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Background:  The possibility of coil dislocation in computed tomography (CT)-guided microcoil localization of superficial pulmonary nodules is relatively high. The aim of the study is to investigate the outcomes of deeper localization technique during CT-guided microcoil localization of superficial pulmonary nodules before video-assisted thoracoscopic surgery (VATS)., Methods:  Fifty-seven identified superficial pulmonary nodules (nodule-pleural distance ≤ 1 cm on CT image) from 51 consecutive patients underwent CT-guided microcoil localization, and subsequent VATSs were included. The rate of technical success, complications, and excised lung volume were compared between deeper localization technique group and conventional localization technique group., Results:  The technical success rate of the localization procedure was 100% (25/25) in the deeper localization group and 81.3% (26/32) in the conventional localization group ( p  = 0.030). Excluding one case of lobectomy, the excised lung volume in the deeper localization group and the conventional localization group was 39.3 ± 23.5 and 37.2 ± 16.2 cm 3 , respectively ( p  = 0.684). The incidence of pneumothorax was similar between the deeper localization group and the conventional localization group (24.0 vs. 21.9%, respectively, p  = 0.850). The incidence of intrapulmonary hemorrhage in the deeper localization group was higher (16.0%) than that in the conventional localization group (6.3%), but the difference was not statistically significant ( p  = 0.388)., Conclusion:  CT-guided microcoil localization of superficial pulmonary nodules prior to VATS using a deeper localization technique is feasible. Deeper localization technique reduced the occurrence of dislocation but did not increase excised lung volume., Competing Interests: None declared., (Thieme. All rights reserved.)

Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Its diagnosis and monitoring can be challenging. Recently, extracellular vesicle (EV) miRNAs have become a new noninvasive diagnostic biomarker. The purpose of this study was to examine the clinical value and role of EV miRNAs in NSCLC-LM. Next-generation sequencing analysis revealed that miRNAs with differential expression of EVs in sera of patients with NSCLC with LM and non-LM were detected to identify biological markers for the diagnosis of LM. Cellular and in vivo experiments were conducted to explore the pathogenesis of EV miRNA promoting LM in NSCLC. In the present study, we first demonstrated that the serum level of EV-associated miR-374a-5p in patients with LM of lung cancer was much higher than that in patients without LM and was correlated with the survival time of patients with LM. Further studies showed that EV miR-374a-5p efficiently destroys tight junctions and the integrity of the cerebral microvascular endothelial cell barrier, resulting in increased blood-brain barrier permeability. Mechanistically, miR-374a-5p regulates the distribution of ZO1 and occludin in endothelial cells by targeting γ-adducin, increasing vascular permeability and promoting LM. Implications: These results suggest that serum NSCLC-derived EV miR-374a-5p is involved in premetastatic niche formation by regulating the permeability of the blood-brain barrier to promote NSCLC-LM and can be used as a blood biomarker for the diagnosis and prognosis of NSCLC-LM., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: To investigate the advantages of adjustable angle needle path template compared with CT-guided 125 I seeds free-hand implantation in the treatment of non-small cell lung carcinoma. Methods: This randomized controlled trial involved the retrospective analysis of the clinical data of 45 patients with non-small cell lung carcinoma who underwent 125 I seeds implantation at the Shandong Cancer Hospital, Shaanxi Provincial Tumor Hospital and The Third Affiliated Hospital of Shandong First Medical University from May 2018 to January 2023. Patients were divided into the template ( n =21) and free-hand ( n =24) groups, according to the modality used. The template group comprised 16 males and 5 females, aged (66±12) years, while the free-hand group comprised 16 males and 8 females, aged (62±8) years. The dose distribution, implant quality, intraoperative computed tomography (CT) scan times, and 125 I seed reseeding numbers after implantation were compared between the two groups to evaluate the potential advantages of adjustable angle needle path template-assisted implantation over free-hand 125 I implantation. Results: Statistical comparison revealed no significant differences in age ( t =1.16, P =0.253), tumor volume [(71±26) vs. (71±22) cm 3 , t =0.21, P =0.837), or any other baseline characteristics between the template and free-hand groups. Overall, 45 patients successfully completed the operation. In the template group, the mean values of the D90 (dose that was delivered to 90% of the target volume), V100 (the target volume receiving 100% of the prescription dose), coverage index (CI), relative dose homogeneity index (HI), and external volume index (EI) pre-and post-implantation were (131.0±2.1) vs. (131.1±5.5) Gy, 90.0%±0.4% vs. 91.0%±2.8%, 0.83±0.07 vs. 0.82±0.05, 41%±11% vs. 37%± 13%, and 4.3%(2.9%, 14.0%) vs.8.8%(5.2%,14.6%), respectively. None of these parameters showed any significant difference (all P >0.05). In the free-hand group, the mean value of D90 pre- and post-implantation was (131.4±2.9) vs.(128.6±8.6) Gy, showing no significant difference ( P >0.05), the mean values of V100, CI, HI, and EI pre-and post-implantation were 90.0%±0.5% vs. 89.0%± 3.0%, 0.84±0.04 vs. 0.71±0.09, 41%±9% vs. 34%±10%, and 7.7% (4.9%,11.0%) vs.24.2% (14.3%, 35.3%), respectively, showing significant differences (all P <0.05). The number of reseeding seeds in the template group was lower than that in the free-hand group [2.0 (0,2.5) vs. 4.0 (2.0, 7.0), Z =-3.36, P =0.001], showing a statistically significant difference. Further, the number of CT scans in the template group was significantly less than that in the free-hand group (3.9±0.5 vs. 4.6±1.2, t =-2.54, P =0.016). The incidences of adverse reactions were 23.8% (5/21) and 33.3% (8/24) ( χ 2 =12.86, P =0.002) in the template and free-hand groups, respectively, indicating a significant difference. Conclusion: Compared with free-hand implantation, use of the adjustable angle needle path template technique can shorten the operation time, reduce the number of scans, reduce the incidence of complications, and improve treatment efficacy to a certain extent.

HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4- de ]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4- de ]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

Objectives: Lung cancer is a major public health concern and represents the most common cause of cancer-related death worldwide. Among eukaryotes, the G protein-coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein-coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non-small-cell lung cancer (NSCLC) METHODS: We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin-induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms., Results: (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial-mesenchymal transition (EMT), thereby promoting the progression of NSCLC., Conclusions: It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of the study is to analyze the effect of multiple punctures in computed tomography (CT)-guided microcoil localization of pulmonary nodules with other risk factors for common complications., Methods: Consecutive patients who underwent CT-guided microcoil localization and subsequent video-assisted thoracoscopic surgery (VATS) between January 2020 and February 2021 were enrolled. Nodules successfully located after only one puncture were defined as the single puncture group, and nodules requiring two or more punctures were defined as the multiple puncture group. Binary logistic regression analysis was performed to assess the relationship between the number of punctures and pneumothorax and intrapulmonary hemorrhage., Results: A total of 121 patients were included. There were 98 (68.1%) pulmonary nodules in the single puncture group compared with 46 (31.9%) nodules in the multiple puncture group. The frequencies of pneumothorax and intrapulmonary hemorrhage were higher in the multiple puncture group than in the single puncture group ( p  = 0.019 and <0.001, respectively). Binary logistic regression demonstrated that independent risk factors for developing pneumothorax included lateral positioning of the patient ( p  < .001) and prone positioning ( p  = 0.014), as well as multiple punctures ( p  = 0.013). Independent risk factors for intrapulmonary hemorrhage included the distance between the distal end of the coil and the surface of the pleura ( p  = 0.033), multiple punctures ( p  = 0.003), and passage through the pulmonary vasculature ( p  < 0.001)., Conclusion: Multiple punctures resulted in an increased incidence of pneumothorax and intrapulmonary hemorrhage compared with single puncture during CT-guided microcoil localization of pulmonary nodules and were independently associated with both pneumothorax and intrapulmonary hemorrhage., Competing Interests: None declared., (Thieme. All rights reserved.)

D-1553 is a small molecule inhibitor selectively targeting KRAS G12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRAS G12C mutation were determined by thermal shift assay and KRAS G12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRAS G12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRAS G12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRAS G12C mutation. Compared to the KRAS WT and KRAS G12D cell lines, D-1553 selectively inhibited cell viability in multiple KRAS G12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRAS G12C mutation., (© 2023 InventisBio Co., Ltd and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies., Methods: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively., Conclusions: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC., Trial Registration: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018., (© 2023. The Author(s).)

Background: Anwuligan (ANW) isolated from nutmeg, also known as myristyl lignan, has attracted attention due to its therapeutic potential in diseases. However, its effect on lung cancer is still unclear., Methods: In this study, the cytotoxicity of ANW on non-small cell lung cancer (NSCLC) cells was detected using a Cell Counting Kit-8 (CCK-8) assay. In vitro, clone formation, wound healing, and Transwell assays were used to investigate the migratory and invasive abilities of NSCLC cells after ANW treatment. The expression levels of the associated proteins were detected using Western blotting. A luciferase assay was used to validate the binding of let-7c-3p to the 3'-untranslated region (UTR) of PIK3CA. In vivo, an A549 cell xenograft mouse model was used to verify the effect of ANW on tumor growth., Results: The results showed that ANW treatment (20 or 50 μM) had obvious cytotoxicity against A549 and H460 cells, suppressing cell proliferation and migration in vitro. In vivo, the growth of the implanted tumor was inhibited by ANW in a nude mouse model. The growth of NSCLC cells was also inhibited by let-7c-3p overexpression in vitro and in vivo. The inhibitory effect of ANW on the proliferation and metastasis of NSCLC cells was weakened by the downregulation of let-7c-3p, whereas it was enhanced by the overexpression of let-7c-3p; PIK3CA was the main target of let-7c-3p., Conclusions: In summary, ANW inhibits the growth and metastasis of NSCLC cells in vivo and in vitro by upregulating the expression of let-7c-3p, which can regulate the PI3K/AKT/mTOR signaling pathway. PIK3CA is the main target of let-7c-3p., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To retrospectively analyze the effectiveness and safety of computed tomography (CT)-guided microcoil localization for scapula-blocked pulmonary nodules using penetrating lung puncture prior to video-assisted thoracic surgery (VATS)., Methods: One hundred thirty-eight patients with 138 pulmonary nodules were included in this single-center retrospective study. Among them, 110 patients who underwent CT-guided microcoil localization using the routine puncture technique formed the routine group; the other 28 patients who underwent the CT-guided microcoil localization using the penetrating lung puncture technique formed the penetrating lung group. The main outcomes were the success rate and complication rate of the two groups., Results: The localization success rate was 95.5% (105/110) in the routine group and 89.3% (25/28) in the penetrating lung group ( P = 0.205). There was no statistical difference in any of the complications (pneumothorax, intrapulmonary hemorrhage, or moderate and severe chest pain) in both groups ( P = 0.178, P = 0.204, P = 0.709, respectively). Localization procedure time was significantly increased in the penetrating lung group compared with the routine group (31.0 ± 3.0 min vs. 21.2 ± 2.8 min, P < 0.001)., Conclusion: CT-guided microcoil localization for scapula-blocked pulmonary nodules using penetrating lung puncture prior to VATS resection is effective and safe. However, the deployment of the microcoil using penetrating lung puncture required more time than the routine puncture method.

Introduction: Patients with non-small-cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) rearrangements can be treated with ALK tyrosine kinase inhibitors. We assessed real-world ALK biomarker testing and treatment patterns of patients with NSCLC in the United States., Patients and Methods: Data were extracted from the Flatiron Health electronic health record-derived deidentified database for patients aged ≥18 years with stage IIIB or IV NSCLC and ≥2 clinic visits between January 2011 and December 2019., Results: Among 60,025 eligible patients, tumors from 36,691 (61.1%) patients were tested for ALK rearrangements, and 1042 (2.8%) tested positive (ALK+). From 2011 to 2019, ALK testing rates increased from 33.1% to 73.0%; testing via fluorescence in situ hybridization declined from 68.3% to 32.1% while next-generation sequencing increased from <1% to 52.2%. Although tissue samples were more commonly used than blood (85.1% vs. 13.5% of tests), blood sample testing increased from 0.1% in 2011 to 28.2% in 2019. Median (interquartile range) time from diagnosis of advanced NSCLC to first ALK+ test result was 23 (13-43) days, including laboratory processing time of 9 (6-14) days. For the 24.7% of patients with an ALK+ test result who began treatment before receiving the positive result, chemotherapy was initiated most often overall until 2018 when immuno-oncology agents became most common., Conclusion: Although ALK testing in NSCLC increased over time, testing rates among eligible patients did not reach 100% during the study period. Treatment decisions for some patients with NSCLC may have been made without important, guideline-recommended biomarker data., (Copyright © 2022. Published by Elsevier Inc.)

