Safety and efficacy of multi-target TKI combined with nivolumab in check-point inhibitor-refractory patients with advanced NSCLC: a prospective, single-arm, two-stage study.

BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. METHODS: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. RESULTS: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. CONCLUSION: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. TRIAL REGISTRATION: NCT04507906 August 11, 2020.

China lung cancer screening (CLUS) version 2.0 with new techniques implemented: Artificial intelligence, circulating molecular biomarkers and autofluorescence bronchoscopy.

OBJECTIVE: The present study, CLUS version 2.0, was conducted to evaluate the performance of new techniques in improving the implementation of lung cancer screening and to validate the efficacy of LDCT in reducing lung cancer-specific mortality in a high-risk Chinese population. METHODS: From July 2018 to February 2019, high-risk participants from six screening centers in Shanghai were enrolled in our study. Artificial intelligence, circulating molecular biomarkers and autofluorescencebronchoscopy were applied during screening. RESULTS: A total of 5087 eligible high-risk participants were enrolled in the study; 4490 individuals were invited, and 4395 participants (97.9%) finally underwent LDCT detection. Positive screening results were observed in 857 (19.5%) participants. Solid nodules represented 53.6% of all positive results, while multiple nodules were the most common location type (26.8%). Up to December 2020, 77 participants received lung resection or biopsy, including 70 lung cancers, 2 mediastinal tumors, 1 tracheobronchial tumor, 1 malignant pleural mesothelioma and 3 benign nodules. Lung cancer patients accounted for 1.6% of all the screened participants, and 91.4% were in the early stage (stage 0-1). CONCLUSIONS: LDCT screening can detect a high proportion of early-stage lung cancer patients in a Chinese high-risk population. The utilization of new techniques would be conducive to improving the implementation of LDCT screening.

Genetic Polymorphisms of ACE1 Rs4646994 Associated with Lung Cancer in Patients with Pulmonary Nodules: A Case-Control Study.

BACKGROUND: Currently, many detection methods have high sensitivity to the diagnosis of lung cancer. However, some postoperative patients with pulmonary nodules are eventually diagnosed as having benign nodules. The ideal evaluation of an individual with a pulmonary nodule would expedite therapy for a malignant nodule and minimize testing for those with a benign nodule. METHODS: This case-control study is designed to explore the relationship between ACE1 rs4646994 polymorphism and the risk of lung cancer in patients with pulmonary nodules, for which 400 individuals with lung cancer and benign pulmonary nodules were included. A DNA extraction kit was used to extract DNA from peripheral blood. The relationship between ACE1 rs4646994 and the risk of lung cancer in patients with pulmonary nodules was determined by the chi-square test, logistic regression analysis and cross analysis. RESULTS: The results showed that after adjusting for age and gender confounding factors, the risk of lung cancer in patients with pulmonary nodules carrying the DD genotype was more than three times that of the I carriers (II + ID) genotype (OR = 3.035, 95% CI, 1.252-7.356, p = 0.014). There was no significant difference between lung squamous cell carcinoma and lung adenocarcinoma in the polymorphism of ACE1 rs4646994 (p > 0.05). We also found that the ACE1 rs4646994 DD genotype frequency was inversely correlated with the risk of EGFR mutation in lung adenocarcinoma patients. CONCLUSIONS: Our study indicated that ACE1 rs4646994 polymorphism increases the risk of lung cancer in patients with pulmonary nodules from China.

Efficacy and safety of first-line anlotinib-based combinations for advanced non-small cell lung cancer: a three-armed prospective study.

Background: The evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), chemotherapy, or immune checkpoint inhibitor (ICI) in advanced NSCLC. Methods: This open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients with EGFR mutation NSCLC received anlotinib and erlotinib (cohort A). Patients without EGFR/ALK/ROS1 mutation received anlotinib combined with carboplatin plus pemetrexed/gemcitabine (cohort B), or sintilimab (cohort C). The primary outcomes were safety and objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Treatments were performed for at least 2 cycles and efficacy was evaluated every 2 cycles using RECIST version 1.1. Safety was assessed throughout the study. Results: A total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively. Conclusions: Anlotinib-based combinations with EGFR-TKI, chemotherapy, and ICI are well-tolerated and encouraging as first-line therapies for advanced NSCLC, which could be verified in future studies. Anlotinib-based combination might provide multiple choices for first-line treatment in patients with advanced NSCLC.

