/mL vs. 10.29 ± 3.08 pg/mL; p = 0.001, respectively). There was a statistically significant decline in serum sPD-1 and sPD-L1 levels at the preoperative and postoperative 1st, 7th, and 30th days following surgical resection (44.12 ± 22.25 pg/mL, 37.86 ± 18.02 pg/mL, 36.33 ± 18.36 pg/mL, 34.14 ± 13.71 pg/mL; p = 0.007 and 26.15 ± 18.03 pg/mL, 20.60 ± 15.50 pg/mL, 18.31 ± 14.04 pg/mL, 13.64 ± 10.60 pg/mL; p = 0.001, respectively).There was a positive correlation between the preoperative and postoperative 30th day serum sPD-1 levels and the tumor size (p = 0.031, r = 0.352; p = 0.024, r = 0.371; respectively). We also found a positive correlation between the preoperative and postoperative 30th day serum sPD-L1 levels and pleural invasion (p = 0.001, p = 0.001; respectively), and the N category (p = 0.015, p = 0.013; respectively). Conclusion: We think that sPD-1 and sPD-L1 levels may be used as a potential biomarker for lung cancer screening, prediction of the stage, and besides to detect recurrences and/or metastases following resection in NSCLC following validation with multicenter and larger-scale prospective trials. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors targeting the programmed cell death‐1 (PD‐1)/PD‐1 ligand 1 (PD‐L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD‐L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ‐induced PD‐L1 is one of the major mechanisms by which cancer cells escape host immunity. Methods Here, we found that the NSCLC cell line, LC‐2/ad, has a unique character; the PD‐L1 expression in these cells is up‐regulated by both IFNγ and epidermal growth factor (EGF). Results Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC‐2/ad cells. IFNγ‐induced PD‐L1, but not EGF‐induced PD‐L1, was clearly blocked by the JAK‐STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell‐activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell‐mediated cytotoxicity in LC‐2/ad cells, which was, however, blocked by tofacitinib. Conclusions Taken together, our study shows that tofacitinib blocks the IFNγ‐induced transformation from an NK cell‐sensitive phenotype to an NK cell‐resistant one in IFNγ‐reacted LC‐2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ‐induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.

Objective : About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG 2 monoclonal antibody panitumumab. The main goal of the present study was to investigate 64 Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. Methods: Bifunctional chelating agent 2- S -(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of 64 Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for in vitro and in vivo experiments. Cell uptake of [ 64 Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [ 18 F]FLT PET. Immuno-PET with [ 64 Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed ex vivo biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. Results: MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [ 64 Cu]CuCl 2 was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [ 64 Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein ( n = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein ( n = 3). PET imaging revealed high uptake of [ 64 Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV) mean reached 4.70 ± 0.42 and 5.37 ± 0.40 ( n = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 ( n = 4; p < 0.001). In the metastatic model, the following SUV mean were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both n = 16 lesions from 4 mice; p < 0.001) after injection of 1 mg panitumumab. Detailed ex vivo biodistribution confirmed immuno-PET analysis in both models. Panitumumab reduced radioactivity uptake into subcutaneous tumors from 11.01 ± 0.72 ( n = 4) to 3.67 ± 0.33% ID/g ( n = 5; p < 0.001), and in metastatic liver lesions from 29.44 ± 8.14 ( n = 4) to 8.35 ± 1.30% ID/g ( n = 5; p < 0.001), respectively. Conclusions: [ 64 Cu]Cu-NOTA-panitumumab was successfully used for immuno-PET imaging of EGFR-expressing subcutaneous and metastatic NSCLC tumors. This result represents the basis for developing radiotheranostics for targeting EGFR in cancers and for selecting the right patients for the right treatment at the right time.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are a class of RNAs participating in many biological processes such as imprinting, alternative splicing and RNA decay. Recently, lncRNAs have drawn a great deal of attention for their critical role in cancer progression. LINC00461, a newly identified lncRNA, has been reported to be significantly overexpressed in breast cancer and markedly expedited breast cancer progression. However, the specific role of LINC00461 in nonsmall cell lung cancer (NSCLC) remains unknown. In this study, we for the first time showed the biological functions of LINC00461 in NSCLC. Our results demonstrated that LINC00461 was significantly up-regulated in NSCLC tissues and cell lines. Furthermore, knockdown of LINC00461 inhibited NSCLC cell proliferation and invasion in vitro as well as suppressed tumor growth and metastasis in vivo. We also performed luciferase reporter assays and found that LINC00461 functioned as a sponge for miR-518a-3p and WDR1 was a target of miR-518a-3p. Taken together, we suggested an essential role of LINC00461/miR-518a-3p/WDR1 axis in NSCLC, which could be used as a potential therapeutic target for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomized pilot trial from our laboratory, this single-arm phase II trial investigated administering flaxseed as a radioprotector in patients receiving definitive chemoradiation for nonsmall cell lung cancer (NSCLC). Methods: Between June 2015 and February 2018, 33 patients with locally advanced or metastatic NSCLC with planned definitive chemoradiation were enrolled. Finely-ground Linum usitatissimum L. (Linaceae; flaxseed or linseed) in 40-g packets were provided for daily consumption in any patient-desired formulation 1 week before radiotherapy and throughout radiotherapy as tolerated. The primary outcomes were overall adverse events, with particular focus on Grade ≥3 RP, and flaxseed tolerability. Adverse events were graded according to CTCAE v4.0. Results: Of the 33 patients enrolled, 5 patients (15%) did not receive chemoradiation, 4 (12%) withdrew promptly after enrollment, 4 (12%) did not return a flaxseed consumption log, and 1 patient had irritable bowel syndrome (3%). The remaining 19 patients (57%) had chemoradiation and flaxseed ingestion with a mean completion and standard deviation of the intended flaxseed course of 62% ± 8.3%. Nine (50%) of these 19 patients reported difficulties with flaxseed consumption, citing nausea, constipation, odynophagia, or poor taste or texture. One patient (5%), with unverifiable flaxseed consumption, developed Grade 3 RP. There were no cases of Grade 2 RP. Six patients (32%) developed Grade 2 RE, but no patients developed Grade ≥3 RE. Median overall and progression-free survival were 31 and 12 months, respectively. Conclusions: Despite the low incidence of acute radiation-induced complications reported, significant treatment-related gastrointestinal toxicities and subsequently low flaxseed tolerability inhibit accurate determination of flaxseed effect in patients receiving concurrent thoracic chemoradiation. Thus, further investigations should focus on optimizing flaxseed formulation for improved tolerability and evaluation. ClinicalTrials.gov ID: NCT02475330 [ABSTRACT FROM AUTHOR]