The aim of this single-centre 10-year retrospective observational study was to evaluate the profile of Chinese cancerous patients complicated with venous thromboembolism (VTE) based on demographic features, clinical characteristics, and medication exposure. Consecutive 1482 patients with solid tumor complicated with VTE at a tertiary center between 2012 and 2021 were retrospectively enrolled. Data were collected on demographics, comorbidities, discharge diagnoses, laboratory examination data, treatment details, and imaging description of the lesion. The overall incidence of clinical VTE was 1.35% in hospitalized patients with cancer in our center. Lung cancer was the most frequent tumor subtype for developing VTE events, accounting for 24.83% of all cases. Over half of the patients (66.60%) were observed to have an increased risk of VTE within the first 6 months of cancer diagnosis. Close to half of the patients (46.49%) had received chemotherapy within 6 months prior to the diagnosis of VTE. The frequency of massive ascites group (＞2000 mL) in gynecological patients with VTE was significantly larger than that of nonmassive ascites group (≤2000 mL) ( P  < .001). Patients with ovarian, vulvar, lung cancers were considered at high risk for VTE. The assessment and monitoring of VTE in patients with cancer within the first 6 months of cancer diagnosis should be strengthened. VTE occurrence was closely related to advanced age and stage, adenocarcinoma, obesity and noval anticancer therapies in patients with cancer. Early detection of VTE-related examination may lead to earlier intervention for patients with gynecological tumors with preoperative massive ascites.

Background: The aim of the study was to investigate and summarize the effectiveness and safety of CT-guided microcoil localization before video-assisted thoracic surgery (VATS) for the removal of ground-glass opacity (GGO)., Methods: A total of 147 patients with GGO who were treated at our hospital between January 2019 and February 2021 were retrospectively analyzed. They were divided into two groups according to the final position at the end of the microcoil: intracavity (n = 78) and extracavity (n = 69), which were compared based on puncture complications and influence of the coil end position on VATS., Results: The proportions of supine and prone positions in the intracavity group were significantly higher than those in the extracavity group (82.1% vs. 66.7%, P < 0.05). The incidence of intrapulmonary hemorrhage, chest pain, and coil displacement in the intracavity group was significantly lower than that in the extracavity group (28.2% vs. 46.4%, 19.2% vs. 39.1%, 1.3% vs. 11.6%, P < 0.05, respectively); however, the incidence of pneumothorax was not significantly different (P > 0.05). The time of VATS and the rate of conversion to thoracotomy in the intracavity group were significantly lower than those in the extracavity group (103.4 ± 21.0 min vs. 112.2 ± 17.3 min, 0% vs. 5.8%, P < 0.05, respectively)., Conclusion: CT-guided placement of the microcoil is a practical, simple, and convenient localization method before VATS, with a high success rate and few complications. Furthermore, it is a better alternative method to place the end of the coil in the pleural cavity because of the lower complication rate, shorter VATS time, and lower rate of thoracotomy conversion., (© 2022. The Author(s).)

Background: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC., Methods: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m 2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety., Results: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment., Conclusions: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Introduction: Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors., Methods: In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed., Results: Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5-17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%., Conclusions: In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: As a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation., Methods: This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on., Results: A total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee-assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4-68.8) in part A and 60.4% (95% CI: 53.7-66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3-20.8) in part A and 12.6 months (95% CI: 9.7-15.3) in part B. The median OS was 26.0 months (95% CI: 23.3-not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study., Conclusions: SH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: The advanced lung cancer inflammation index (ALI) can predict the survival of patients with lung cancer and other malignancies. However, the prognostic significance of ALI in neuroblastoma has not been reported. This study aimed to evaluate the correlation between ALI and neuroblastoma patient prognosis., Methods: We retrospectively analyzed the data of 72 neuroblastoma patients treated between January 2014 and August 2020. ALI calculation: Body mass index (BMI) × serum albumin (ALB)/neutrophil-to-lymphocyte ratio (NLR). The optimal cutoff points of prognostic biomarkers were determined by generating receiver operating characteristic (ROC) curves. According to the cutoff value, the patients were categorized into low or high ALI groups. The chi-square test was used to compare clinical parameters between the two groups. Potential prognostic factors associated with overall survival (OS) were assessed using Kaplan-Meier and Cox regression analyses., Results: The optimal cutoff value of ALI was 49.17. The low ALI group showed more severe clinical characteristics and poorer survival rates. Univariate and multivariate Cox analyses suggested that ALI and the International Neuroblastoma Staging System (INSS) stage were independent prognostic factors for neuroblastoma patients., Conclusions: Low ALI is associated with poor prognosis in neuroblastoma patients. ALI may be an independent prognostic biomarker for neuroblastoma.

Background: Increased evidence supports the relationship between chromobox protein homolog 3 (CBX3) and tumorigenesis of some cancers. However, the role of CBX3 in pan-cancers remains poorly defined. In the research, we aimed to investigate the prognostic value and the immunological functions of CBX3., Results: We explored the potential oncogenic roles of CBX3 in mRNA and protein levels based on the diverse databases, including the expression, the correlation with prognosis, tumor microenvironment (TME), DNA methylation, protein phosphorylation and enrichment analysis across all TCGA tumors. The results show that CBX3 is overexpressed in multiple cancers, and significant correlations exist between high expression and adverse prognosis in most tumor patients. We observed an enhanced phosphorylation level in uterine corpus endometrial carcinoma, colon cancer and lung adenocarcinoma. A distinct relationship was also found between CBX3 expression and TME, including immune infiltration of tumor-infiltrating lymphocytes and cancer-associated fibroblasts, immune score or matrix score, immune checkpoints. The correlative transcription factors and miRNAs of CBX3-binding hub genes were analyzed to investigate the molecular mechanism. Moreover, alcoholism and alteration of DNA cellular biology may be involved in the functional mechanisms of CBX3., Conclusion: The first pan-cancer study offers a relatively comprehensive cognition on the oncogenic roles of CBX3 as a prognostic and immunological marker in various malignant tumors., (© 2022. The Author(s).)