Clinical value of an electromagnetic navigation system for CT-guided percutaneous lung biopsy of peripheral lung lesions.

BACKGROUND: The purpose of this study was to retrospectively evaluate the clinical value of an electromagnetic navigation system for CT-guided percutaneous lung biopsy of peripheral lung lesions. METHODS: This was a retrospective study. Patients with peripheral lung lesions in our institution between January 2019 and December 2020, who underwent lung biopsy assisted by the electromagnetic navigation system were included in Group A, and those who underwent lung biopsy using conventional CT-guided percutaneous lung biopsy were included in Group B. The general features and clinical and technical information of each patient were collected and evaluated in both groups. RESULTS: A total of 141 patients were included in Group A (78 males and 63 females; median age, 65 years; range, 32-79 years), and 96 patients were included in group B (57 males and 39 females; median age, 65 years; range, 34-80 years). The technical success rate was 100% in both groups. The technical efficacy rate was 92.9% and 90.6% in Groups A and B (P=0.525), respectively. There was no significant difference in surgical time and the number of CT scans between the two groups, and only grade 1-2 complications occurred in the patients. CONCLUSIONS: The electromagnetic navigation system is an effective and safe auxiliary tool for CT-guided percutaneous lung biopsy of peripheral lung lesions.

Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC.

INTRODUCTION: Although the interaction between tumor immune microenvironment and angiogenesis has been well established, evidence supporting the chemo-free combination of immune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors in treatment-naive patients with advanced NSCLC is insufficient. This report provides the efficacy and safety of sintilimab combined with anlotinib as first-line therapy for advanced NSCLC from a phase 1b trial (NCT03628521). METHODS: Eligible patients who were treatment-naive and had unresectable stage IIIB/C or IV NSCLC without EGFR/ALK/ROS1 mutations received sintilimab (200 mg, day 1) and anlotinib (12 mg, day 1-14) every 3 weeks till disease progression or unacceptable toxicity. Baseline programmed death-ligand 1 expression and tumor mutation burden status was assessed in all patients. The primary end points were objective response rate and safety. RESULTS: A total of 22 patients received sintilimab and anlotinib. Median follow-up was 15.8 months (range: 8.3-19.3). Sixteen patients achieved confirmed partial response with an objective response rate of 72.7% (95% confidence interval [CI]: 49.8%-89.3%) and disease control rate of 100% (95% CI: 84.6%-100%). Median progression-free survival was 15 months (95% CI: 8.3 m, not reached), and the 12-month progression-free survival rate was 71.4% (95% CI: 47.2%-86.0%). The incidence rate of grade 3 or higher treatment-related adverse events was 54.5%, and grade 3 hypertension was predominant (two of 22, 9.1%). No grade 4 treatment-related adverse events were observed, and one case of grade 5 immune-related pneumonitis occurred. CONCLUSIONS: To the best of our knowledge, this is the first study that assessed an anti-programmed cell death protein 1 antibody combined with a multitarget antiangiogenic tyrosine kinase inhibitor in the frontline setting for patients with NSCLC. In view of its encouraging efficacy, durability, and safety profile, sintilimab plus anlotinib represents a novel chemotherapy-free regimen in this patient population.

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study.

INTRODUCTION: Continuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non-small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients' disease gradually progressed after first-line EGFR-TKI treatment. PATIENTS AND METHODS: Patients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients' progression-free survival (PFS) and overall survival times. RESULTS: Ninety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038). CONCLUSION: For patients with advanced non-small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.

Does surgically resected small-cell lung cancer without lymph node involvement benefit from prophylactic cranial irradiation?