Abstract Background Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population. Methods We conducted a 10 years (2005‐2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions. Results A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P

Background: Immune checkpoint inhibitors targeting the programmed cell death‐1 (PD‐1)/PD‐1 ligand 1 (PD‐L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD‐L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ‐induced PD‐L1 is one of the major mechanisms by which cancer cells escape host immunity. Methods: Here, we found that the NSCLC cell line, LC‐2/ad, has a unique character; the PD‐L1 expression in these cells is up‐regulated by both IFNγ and epidermal growth factor (EGF). Results: Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC‐2/ad cells. IFNγ‐induced PD‐L1, but not EGF‐induced PD‐L1, was clearly blocked by the JAK‐STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell‐activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell‐mediated cytotoxicity in LC‐2/ad cells, which was, however, blocked by tofacitinib. Conclusions: Taken together, our study shows that tofacitinib blocks the IFNγ‐induced transformation from an NK cell‐sensitive phenotype to an NK cell‐resistant one in IFNγ‐reacted LC‐2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ‐induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients. [ABSTRACT FROM AUTHOR]

The side effects of docetaxel have limited its antitumor performances in the treatment of nonsmall cell lung cancer (NSCLC). To address the problem, baicalein, a bioactive flavone that exhibits antitumor activity, was combined with docetaxel so as to achieve better efficacy and lower toxicity. The combination treatment enhanced the stabilization of microtubules and halted the cell-cycle progression, thus synergistically inhibiting the proliferation and inducing the apoptosis of A549 cells and Lewis lung carcinoma cells. The decreased expression of Cyclin-dependent kinase 6 and Cyclin B1 confirmed its regulation in cell cycle, with β-catenin being an important upstream effector, as evidenced by the decreased expression in the cytoplasm and nucleus as well as the attenuated aggregation in the nucleus. Furthermore, baicalein plus docetaxel evinced better antitumor efficacy by the suppressed tumor growth, increased apoptosis, and decreased tumor angiogenesis in vivo, with no increased toxicity discovered in both tumor-bearing and non-tumor-bearing mice, and an improvement in therapeutic index. This study has demonstrated that baicalein plus docetaxel is an appropriate combination simultaneously with augmented antitumor efficacy and acceptable safety, which might be a promising strategy for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population. Methods: We conducted a 10 years (2005‐2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions. Results: A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P < 0.0001) and sputum with blood (P < 0.0001) than patients with other pathological types and clinical stages, respectively. Metastases pain (P < 0.0001) and neck and supraclavicular lymphadenectasis (P = 0.0006) were more likely to occur in patients with nonsquamous carcinoma than in patients with other carcinomas. Additionally, patients with stage IV disease had a higher percentage of chest pain, shortness of breath, dyspnea, weight loss, and fatigue than patients with other stages of disease. In multivariable logistic analyses, compared with patients with adenocarcinoma, patients with squamous carcinoma were more likely to experience symptoms (OR = 2.885, 95% confidence interval [CI] 2.477‐3.359) but were less likely to present physical signs (OR = 0.844, 95% CI 0.721‐0.989). The odds of having both symptoms and physical signs were higher in patients with late‐stage disease than in those with early‐stage disease (P < 0.0001). Conclusions: The symptoms and physical signs of lung cancer were associated with the stage and pathological diagnosis of NSCLC. Patients with squamous carcinoma were more likely to develop symptoms, but not signs, than patients with adenocarcinoma. The more advanced the stage at diagnosis, the more likely that symptoms or physical signs are to develop. Further prospective cohort studies are needed to explore these results. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the use and efficiency of 3‐D deep learning, fully convolutional networks (DFCN) for simultaneous tumor cosegmentation on dual‐modality nonsmall cell lung cancer (NSCLC) and positron emission tomography (PET)‐computed tomography (CT) images. Methods: We used DFCN cosegmentation for NSCLC tumors in PET‐CT images, considering both the CT and PET information. The proposed DFCN‐based cosegmentation method consists of two coupled three‐dimensional (3D)‐UNets with an encoder‐decoder architecture, which can communicate with the other in order to share complementary information between PET and CT. The weighted average sensitivity and positive predictive values denoted as Scores, dice similarity coefficients (DSCs), and the average symmetric surface distances were used to assess the performance of the proposed approach on 60 pairs of PET/CTs. A Simultaneous Truth and Performance Level Estimation Algorithm (STAPLE) of 3 expert physicians' delineations were used as a reference. The proposed DFCN framework was compared to 3 graph‐based cosegmentation methods. Results: Strong agreement was observed when using the STAPLE references for the proposed DFCN cosegmentation on the PET‐CT images. The average DSCs on CT and PET are 0.861 ± 0.037 and 0.828 ± 0.087, respectively, using DFCN, compared to 0.638 ± 0.165 and 0.643 ± 0.141, respectively, when using the graph‐based cosegmentation method. The proposed DFCN cosegmentation using both PET and CT also outperforms the deep learning method using either PET or CT alone. Conclusions: The proposed DFCN cosegmentation is able to outperform existing graph‐based segmentation methods. The proposed DFCN cosegmentation shows promise for further integration with quantitative multimodality imaging tools in clinical trials. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Non-small cell lung cancer (NSCLC) is the most common cause for cancer-related mortality worldwide. Currently, early detection of NSCLC is one of the main available strategies for improving its prognosis. Due to the lack of non-invasive and convenient tools, early diagnosis of NSCLC remains poor. Recently, it has been reported that circulating microRNAs (miRNAs) can be stably detected in serum. Meanwhile, they play a powerful role as biomarkers in various tumors. Therefore, the aim of this study was to detect the expression levels of serum miR-182, 200b and 205 in NSCLC patients, and to investigate their diagnostic and prognostic values. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was carried out to measure the expressions of miR- 182, 200b and 205 in NSCLC tissues and normal controls. Receiver-operating characteristic (ROC) curve analysis was performed to assess the potential value of serum miRNAs for NSCLC diagnosis. Meanwhile, transwell assays were performed to observe the functional effects of miRNAs on the invasion and migration of NSCLC cells. RESULTS: Compared with normal controls, serum levels of miR-182 and 205 in NSCLC patients were significantly upregulated, whereas miR-200b was remarkably downregulated. ROC analysis indicated that miRNA array (miR-182, 200b and 205) was useful biomarkers for early diagnosis of NSCLC. In addition, transwell assays demonstrated that miR-182 promoted the invasion and migration of NSCLC cells. CONCLUSIONS: Our findings revealed that serum miR-182, 200b and 205 might serve as promising biomarkers for early detection and treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Background: This study detected osteopontin (OPN) and matrix metalloproteinase-7 (MMP-7) expressions to explore the roles of OPN and MMP-7 in the occurrence, progression, and prognosis of nonsmall cell lung cancer (NSCLC). Materials and Methods: A retrospective study was conducted on NSCLC tissues (n = 152; case group) and adjacent nonneoplastic lung parenchyma (adjacent to tumor >5 cm; n = 152; control group) collected from 152 NSCLC patients. The protein expressions of OPN and MMP-7 were detected by immunohistochemistry. OPN and MMP-7 messenger RNA (mRNA) expressions were detected by reverse transcription polymerase chain reaction (RT-PCR). Results: The protein and mRNA expressions of OPN and MMP-7 in NSCLC tissues were evidently higher than those in adjacent nonneoplastic lung parenchyma (all P < 0.05). OPN protein and mRNA expression were associated with the degree of differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis in NSCLC (all P < 0.05). MMP-7 protein expression was associated with TNM staging and lymph node metastasis (both P < 0.05) while MMP-7 mRNA expression was associated with the degree of differentiation, TNM staging, and lymph node metastasis (all P < 0.05). A significantly positive relativity was revealed between OPN expression and MMP-7 expression (protein: r = 0.789, P < 0.001; mRNA: r = 0.377, P < 0.001). Lymph node metastasis, TNM staging, OPN, and MMP-7 protein expressions were independent risk factors for the prognosis of NSCLC (all P < 0.05). Conclusion: High MMP-7 and OPN protein expressions are closely related to the occurrence, progression, and prognosis of NSCLC, and can be served as unfavorable prognostic factors for NSCLC.