Background: To investigate the effect of miR-188-5p overexpression on the invasion and migration of cultured lung cancer cells, and on related cellular mechanisms that underlie epithelial mesenchymal transition (EMT)., Methods: Human lung cancer cell line 95D was transfected with miR-188-5p mimic. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to quantify the expression levels of genes including E-cadherin, Snail, α-SMA, and MGAT3. Changes in cell motility, invasion and proliferation were studied using scratch migration assay, transwell invasion assay, and colony formation assay, respectively. The expression levels of EMT-related proteins and MGAT3 protein were also determined via immunofluorescent staining. The ability of miR-188-5p to regulate its target gene, MGAT3, was assessed using dual luciferase activity assay., Results: Lung cancer cell line 95D showed the lowest miR-188-5p expression level thus was used in this study. Transfection with miR-188-5p mimic significantly suppressed migration, invasion and clonal formation potency of 95D cells. Dual luciferase activity assay implicated that miR-188-5p exerts its negative regulatory effect on MGAT3 expression through recognizing the 3' untranslated region (3'UTR) of the MGAT3 gene. Over-expression of miR-188-5p in 95D cells also remarkably increased E-cadherin protein expression and decreased the expression levels of Snail and α-SMA, which suppressed the EMT process., Conclusion: MiR-188-5p reduces the expression of MGAT3 and inhibits the metastatic properties of a highly invasive lung cancer cell line, probably via targeted regulation of EMT process. Further research to explore the potential therapeutic value of miR-188-5p, both as a biomarker and as a drug candidate for the management of metastatic lung cancer may be warranted., Competing Interests: Conflicts of interest Authors declare no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Purpose: Persistent abnormal proliferation and long distant metastasis of tumors contribute to high mortality rate in non-small cell lung cancer (NSCLC) patients. Strategies that prevent NSCLC proliferation and/or metastasis have been studied but still need to be further explored. Numerous studies have proved the diversity functions of long noncoding RNAs (lncRNAs) exerted in cancer, including NSCLC. In this study, we aim to identify and investigate the role of novel lncRNAs in NSCLC progression., Methods: RNA sequence data were retrieved from the Cancer Genome Atlas (TCGA), differentially expressed lncRNAs (DElncRNAs) were screened out based on the R language, then real-time PCR experiment was introduced to detect the DElncRNA expression levels. A series of experiments including MTT, cell cycle, transwell, and wound healing assays were employed to explore the effect of DElncRNA MGC27382 on cell proliferation and invasion ability., Results: We detected that DElncRNA MGC27382 is down-regulated in NSCLC tissues and cells. Overexpression of MGC27382 prevented NSCLC cell proliferation via down-regulating cyclin D1 and cyclin E. Moreover, wound healing and transwell assays indicated that the ability of cell invasion and migration could be impaired when cells were treated with MGC27382 overexpression. Further studies demonstrated that MGC27382-mediated inhibition on NSCLC progression can be impaired by LY294002, which is a frequently used inhibitor of AKT/GSK3β pathway., Conclusion: MGC27382 is down-regulated in NSCLC. It exerts an inhibitory role in NSCLC development through suppressing the AKT/GSK3β pathway. Our results indicate that the lncRNA MGC27382 might be a tumor-suppressor gene in NSCLC. Overexpression of MGC27382 is thought to be a potential strategy for overcoming NSCLC progression., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Introduction: In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor-naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results., Methods: Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee-assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy., Results: A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35-0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53-1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21-0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed., Conclusions: In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitising EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to assess the efficacy and safety of furmonertinib in patients with EGFR T790M mutated advanced non-small-cell lung cancer (NSCLC)., Methods: This study was a single-arm, open-label, phase 2b study at 46 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumour tissue who progressed after first or second generation EGFR TKIs or with primary EGFR T790M mutations received furmonertinib 80 mg orally once daily. The primary endpoint was objective response rate. Efficacy was assessed by blinded independent central review as per the Response Evaluation Criteria in Solid Tumors (version 1.1) in all patients who had measurable disease at baseline and received at least one dose of furmonertinib. Safety was assessed as per the Common Terminology Criteria for Adverse Events (version 4.03) in all patients who received at least one dose of furmonertinib with at least one safety assessment during follow-up. This study is registered with ClinicalTrials.gov (NCT03452592) and is ongoing for survival follow-up., Findings: From Jun 4, 2018, to Dec 8, 2018, 220 patients received furmonertinib treatment. All 220 patients were included in the efficacy and safety analyses. At the data cutoff point of Jan 29, 2020, 71 (32%) patients remained on treatment. The median duration of follow-up was 9·6 months (range 0·7-19·4). The objective response rate was 74% (163 of 220 [95% CI 68-80]). Grade 3 or higher adverse events occurred in 58 (26%) patients and treatment-related grade 3 or higher adverse events occurred in 25 (11%) patients. The most common all-cause grade 3 or higher adverse events were increased γ-glutamyltransferase (five; 2%), increased aspartate aminotransferase, increased alanine aminotransferase, hyponatraemia, hypertension, pulmonary infection, hypermagnesaemia, and pericardial effusion (three each; 1%). Treatment-related diarrhoea was reported in ten (5%) patients and rashes were reported in 16 (7%) patients, all grade 1-2. Serious adverse events were reported in 52 (24%) patients, of which 12 (5%) were possibly treatment-related as evaluated by the investigator., Interpretation: Furmonertinib has promising efficacy and an acceptable safety profile for the treatment of patients with EGFR T790M mutated NSCLC. Furmonertinib is expected to become a new treatment option after first or second generation EGFR TKIs in the Chinese population., Funding: Shanghai Allist Pharmaceutical Technology, Ministry of Science and Technology of the People's Republic of China, and Chinese Academy of Medical Sciences., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests YJ and CG are employees and shareholders of Shanghai Allist Pharmaceutical Technology. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Tumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication, however, the exact role and regulation of the OPN splicing isoforms was not well understood., Methods: In this study, the effects of conditioned medium from the culture of OPN splicing isoforms overexpressing cells on cell functions were evaluated. The methods of nuclear calcium reporter assays and subcellular distribution of nuclear factor of activated T cells c2 (NFATc2) assays were used to investigate the molecular mechanism underlining the roles of OPN splicing isoforms., Results: We found that the survival of NSCLC cells treated with cisplatin was increased by secretory OPNc in the condition medium, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent nuclear translocation of NFATc2., Conclusions: The results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment.