BACKGROUND: It has previously been demonstrated that surgically resected small-cell lung cancer (SCLC) patients could benefit from prophylactic cranial irradiation (PCI). However, PCI in patients without lymph node involvement remains controversial. This study includes a larger sample size to evaluate the benefit of PCI therapy in this specific population. METHODS: The records of surgically resected SCLC patients without lymph node involvement (N0M0) in Shanghai Chest Hospital were retrospectively reviewed. RESULTS: Between January 2006 and May 2017, a total of 146 cases of surgically resected SCLC without lymph node involvement were included. A total of 46 patients received PCI therapy and 100 patients received no therapy. During the observation period, 12.0% (12/100) of the patients who did not receive PCI therapy developed brain metastases while 10.9% (5/46) of patients who received PCI therapy developed brain metastases. With regard to time to recurrence, no significant difference was observed among the groups (P = 0.798). Moreover, there was no significant difference in either the overall survival benefit (hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.49-1.45, P = 0.532) or disease-free survival rate (HR = 0.95, 95% CI: 0.52-1.75, P = 0.864). CONCLUSIONS: The evidence obtained does not support PCI therapy in the management of surgically resected SCLC with no lymph node involvement. KEY POINTS: Prophylactic cranial irradiation (PCI) remains controversial for resected small-cell lung cancer (SCLC) without lymph node involvement. In this study, the results indicated that PCI does not reduce the risk of cerebral recurrence of resected p-T1-2N0M0 SCLC. This is the largest sample size study focused on PCI in resected p-T1-2N0M0 SCLC. Future revised versions of the guidelines should address this issue.

Radiofrequency ablation of synchronous multiple primary lung cancer assisted by a magnetic navigation system: a case report.

With the widespread use of low-dose chest computed tomography (LDCT) screening for lung cancer in China, the incidence of multiple primary lung cancer (MPLC) has increased in recent years. Surgical resection is the standard treatment for early-stage MPLC; however, a significant proportion of patients with MPLC cannot undergo surgery. For patients with multiple pulmonary nodules who cannot tolerate surgical treatment, radiofrequency ablation (RFA) of multiple pulmonary lesions under the help of electromagnetic navigation system is a new treatment method. Compared with the traditional CT-guided percutaneous RFA, electromagnetic navigation-guided percutaneous RFA has higher accuracy and can effectively reduce postoperative complications. Herein we report a treatment procedure involving a 68-yearold man who presented with synchronous multiple tumor lesions in separate lung lobes. We utilized the electromagnetic navigation system to assist the clinician in inserting the RFA electrode into lung tumors. This case shows a feasible role for electromagnetic navigation-guided percutaneous RFA for early-stage MPLC.

Application of endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymphangioma.

BACKGROUND: Mediastinal lymphangioma is a rare lymphatic malformation, and the standard treatment strategy is surgical dissection. Endobronchial ultrasound-guided transbronchial needle aspiration has good diagnostic abilities for paratracheal, mediastinal, and hilar lymph node lesions. Endoscopic ultrasound is a new technique which can be used for the treatment of mediastinal lymphangioma to reduce the incidence of surgical-related complications. This study was designed to investigate the value of endobronchial ultrasound-guided transbronchial needle aspiration in the treatment of mediastinal lymphangioma. METHODS: Retrospective analysis was carried out on nine patients with mediastinal lymphangioma who underwent endoscopic ultrasound-guided fine-needle aspiration from 2010 to 2018 in Shanghai Chest Hospital. RESULTS: No patients suffered serious complication. The amount of fluid aspirated was 50-205 mL. The disease was stable over a period of 9 months to 2 years. CONCLUSIONS: Endobronchial ultrasound-guided transbronchial needle aspiration could be an effective method for the treatment of mediastinal lymphangioma with a little trauma compared with surgical dissection, which may have significant therapeutic effects.

The relationship between preliminary efficacy and prognosis after first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment of advanced non-small cell lung cancer.