ABSTRACT Background Not-infrequently patients with head and neck cancer are also diagnosed with synchronous lung cancer or metachronous primary lung cancer, which complicates the treatment decisions and prognosis. Methods Patients were identified from a database of patients with head and neck cancer with second primary non-small cell lung cancer (NSCLC). Results Thirty-four eligible patients (15 with synchronous lung cancer and 19 with metachronous lung cancer) were identified. Thirteen of 15 patients with synchronous lung cancer received curative intent treatment for head and neck cancer first. Six of 15 patients were in complete remission, 5 of 15 patients had died, and 4 were alive with progressive disease. Median time between 2 diagnoses was 47 months in the metachronous lung cancer group. Twelve patients had died, 3 were alive with disease, and 4 were lost to follow-up. Median survival from the time of lung cancer diagnosis was 13 months with a trend to better survival with synchronous lung cancer (15 vs 11 months; p = .11). Conclusion Aggressive multidisciplinary management of second primary lung malignancies in patients with head and neck cancer can result in respectable long-term disease control particularly in patients with synchronous lung cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1544-1549, 2017 [ABSTRACT FROM AUTHOR]

Deregulation of the microRNAs (miRNAs), a cluster of important posttranscriptional regulators, has been frequently associated with lung cancer (LCa). However, the emerging mechanism for how miRNAs is linked causally in the development of LCa chemoresistance is poorly understood. Herein, we established for the time the up-regulation of miR-369-3p in cisplatin (DDP)-resistant nonsmall cell lung cancer (NSCLC) tissues and cells. Its deregulation was found to be correlated to the magnitude of malignancy in well-characterized LCa cells. Functionally, inhibition of miR-369-3p sensitized LCa cells to DDP and suppressed the invasive capability in the presence of DDP treatment, whereas miR-369-3p overexpression promoted DDP resistance and thereby enhanced LCa cells invasiveness. Mechanistically, bioinformatics coupled with luciferase and gain-of-function, loss-of-function assays revealed that miR-369-3p may regulate DDP chemoresistance by directly targeting the 3′ untranslated region (UTR) of human solute carrier 35F5 (SLC35F5), as application of miR-369-3p inhibitors or reintroduction of epigenetically silenced SLC35F5 both individually sensitized LCa cells to DDP, but combined treatment with miR-369-3p inhibitors and SLC35F5 overexpression failed to sensitized LCa cells further to DDP-elicited cell death. Our results provide evidence that the oncomiR effect of miR-369-3p may be mediated through disrupting the nucleotide sugar transportation and that SLC35F5 is a key effector of this chemoresistance-promoting activity. [ABSTRACT FROM AUTHOR]