Introduction: Increasing evidence indicates that lncRNA TUG1 represents an oncogenic factor in cancer. But, the mechanisms by which lncRNA TUG1 contributes to lung adenocarcinoma (LAC) remain undocumented., Methods: The relationship between lncRNA TUG1/miR-138-5p expression and clinical outcomes in patients with LAC was indicated by qPCR, FISH, and TCGA cohort. Gain- or loss-of-function experiments and in vivo tumorigenesis were used to assess the role of lncRNA TUG1 in LAC. The interplay between TUG1 and miR-138-5p was validated by luciferase gene report and RIP assays. qPCR and Western blot analyses were used to investigate the effects of TUG1 on miR-138-5p/HIF1A axis in LAC cells., Results: We found that upregulation of TUG1 or downregulation of miR-138-5p was associated with lymph node or distant metastasis and indicated a poor survival in LAC. Reduced expression of TUG1 restrained the growth of LAC cells, while restored expression of TUG1 had the opposite effects. TUG1 was identified to negatively regulate miR-138-5p expression, and miR-138-5p reversed TUG1-induced cell proliferation by targeting HIF1A. Elevated expression of HIF1A predicted a poor survival in LAC., Conclusion: Our findings demonstrate that lncRNA TUG1 promotes the growth of LAC by regulating miR-138-5p-HIF1A axis.

The CellSearch system is the only FDA approved and successful used detection technology for circulating tumor cells(CTCs). However, the process for identification of CTCs by CellSearch appear to damage the cells, which may adversely affects subsequent molecular biology assays. We aimed to explore and establish a membrane-preserving method for immunofluorescence identification of CTCs that keeping the isolated cells intact. 98 patients with lung cancer were enrolled, and the efficacy of clinical detection of CTCs was examined. Based on the CellSearch principle, we optimized an anti-EpCAM antibody and improved cell membrane rupture. A 5 ml peripheral blood sample was used to enrich CTCs with EpCAM immunomagnetic beads. Fluorescence signals were amplified with secondary antibodies against anti-EpCAM antibody attached on immunomagnetic beads. After identifying CTCs, single CTCs were isolated by micromanipulation. To confirm CTCs, genomic DNA was extracted and amplified at the single cell level to sequence 72 target genes of lung cancer and analyze the mutation copy number variations (CNVs) and gene mutations. A goat anti-mouse polyclonal antibody conjugated with Dylight 488 was selected to stain tumor cells. We identified CTCs based on EpCAM+ and CD45+ cells to exclude white blood cells. In the 98 lung cancer patients, the detection rate of CTCs (≥1 CTC) per 5 ml blood was 87.76%, the number of detections was 1-36, and the median was 2. By sequencing 72 lung cancer-associated genes, we found a high level of CNVs and gene mutations characteristic of tumor cells. We established a new CTCs staining scheme that significantly improves the detection rate and allows further analysis of CTCs characteristics at the genetic level.