BACKGROUND: Nowadays, patients with EGFR tyrosine kinase inhibitor (EGFR-TKI)-sensitive advanced non-small cell lung cancer (NSCLC) receive EGFR-TKIs as first-line treatment. We aimed to analyze the relationship between preliminary efficacy (tumor shrinkage within 1 month) and progression-free survival (PFS) after first-line EGFR-TKI treatment. METHODS: A total of 82 patients with EGFR-TKI-sensitive advanced NSCLC confirmed by histopathology from January 2013 to January 2017 were retrospectively analyzed. All patients received first-line EGFR-TKI treatment and follow-up at Shanghai Chest Hospital. RESULTS: Of a total of 82 patients, 42 (51.2%) patients achieved partial response (PR) within 1 month, and 40 (48.8%) patients achieved stable disease (SD: -30% to 0) within 1 month. The median PFS among all patients was 10 months. The median PFS in patients achieving PR within 1 month was 10.0 months. The median PFS in patients achieving SD (-30% to 0) within 1 month was 9.3 months. There was no statistically significant difference between PR within 1 month and SD (-30% to 0) within 1 month (P=0.620). In the EGFR-sensitive mutation subgroup, there was also no statistically significant difference between PR within 1 month and SD (-30% to 0) within 1 month. Univariate and multivariate analysis of first-line EGFR-TKI treatment showed that age, EGFR mutation type, and T staging had effects on PFS. Patients who were more than 65 years old, had EGFR 19del mutation, along with a T staging less than 4, had a longer PFS; these differences were statistically significant. Liver metastasis, bone metastasis, and brain metastasis were not shown to be related to PFS. CONCLUSIONS: For patients with EGFR-TKI-sensitive advanced NSCLC, there is no correlation between preliminary efficacy (tumor shrinkage within 1 month) and PFS after first-line EGFR-TKI treatment.

Adjuvant Chemotherapy Improves Survival in Surgically Resected Stage IB Squamous Lung Cancer.

BACKGROUND: At present there is a significant lack of clinical data for patients with surgically resected stage I squamous lung cancer. The purpose of this study was to investigate the impact of postoperative chemotherapy in this specific population. METHODS: We retrospectively identified patients who had undergone complete squamous lung cancer resection at the Shanghai Chest Hospital between January 2008 and January 2014. RESULTS: A total of 596 patients (236 stage IA, 360 stage IB) were included in this study. Results demonstrated that adjuvant chemotherapy (ACT) could provide longer overall survival for patients with p-stage IB disease (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.34-0.90; p = 0.017). Among p-stage IB patients the ACT-treated cohort trended toward a benefit (HR, 0.69; 95% CI, 0.45-1.04) in recurrence-free survival but failed to reach statistical significance (p = 0.076). After propensity score matching the HRs of recurrence-free survival and overall survival were 0.58 (95% CI, 0.35-0.96; p = 0.033) and 0.49 (95% CI, 0.27-0.88; p = 0.017), respectively. With regards to patients with p-stage IA disease, neither overall survival (HR, 0.87; 95% CI, 0.34-2.27; p = 0.783) nor recurrence-free survival (HR, 0.79; 95% CI, 0.38-1.65; p = 0.534) was significantly different when compared between patients receiving ACT and those who did not. Similar results were also achieved after propensity score matching. CONCLUSIONS: The data presented herein demonstrated that ACT might provide survival benefits for squamous lung cancer patients with p-stage IB disease.

Value of adjuvant chemotherapy in patients with resected stage IB solid predominant and solid non-predominant lung adenocarcinoma.

BACKGROUND: The use of adjuvant chemotherapy (ACT) for stage IB lung adenocarcinoma remains controversial. We examined the benefits of ACT in stage IB patients with tumors composed of solid material. METHODS: The records of 309 patients with stage IB lung adenocarcinoma who had undergone complete resection between 2006 and 2015 were reviewed. All pathological slides were evaluated for the composition of solid material. RESULTS: Our data showed that although disease-free survival (DFS) and overall survival (OS) were not significantly different (P = 0.306 and P = 0.061, respectively) between patients displaying a solid pattern of tumor growth and treated with or without ACT, patients with a solid predominant pattern of tumor growth treated with ACT had longer DFS (hazard ratio 0.359; P = 0.033) and OS (hazard ratio 0.205; P = 0.003). In patients with solid non-predominant patterns, treatment with ACT had no effect on DFS (P = 0.326) or OS (P = 0.508). CONCLUSIONS: Postoperative patients with the solid predominant pattern of stage IB lung adenocarcinoma may benefit from ACT, while those with the solid non-predominant pattern will not.