Nonsmall cell lung cancer (NSCLC) is a commonly occurring lung cancer. A combination of molecular biological treatments with regular chemotherapy may result in improved therapeutic outcome. Here, we reported significantly higher levels of fibroblast growth factor receptor 3 (FGFR3) and significantly lower levels of miR-100 in the NSCLC specimen, compared to the paired NSCLC-adjacent normal lung tissues. Moreover, the levels of FGFR3 and miR-100 were inversely correlated. Bioinformatics analyses followed by luciferase reporter assay showed that miR-100 bound to the 3′-UTR of FGFR3 messenger RNA (mRNA) to inhibit its translation. Overexpression of miR-100 in NSCLC cells decreased FGFR3 protein levels, whereas inhibition of miR-100 increased FGFR3 protein levels, without affecting FGFR3 mRNA levels. Furthermore, overexpression of miR-100 suppressed cancer growth, migration, and chemosensitivity in NSCLC cells, while inhibition of miR-100 significantly facilitated them. Taken together, our data demonstrate that miR-100 may inhibit NSCLC through FGFR3. [ABSTRACT FROM AUTHOR]

Myofibroblasts play a critical role in the cancer cell growth, invasion, and tumor-associated vascularization during the carcinogenesis of nonsmall cell lung cancer (NSCLC), whereas the underlying molecular bases are not completely understood. We isolated Lin-negative, Sca1-low, and CD49e-high myofibroblasts from the NSCLC tissues of the patients and modified the levels of either transforming growth factor β 1 (TGFβ1) or vascular endothelial growth factor A (VEGF-A) in these cells. We found that coculture with TGFβ1-overexpressing myofibroblasts significantly decreased the NSCLC cell growth in an MTT assay through proliferation suppression rather than modulation of cell apoptosis, while significantly increased the NSCLC cell invasiveness in either a transwell migration assay or a scratch wound healing migration assay. However, modulation of TGFβ1 levels in myofibroblasts did not significantly alter vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. On the other hand, overexpression of VEGF-A in myofibroblasts significantly increased vessel formation in the HUVECs transwell collagen gel assay. Together, these data suggest that myofibroblasts may regulate cancer cell growth and invasion through TGFβ1 but modulate cancer-associated neovascularization through VEGF-A. Hence, targeting different signaling pathways in myofibroblasts may delicately control NSCLC growth and invasion. [ABSTRACT FROM AUTHOR]

Radiotherapy has a crucial role in the treatment strategy for patients with tumor localized in the thorax. Accurate diagnosis and staging of the cancer is essential for precise administration of curative intent using radiation therapy. The main objective of radiotherapy is to achieve improved local control with dose escalation to the tumor while decreasing the probability of side effects by reducing radiation exposure to healthy surrounding organs. Computed tomography (CT) is generally the primary modality for image-based treatment planning, but conventional anatomic imaging with CT has limited sensitivity in distinctly identifying the anatomic borders of the tumor. The radiation oncologists still manually contour the tumor using CT images, and this component is significantly related with inter-observer and intra-observer contouring variability. Precise and accurate localization of radiotherapy targeted to the tumor is critical for optimizing the therapeutic ratio by limiting the amount of normal tissues receiving radiation, maximizing coverage of tumor volumes, and limiting geometric miss of tumor using advanced radiotherapy techniques. A new imaging technique has therefore been sought to allow precise delineation of the cancer target to be irradiated. F18 fluorodeoxyglucose positron emission tomography/computed tomography (F18 FDG PET/CT) has been reported as a reliable method for staging and detection of tumor that is located at thorax such as lung or esophageal tumors. Because F18 FDG PET/CT provides biological information of tumor in addition to anatomical information, it significantly decreases intraobserver variability in terms of target delineation. For instance, it decreases the sizes of tumors and accurate definition of the involved lymph nodes by separating tumor tissue from atelectasis area and identifying lymph nodes, whose sizes are increased because of benign, therefore provides precise radiotherapy. The accurate delineation of the tumor using F18 FDG PET/CT allows dose escalation for lung cancer treatment while minimizing any side effects. Furthermore, it can help in treatment planning by deciding the treatment volume by detecting lymph nodes and distant metastatic area which cannot be identified by other imaging modalities for esophageal cancer. In this study, the contribution of F18 FDG PET/ CT to the radiotherapy planning process for cancer located in the thorax was evaluated. [ABSTRACT FROM AUTHOR]