Introduction: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC., Methods: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated., Results: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths., Conclusions: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Radiotherapy is an effective approach for the treatment of lung adenocarcinoma. However, evidence suggests that lung adenocarcinoma can easily develop tolerance to radiotherapy. The purpose of this study was to investigate the effect and mechanism of SMAD3 on the radiosensitivity of lung adenocarcinoma in vitro and in vivo . We found that knockdown of SMAD3 using two short hairpin RNAs in lentivirus vectors significantly inhibited cell growth and increased radiosensitivity of the lung adenocarcinoma cell lines A549, H1299, and H1975. Using RNA sequencing and bioinformatics analyses, we found that the significantly differentially expressed genes in SMAD3 knockdown cells were mainly enriched in the cell cycle process. We then showed that knockdown of SMAD3 significantly reduced expression of cyclin-dependent kinase inhibitor 1 (p21) and increased the proportion of G2/M phase cells and the radiosensitivity of lung adenocarcinoma. Chromatin immunoprecipitation results in the Gene Expression Omnibus (GEO) database and our luciferase assay verified that SMAD3 directly bound the p21 promoter. A series of rescue experiments showed that overexpression of p21 partly reversed the effect of SMAD3 on proliferation and radioresistance in vitro and in vivo . Moreover, we found that the expression levels of SMAD3 and p21 were highly correlated, and both correlated with the patients' survival in online databases and clinical specimens. Expression of SMAD3 and p21 was also significantly different between radioresistant and radiosensitive patients in our hospital. Our results indicate that SMAD3 is a potential prognosis and radiosensitivity indicator as well as a target for radiotherapy and other treatments of patients with lung adenocarcinoma., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Both genetic and environmental factors contribute to the development of cancer and its mutant spectrum. Lung cancer has familial aggregation. Lung cancer caused by non-tobacco factors has unique pathological and molecular characteristics. The interaction between genetic lung cancer susceptibility and carcinogens from coal burning remains complex and understudied., Methods: We selected 410 non-small cell lung cancer (NSCLC) patients with a family history of lung cancer (FLC) and exposure to coal combustion between 2014 and 2017. Clinicopathologic parameters were analyzed. Reverse transcription-PCR was performed to detect ALK, ROS1, RET, and NTRK1 rearrangement., Results: Among the 410 NSCLC patients, 192 had FLC and 204 (49.8%) were exposed to occupational or domestic coal combustion. FLC patients had the same characteristics regardless of gender and coal exposure: younger age, high female ratio, adenocarcinoma, increased metastasis, later stage at diagnosis, and higher frequency of gene fusion. Sixty-seven patients (16.3%) had gene rearrangement: 51 (12.4%) harbored EML4-ALK fusions and 16 ROS1 fusions (3.9%). The highest gene fusion rate (35.1%, 33/94) occurred in patients with both FLC and high tobacco and coal exposure. ALK fusions and total gene rearrangement were closely associated with women, never smokers, younger age, FLC, and coal exposure., Conclusion: FLC and exposure to coal combustion have an important impact on the clinicopathological characteristics and gene fusion mode of NSCLC, particularly in cases of higher levels of carcinogens, and genetic susceptibility has a greater impact. Our findings may help evaluate the effect of FLC and coal exposure on the pathogenesis of lung cancer., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Chronic obstructive pulmonary disease (COPD) will reduce the cardiopulmonary function and increase perioperative risk. The aim of this study is to investigate the effect of preoperative short-term high intensity lung rehabilitation training on lung function and postoperative complications in patients with COPD who are eligible for lung cancer surgery., Methods: We analysis of 101 patients with COPD and a diagnosis of lung cancer, with 43 patients in pulmonary rehabilitation group and 58 patients in conventional group. The pulmonary function, postoperative pulmonary complications (PPCs) and length of stay (LOS) will be compared between the two groups, the lung function will be compared before and after the rehabilitation at the same time., Results: There were no significant difference between the two groups in general information, lung function before surgery, postoperative pulmonary infection [8 (18.6%) vs 17 (29.3%)], atelectasis [1 (2.3%) vs 1 (1.7%)], respiratory failure [1 (2.3%) vs 2 (3.4%)] and postoperative LOS [(8.93±3.78) d vs (9.62±3.98) d, P>0.05]. In the rehabilitation group, the FEV1 [(2.06±0.45) L vs (2.15±0.45) L, P<0.001] and PEF [(4.32±0.90) L/s vs (5.15±1.05) L/s, P<0.001) were higher, and PCO2 [(42.42±2.79) mmHg vs (41.58±2.98) mmHg, P=0.009] was lower after rehabilitation, significantly. The increase value of FEV1 in moderate to severe COPD group was higher than that of the mild COPD group after the rehabilitation [(0.16±0.05) L, 8.6% vs (0.06±0.05) L, 2.8%, P<0.001)., Conclusions: The short-term highly-intensity lung rehabilitation can improve lung function in lung cancer patients with COPD, and the improvement of pulmonary function in moderate to severe COPD patients is more obviously.

Objective: To investigate the expression status of anaplastic lymphoma kinase (ALK) fusion gene in lung sarcomatoid carcinoma (LSC) and the role of ALK inhibitors for treatment. Methods: Total of 84 cases of LSC confirmed by histopathology were detected for ALK fusion gene from January 2011 to December 2014 in the Cancer Hospital of Chinese Academy of Medical Science&Peking Union Medical College and Shandong Zibo Wanjie Cancer Hospital. All patients were primarily treated by the multi-disciplinary mode in combination with chemotherapy or targeted therapy based on surgery. Postoperative adjuvant chemotherapy was given on platinum based two-drug combination regimen. In ALK fusion gene (+ ) patients with recurrence or metastasis, crizotinib target therapy was prefered. Chi-square test was applied for the comparison of 1, 3, 5-year survival rates between the two groups. Results: Eighty-two cases completed the follow-up. ALK fusion gene was found in 9(10.7%) patients. After application of crizotinib, 1 case was evaluated as complete remission, 6 cases as partial response, 2 cases as stable disease; the 1, 3, 5-year survival rate was 100% (9/9), 100% (9/9) and 88.9% (8/9) for the patients with ALK fusion gene, and it was 65.8% (48/73), 15.1% (11/73) and 6.8% (5/73) respectively for patients without ALK fusion gene. There was significant difference in the survival rate between the two groups (χ(2)=1.56, 1.56, 0.83, all P <0.05). Conclusion: ALK fusion gene maybe expressed in LSC patients. Compared with conventional chemotherapy, crizotinib can significantly prolong the survival time of patients with ALK fusion gene.

Background: Interferon induced transmembrane protein 3 (IFITM3) plays an important role in the tumorigenesis and progression of multiple cancers. This study investigated the expression and function of IFITM3 in human lung adenocarcinoma., Methods: Fifty human lung adenocarcinoma tissues were collected. IFITM3 expression was assessed by immunohistochemical staining. The clinicopathologic characteristics of all patients were analyzed., Results: IFITM3 was mainly detected in the cytoplasm of advanced cancer tissues and its expression was correlated with tumor malignancy grade. Knockdown of IFITM3 in vitro markedly inhibited the proliferation and invasion of lung adenocarcinoma cells., Conclusion: IFITM3 represents a potential therapeutic target for the treatment of lung adenocarcinoma., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Currently, the nonsmall-cell lung cancer (NSCLC) is a worldwide disease, which has very poor influence on life quality, whereas the therapeutic effects of drugs for it are not satisfactory. The aim of our PRISMA-compliant systematic review and meta-analysis was to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with Taxanes in patients with lung tumors., Methods: We collected randomized controlled trials (RCTs) of EGFR-TKIs (gefitinib, erlotinib) versus Taxanes (docetaxel, paclitaxel) for the treatment of NSCLC by searching PubMed, EMbase, and the Cochrane library databases until April, 2016. The extracted data on progression-free survival (PFS), progression-free survival rate (PFSR), overall survival (OS), overall survival rate (OSR), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and adverse event rates (AEs) were pooled. Disease-relevant outcomes were evaluated using RevMan 5.3.5 software and STATA 13.0 software., Results: We systematically searched 26 RCTs involving 11,676 patients. The results showed that EGFR-TKIs could significantly prolong PFS (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) and PFSR (risk ratio [RR] = 2.10, 95% CI: 1.17-3.77), and improve ORR (RR = 1.62, 95% CI: 1.38-1.91) and QoL. EGFR-TKIs had similar therapeutic effects to taxanes with respect to OS (HR = 1.00, 95% CI: 0.95-1.05) and OSR (RR = 1.03, 95% CI: 0.94-1.14). Furthermore, there were no significant differences between them in DCR (RR = 0.95, 95% CI: 0.88-1.03). Finally, EGFR-TKIs were superior to taxanes in most of all grades or grade ≥3 AEs., Conclusion: In the efficacy and safety evaluation, EGFR-TKIs had an advantage in the treatment of NSCLC, especially for patients with EGFR mutation-positive. The project was prospectively registered with PROSPERO database of systematic reviews, with number CRD42016038700., Competing Interests: The authors have no conflicts of interest to disclose.

Background: MicroRNA-663a expression is downregulated in several tumors. However, its functions and mechanisms in human non-small cell lung (NSCLC) cancer remain obscure. The present study aimed to identify the expression pattern, biological roles and potential mechanisms by which miR-663a dysregulation is associated with NSCLC., Methods: We examined expression level of miR-663a in 62 cases of NSCLC tissues and 5 NSCLC cell lines by reverse transcription PCR. In vitro, gain-of-function and loss-of-function experiments were performed to examine the impact of miR-663a on proliferation, cell cycle progression and invasion of NSCLC cells. Using fluorescence reporter assays, we also explored the potential targets and possible mechanisms of miR-663a in NSCLC cells., Results: Downregulation of miR-663a was observed in 42 of 62 of lung cancer tissues compared with paired normal tissues (mean cancer/normal value = 0.745) and its downregulation correlated with nodal metastasis. Transfection of miR-663a mimic suppressed cell proliferation, cell cycle progression and invasion, with downregulation of cyclin D1, cyclin E and MMP9 in both H460 and H1299 cell lines. Transfection of miR-663a inhibitor in both H460 and H1299 cell lines exhibited the opposite effects. In addition, we confirmed that miR-663a could inhibit AP-1 activity and AP-1 component JunD was a direct target of miR-663a in lung cancer cells. Transfection of miR-663a mimic downregulated JunD expression. In addition, JunD siRNA treatment abrogated miR-663a inhibitor-induced expression of cyclin D1, cyclin E and MMP9. Above all, both miRNA mimic and inhibitor in two different NSCLC cell lines demonstrated that miR-663a inhibits proliferation and invasion by targeting AP-1 transcription factor JunD., Conclusions: This study indicates that miR-663a downregulation might be associated with NSCLC progression. MiR-663a suppresses proliferation and invasion by targeting AP-1 component JunD in NSCLC cells.

LRRC3B has emerged as a tumor suppressor in several human cancers. However, its expression pattern and biological roles in human non-small-cell lung cancer (NSCLC) have not been explored. In the present study, we investigated clinical significance of LRRC3B in 101 NSCLC specimens. We found that LRRC3B expression was downregulated in NSCLC tissues compared with normal bronchial epithelium and that its downregulation significantly correlated with tumor-node-metastasis (TNM) stage (p < 0.0001), nodal metastasis (p < 0.0001), and poor patient prognosis (p = 0.0016, log-rank test). We also checked LRRC3B levels in several lung cancer cell lines and found that its expression was downregulated in four of nine lung cancer cell lines compared with normal human bronchial epithelial (NHBE) cell line. We further explored the biological role of LRRC3B. LRRC3B plasmid transfection in H460 and A549 cell lines inhibited proliferation, colony formation ability, and invading ability. Furthermore, we identified that LRRC3B could inhibit cell cycle progression with downregulation of cyclin D1 and decreased MMP9 expression. In addition, LRRC3B depletion in HBE cells promoted proliferation and invasion. In conclusion, our data suggested that LRRC3B may serve as an important tumor suppressor in NSCLC.

Objective: The soluble form of major histocompatibility complex class I-related chain A (MICA) is released from the surface of tumor cells of epithelial origin. Serum levels of soluble MHC class I-related chain A (sMICA) is related with the prognosis of various types of cancer. However, there are studies on the prognostic value of sMICA in non-small cell carcinoma (NSCLC). In this study, we retrospectively investigated the relationship between sMICA levels and clinical features of NSCLC, and we assessed the prognostic value of sMICA in NSCLC., Patients and Methods: sMICA levels were detected in 207 NSCLC patients and 207 normal control individuals with using enzyme-linked immunosorbent assay (ELISA), and its associations with clinicopathological parameters were evaluated. Survival curves were compared using the Kaplan-Meier method and log-rank tests. Univariate Cox regression was used on each clinical covariate to examine its influence on patient survival. Multivariate models were based on step-wise addition., Results: Serum sMICA levels were significantly higher in NSCLC patients than in healthy controls (mean ± SD [pg/ml], 143.52 ± 27.6 vs. 32.4 ± 7.53 p < 0.01) and were significantly correlated with TNM stage, poorer differentiation, lymph node metastases and distant metastases. Survival analysis showed that a low sMICA level had longer survival time than those with high serum sMICA. Multivariate analyses indicated that high sMICA proved to be an independent predictor of survival time., Conclusions: Serum sMICA level in NSCLC patients is associated with metastasis. It is an indicator of a poorer survival probability. Serum sMICA levels may be an independent prognostic factor for NSCLC.

Lung cancer is the leading cause of cancer‑related mortality in humans. The prognosis for advanced lung cancer patients is extremely poor. Current standard care is rather ineffective for prolonging patient life while preserving satisfactory quality of life due to adverse side-effects. Matrine extracted from the traditional Chinese herbal plant Sophora flavescens was shown to induce cancer cell death in vitro. The aim of this study was to investigate the effect of matrine on the proliferation and apoptosis of lung cancer cells and the molecular basis of matrine-induced apoptosis. The results showed that matrine inhibited cell proliferation and induced apoptosis in lung cancer A549 and 95D cells in a dose- and time-dependent manner. The apoptotic effects of matrine on lung cancer cells appeared to act via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway and downregulation of the expression of the inhibitor of apoptosis protein (IAP) family proteins. Matrine exerts its cancer-killing effect via promoting apoptosis in lung cancer cells and may be a useful adjuvant therapeutic scheme for treating advanced lung cancer patients.