Introduction This study aims to explore whether the intra-tumour 18F-fluorodeoxyglucose ( FDG) uptake heterogeneity affects the reliability of target volume definition with FDG positron emission tomography/computed tomography ( PET/ CT) imaging for nonsmall cell lung cancer ( NSCLC) and squamous cell oesophageal cancer ( SCEC). Methods Patients with NSCLC ( n = 50) or SCEC ( n = 50) who received 18F- FDG PET/ CT scanning before treatments were included in this retrospective study. Intra-tumour FDG uptake heterogeneity was assessed by visual scoring, the coefficient of variation ( COV) of the standardised uptake value ( SUV) and the image texture feature (entropy). Tumour volumes (gross tumour volume ( GTV) ) were delineated on the CT images ( GTVCT), the fused PET/ CT images ( GTVPET-CT) and the PET images, using a threshold at 40% SUVmax ( GTVPET40%) or the SUV cut-off value of 2.5 ( GTVPET2.5). The correlation between the FDG uptake heterogeneity parameters and the differences in tumour volumes among GTVCT, GTVPET-CT, GTVPET40% and GTVPET2.5 was analysed. Results For both NSCLC and SCEC, obvious correlations were found between uptake heterogeneity, SUV or tumour volumes. Three types of heterogeneity parameters were consistent and closely related to each other. Substantial differences between the four methods of GTV definition were found. The differences between the GTV correlated significantly with PET heterogeneity defined with the visual score, the COV or the textural feature-entropy for NSCLC and SCEC. Conclusions In tumours with a high FDG uptake heterogeneity, a larger GTV delineation difference was found. Advance image segmentation algorithms dealing with tracer uptake heterogeneity should be incorporated into the treatment planning system. [ABSTRACT FROM AUTHOR]

Lung cancer is a major cause of cancer death worldwide. Programmed cell death 4 (PDCD4), an important tumor suppressor, influences transcription and translation of multiple genes and modulates different signal transduction pathways. However, the upstream regulation of this gene is largely unknown. In our study, we found that microRNA-182 (miR-182) was upregulated, whereas PDCD4 was downregulated in lung cancer cell lines. We performed methyl thiazolyl tetrazolium and colony formation assays to study the influence of miR-182 on proliferation of the lung cancer cell lines A549 and SPC-A-1. We also carried out Transwell and wound healing assays to investigate the effect of miR-182 on invasion and migration of A549 and SPC-A-1. Finally, using the luciferase reporter assay and restore assay, we demonstrated that PDCD4 is a direct target of miR-182. These results suggest that in lung adenocarcinoma cells, miR-182 plays an oncogenic role as a direct negative regulator of PDCD4. [ABSTRACT FROM AUTHOR]

Abstract: A majority of small cell lung cancer (SCLC) cells lack a metastasis suppressor, tetraspanin CD9, and CD9 expression promotes their apoptosis. By a proteomics-based approach, we compared an SCLC cell line with its CD9 transfectant and found that a calcium-binding neuronal protein, calretinin, is upregulated in CD9-positive SCLC cells. Ectopic or anticancer drug-induced CD9 expression upregulated calretinin, whereas CD9 knockdown down-regulated calretinin in SCLC cells. When calretinin was knocked down, CD9-positive SCLC cells revealed increased Akt phosphorylation and decreased apoptosis. These results suggest that CD9 positively regulates the expression of calretinin that mediates proapoptotic effect in SCLC cells. [Copyright &y& Elsevier]

Before 2009, nonsmall cell lung cancer (NSCLC) was one disease entity treated by cytotoxic chemotherapy that provided a response rate of 20-35 % and a median survival time (MST) of 10-12 months. In 2004, it was found that activated mutations of the epidermal growth factor receptor ( EGFR) gene were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Four phase III studies (North East Japan (NEJ) 002, West Japan Thoracic Oncology Group (WJTOG) 3405, OPTIMAL, and EUROTAC) prospectively compared TKI (gefitinib or erlotinib) with cytotoxic chemotherapy as first-line therapy in EGFR-mutated NSCLC. These studies confirmed that progression-free survival (PFS) with TKIs (as the primary endpoint) was significantly longer than that with standard chemotherapy (hazard ratio [HR] = 0.16-0.49) from 2009 to 2011. Although the NEJ 002 study showed identical overall survival (OS) between the arms (HR = 0.89), quality of life (QoL) was maintained much longer in patients treated with gefitinib. In conclusion, TKI should be considered as the standard first-line therapy in advanced EGFR-mutated NSCLC. Since 2009, a new step has been introduced in the treatment algorithm for advanced NSCLC. [ABSTRACT FROM AUTHOR]

Reliable automated or semiautomated lung tumor delineation methods in positron emission tomography should provide accurate tumor boundary definition and separation of the lung tumor from surrounding tissue or “hot spots” that have similar intensities to the lung tumor. We propose a tumor-customized downhill (TCD) method to achieve these objectives. Our approach includes: 1) automatic formulation of a tumor-customized criterion to improve tumor boundary definition, 2) a monotonic property of the standardized uptake value (SUV) of tumors to separate the tumor from adjacent regions of increased metabolism (“hot spot”), and 3) accounts for tumor heterogeneity. Three simulated lesions and 30 PET–CT studies, grouped into “simple” and “complex” groups, were used for evaluation. Our main findings are that TCD, when compared to the threshold based on 40% and 50% maximum SUV, adaptive threshold, Fuzzy c-means, and watershed techniques achieved the highest Dice's similarity coefficient average for simulation data (0.73) and “complex” group (0.71); the least volumetric error in the “simple” (1.76 mL) and the “complex” group (14.59 mL); and TCD solves the problem of leakage into adjacent tissues when many other techniques fail. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the value of medical care provided to elderly patients diagnosed with nonsmall cell lung cancer in the U.S. between 1983 and 1997. The study based its analysis on the Surveillance, Epidemiology, and End Results (SEER) data. It found that life expectancy of elderly patients with cancer improved minimally while lifetime spending increased by $20,157 per patient.

The article presents a study which aims to determine whether reduced xeroderma pigmentosum complementary group C (XPC) mRNA levels predict the clinical outcome of nonsmall cell lung cancer (NSCLC) patients. It notes that lung cancer is considered the most malignant neoplasm all over the world and represents the leading and second leading cause of cancer death, particularly, in Taiwan. The findings of the study demonstrate that reduced XPC mRNA level may constitute an independent prognostic factor for lung cancer patients.

Epstein–Barr Virus-transformed B lymphoblastoid cell lines (EBV-LCLs) are routinely used for the in vitro expansion of T cells. However, these cell lines are reported to produce the cytokine IL-10, which is inhibitory for T cells. We, therefore, characterized a panel of 37 EBV-LCLs for a variety of cell surface markers, for secretion of various cytokines including IL-10 and for immunoglobulin production. These cell lines were derived from normal donors or patients with nonsmall cell lung cancer, acute myelogenous leukemia, melanoma or colon cancer. Overall, 26 lines were positive for CD19 and CD20, and 11 were negative for both. All of the lines were strongly HLA-DR+, while CD40 expression was variable. Twenty-four (65%) were both CD23+ and secreted immunoglobulin, and 33 expressed κ and/or λ light chains. Additionally, all of the EBV-LCLs were negative for T cell (CD3), NK cell (CD16, CD56), monocyte (CD14) and granulocyte (CD66b) surface markers. Some level of IL-10, IL-6, IL-12p40 and TNF-α cytokine production was detected in 33, 18, 19 and 12 EBV-LCLs, respectively. Together, these data reflect the heterogeneity of EBV-LCLs, which cautions their use nondiscriminately in various immunologic assays. [Copyright &y& Elsevier]

Leptomeningeal carcinomatosis (LMC) is a terminal event in advanced cancer, its incidence in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is increasing due to recent advances in systemic therapy and prolongation of survival. Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) with preclinical and early clinical studies showing activity against LMC resistant to previous TKI treatments and acquired T790M mutation. We report a case of osimertinib in the treatment of LMC in a T790M-negative, EGFR-mutated NSCLC with significant clinical benefit and no toxicity. Osimertinib is a potentially effective treatment for LMC associated with EGFR-mutated NSCLC regardless of T790M status and a well-tolerated treatment for poor performance status patients.