ARID1A (AT-rich interactive domain 1A) is a key member of the SWI/SNF chromatin-modeling complex, and the gene has emerged as a tumor suppressor in various human cancers. In the present study, we investigated the expression and clinical significance of ARID1A in non-small cell lung cancer (NSCLC). We found that ARID1A expression was decreased in NSCLC tissues compared with normal bronchial epithelium and was significantly correlated with nodal metastasis, tumor, node, metastasis (TNM) stage, and poor differentiation. ARID1A expression was lower in lung cancer cell lines than normal bronchial epithelial HBE cell line. We also explored the involvement of ARID1A in biological behavior of lung cancer cell lines. ARID1A depletion by small interfering RNA (siRNA) in H460 and H1299 cell lines promoted proliferation, colony formation ability, and inhibited paclitaxel-induced apoptosis. Furthermore, we identified that ARID1A regulated several cell cycle and apoptosis-related targets such as cyclin D1 and Bcl-2. In addition, the activity of Akt phosphorylation was also enhanced after ARID1A depletion. In conclusion, our data suggested that ARID1A may serve as an important tumor suppressor in NSCLC.

Background: The aim of this study was to evaluate the function of RhoGDI2 in lung cancer epithelial-mesenchymal transition (EMT) process and to illustrate the underlying mechanisms that will lead to improvement of lung cancer treatment., Methods: The RhoGDI2 knock-down and overexpressing A549 cell lines were first constructed. The influence of RhoGDI2 on cytoskeleton in A549 cells was studied using two approaches: G-LISA-based Rac1 activity measurement and immunostaining-based F-actin distribution. The expression levels of key EMT genes were analyzed using real time quantitative polymerase chain reaction (RT-qPCR), western blot and immunostaining in untreated and RhoGDI2 knock-down or overexpressing A549 cells in both in vivo and in vitro experimental settings., Results: Our study showed that the activity of Rac1, a key gene that is crucial for the initiation and metastasis of human lung adenocarcinoma, causing the redistribution of F-actin with partial loss of cell-cell adhesions and stress fibers, was significantly suppressed by RhoGDI2. RhoGDI2 promoted the expression of EMT marker gene E-cadherin and repressed EMT promoting genes Slug, Snail, α-SMA in both A549 cells and lung and liver organs derived from the mouse models. Knocking-down RhoGDI2 induced abnormal morphology for lung organs., Conclusion: These findings indicate that RhoGDI2 repressed the activity of Rac1 and may be involved in the rearrangement of cytoskeleton in lung cancer cells. RhoGDI2 suppresses the metastasis of lung cancer mediated through EMT by regulating the expression of key genes such as E-cadherin, Slug, Snail and α-SMA in both in vivo and in vitro models.

Lung cancer is the leading cause of cancer-related mortality worldwide. The mortality is high mainly due to the lack of known effective screening procedures; there is a high tendency for early spread and systemic therapies do not cure metastatic disease. Thus, it is important to investigate the molecular mechanism(s) of lung cancer development and, specifically, to identify an effective method by which to inhibit the invasion and metastasis of lung cancer. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays a key role in tumorigenesis. Whether Ubc9 is involved in the invasion and metastasis of lung cancer remains unknown. Herein, we report that Ubc9 exhibits an important role in lung cancer invasion and metastasis. We first investigated the biological effect of Ubc9 on lung cancer by cloning the Ubc9 gene into a eukaryotic expression plasmid and stably expressing it in the human small cell lung cancer cell line NCI-H446 in order to observe any biological changes. We further analyzed the effect of Ubc9 in an in vivo experiment, injecting NCI-H446 cells stably overexpressing Ubc9 into nude mice and analyzing their metastatic ability. Our results demonstrated that Ubc9 is expressed at higher levels in primary lung cancer tissue and metastatic nodules as compared to premalignant and/or normal tissue. Furthermore, we demonstrated that upregulation of Ubc9 expression promotes migration and invasion. Ubc9 likely plays an important role in cancer progression by promoting invasion and metastasis in lung cancer.

Background: To elucidate whether rapamycin, the inhibitor of mTOR (mammalian target of rapamycin), can potentiate the cytotoxic effect of docetaxel in lung cancer cells and to probe the mechanism underlying such enhancement., Methods: Lung cancer cells were treated with docetaxel and rapamycin. The effect on the proliferation of lung cancer cells was evaluated using the MTT method, and cell apoptosis was measured by flow cytometry. Protein expression and level of phosphorylation were assayed using Western Blot method., Results: Co-treatment of rapamycin and docetaxel was found to favorably enhance the cytotoxic effect of docetaxel in four lung cancer cell lines. This tumoricidal boost is associated with a reduction in the expression and phosphorylation levels of Survivin and ERK1/2, respectively., Conclusion: The combined application of mTOR inhibitor and docetaxel led to a greater degree of cancer cell killing than that by either compound used alone. Therefore, this combination warrants further investigation in its suitability of serving as a novel therapeutic scheme for treating advanced and recurrent lung cancer patients.

Rho GDP dissociation inhibitors (RhoGDIs) are important regulators of the GTP hydrolase activity and biological functions of Rho GTPases. RhoGDI2 has been shown to be a metastasis suppressor in bladder cancer and several other cancers. However, the underlying mechanism, effector targets, and the cognate biological functions of RhoGDI2 are not fully understood. To investigate the possible role of RhoGDI2 in lung cancer tumorigenesis and metastasis, the expression pattern of RhoGDI2 in various lung cancer tissue samples and lung cancer-derived cell lines were profiled at both mRNA and protein levels. Furthermore, possible interplay between PI3K/Akt/mTOR pathway activation/inhibition and RhoGDI2 signalling is examined in lung cancer-related cell lines. Our results suggest that RhoGDI2 is likely to be involved in lung tumor malignancy and metastasis.

The above therapeutic results show that TCM drugs have excellent effects in counteracting the metastasis of tumors. They can produce a synergistic effect when used together with surgery, radio- and chemotherapy. In analyzing the relationship between the factors that affect the distant metastasis, the authors strongly recommend that the FDM-survival rate be used, i.e. the survival rate free from distant metastasis as suggested by Hong Minghuang et al in their article. An analysis based on FDM-survival rate in a duration of three or five years with the data treated with the Kaplan-Meier and/or Life Table would be rational and convincible.