Background: A growing number of microRNAs have been proved to play significant roles in limiting tumor growth and the epithelial-mesenchymal transition (EMT) process of nonsmall cell lung cancer (NSCLC). Present work aims to study the function of microRNA (miR)-105 in EMT of NSCLC cells, which is unrevealed yet., Methods: Two NSCLC cell lines A549 and Calu-3 were transfected with miR-105 mimic, inhibitor, or scrambled control. And then the effects of miR-105 were evaluated by performing trypan blue staining, transwell assay, ANNEXIN-FITC/propidium iodide (PI) double staining and Western blot analysis. The expression levels of myeloid cell leukemia-1 (Mcl-1) after transfection were tested by real-time quantitative polymerase chain reaction and Western blot analysis. Whether Mcl-1 was a downstream effector of miR-105, and the involvement of mammalian target of Rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways were assessed., Results: The overexpression of miR-105 significantly increased the viability and migration of A549 and Calu-3, but had no impacts on cell apoptosis. Meanwhile, E-cadherin was remarkably downregulated, and N-cadherin, Vimentin, ZEB1, and Snail were upregulated by miR-105 overexpression. Mcl-1 was positively regulated by miR-105, and the effects of miR-105 overexpression on A549 and Calu-3 cells viability, migration and EMT were all flattened by Mcl-1 silence. Both mTOR and p38MAPK pathways were activated in miR-105-overexpressing and Mcl-1-overexpressing cells. Besides, inhibition of mTOR and p38MAPK pathways by using Rapamycin and VX-702 abolished the regulatory effects of Mcl-1 on EMT., Conclusion: Our study underlines the importance of miR-105 in modulating NSCLC cells EMT. miR-105 promoted the EMT of NSCLC cells possibly via upregulation of Mcl-1 and thereby activation of mTOR and p38MAPK signaling., (© 2018 Wiley Periodicals, Inc.)

Myofibroblasts play a critical role in the cancer cell growth, invasion, and tumor-associated vascularization during the carcinogenesis of nonsmall cell lung cancer (NSCLC), whereas the underlying molecular bases are not completely understood. We isolated Lin-negative, Sca1-low, and CD49e-high myofibroblasts from the NSCLC tissues of the patients and modified the levels of either transforming growth factor β 1 (TGFβ1) or vascular endothelial growth factor A (VEGF-A) in these cells. We found that coculture with TGFβ1-overexpressing myofibroblasts significantly decreased the NSCLC cell growth in an MTT assay through proliferation suppression rather than modulation of cell apoptosis, while significantly increased the NSCLC cell invasiveness in either a transwell migration assay or a scratch wound healing migration assay. However, modulation of TGFβ1 levels in myofibroblasts did not significantly alter vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. On the other hand, overexpression of VEGF-A in myofibroblasts significantly increased vessel formation in the HUVECs transwell collagen gel assay. Together, these data suggest that myofibroblasts may regulate cancer cell growth and invasion through TGFβ1 but modulate cancer-associated neovascularization through VEGF-A. Hence, targeting different signaling pathways in myofibroblasts may delicately control NSCLC growth and invasion.

Objective: To evaluate treatment response, survival, and the associations between KRAS mutation status and tumour expression levels of BRCA1, TYMS and SRC retrospectively in a cohort of patients with non-small cell lung cancer (NSCLC), treated exclusively with conjunctive platinum-based doublet chemotherapy., Methods: KRAS mutation status was determined via amplification refractory mutation and multiple quantitative polymerase chain reaction (PCR) analysis. Tumour expression levels of BRCA1, TYMS and SRC were determined via real time quantitative PCR., Results: Patients with KRAS mutations (n = 3) had significantly shorter survival duration than patients with wild type KRAS (n = 42). Tumour expression levels of BRCA1 and TYMS, but not SRC, were significantly lower in patients with, than in those without, KRAS mutations. Tumour expression level of BRCA1 was positively correlated with survival duration., Conclusions: KRAS mutation status and BRCA1 tumour expression are potential biomarkers for tailoring chemotherapy and predicting clinical outcome., (© The Author(s) 2016.)

Objective: This retrospective study attempted to identify serum biomarkers that could help to indicate treatment response in advanced nonsmall-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment., Methods: Two-dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were used to identify proteins expressed in serum samples from NSCLC patients with long (>6-month) progression-free survival (PFS) periods, following EGFR-TKI treatment., Results: Serum amyloid P component (APCS), α1-antitrypsin (AAT), fibrinogen-α (FGA), keratin type I cytoskeletal 10 (KRT10) and serotransferrin (TF) expression differed between samples taken from 18 patients before treatment (baseline) and when progressive disease (PD) was observed, during treatment. Changes in AAT, KRT10 and APCS levels were validated by Western blot analysis in the sample pool; findings were further validated by Western blot analysis in a random sample of four patients. These proteins were also present in serum samples obtained from the same patients at the partial response (PR) timepoint during EGFR-TKI treatment. AAT was upregulated at PD compared with baseline, but downregulated during the PR phase., Conclusion: These observations suggest that AAT could be used as a serological biomarker for predicting the utility of EGFR-TKI treatment for advanced NSCLC.