Community-based lung cancer screening with low-dose CT in China: Results of the baseline screening.

OBJECTIVES: To investigate whether low-dose computed tomography (LDCT) screening is capable of enhancing the detection rate of early-stage lung cancer in high-risk population of China with both smoking and non-smoking related factors. METHODS: From 2013-2014, eligible participants with high-risk factors of lung cancer were randomly assigned to a screening group or a control group with questionnaire inquiries. Any non-calcified nodules or masses with longest diameters of ≥4 mm identified on LDCT images were considered as positive. RESULTS: A total of 6717 eligible participants were randomly enrolled to a study group (3550 to LDCT screening and 3167 to standard care). 3512 participants (98.9%) underwent LDCT screening, and 3145 participants (99.3%) received questionnaire inquiries. A positive screening result was observed in 804 participants (22.9%). In the two-year follow-up period, lung cancer was detected in 51 participants (1.5%) in the LDCT group versus 10 (0.3%) in the control group (stage I: 48 vs 2; stage II to IV or limited stage: 3 vs 8), respectively. Early-stage lung cancer was found in 94.1% vs 20%, respectively. CONCLUSIONS: Compared to usual care, LDCT led to a 74.1% increase in detecting early-stage lung cancer. This study provides insights about the non-smoking related risk factors of lung cancer in the Chinese population.

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in diagnosing non-specific inflammatory intrathorcacic lymphadenitis.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a minimally invasive technique for diagnosing intrathoracic malignancies and some benignancies; however, there are no data available on the utility of EBUS-TBNA for the diagnosis of non-specific inflammatory intrathoracic lymphadenitis. METHODS: A prospective analysis was performed from 104 patients with enlarged lymphadenopathy suspected of non-specific lymphadenitis referred for EBUS-TBNA between October 2009 and March 2012. Rapid on-site cytological evaluation was not adopted. Microbiological tests were carried out in all patients. Patients were excluded from the study if there was other diagnosis being defined. RESULTS: One hundred ninety-one lesions were aspirated in 94 patients with enlarged mediastinal/hilar lymph nodes within reach of EBUS-TBNA, which were diagnosed as non-specific intrathorcacic lymphadenitis by pathology and clinical follow-up. According to EBUS-TBNA pathologies, 94 patients were categorized into four kinds: (i) inflammatory cell infiltrates and/or noncaseating necrosis in 38 cases; (ii) granuloma formed by epithelioid cells and/or fiber hyperplasia in 13 cases; (iii) lymph node tissue/lymphocyte without obvious abnormal lesions in 41 cases; (iv) inadequate sample in 2 cases. Bacterial and/or fungal smears and cultures were carried out in all 94 patients (100%), with pathogens being found in 4 (4.3%) cases. All patients (100%) underwent acid-fast staining and culture for mycobacterium tuberculosis to exclude tuberculosis. No procedure-related complication was observed. CONCLUSIONS: EBUS-TBNA can provide pathological and microbiological evidences for diagnosing non-specific inflammatory intrathoracic lymphadenopathy, and it is a safe and effective first-line investigation for ruling out malignancies and other benign diseases.

Serum dickkopf-1 as a clinical and prognostic factor in non-small cell lung cancer patients with bone metastases.

BACKGROUND: The study was designed to evaluate the association between serum dickkopf-1 (DKK1) and non-small cell lung cancer (NSCLC) bone metastases. MATERIALS AND METHODS: Serum DKK1 levels were quantified in 470 NSCLC patients, 140 with osseous metastases, 178 with extraosseous metastases, and 152 with early stage in complete remission. The Receiver Operating Characteristic (ROC) curve enabled us to identify a threshold value to distinguish patients with bone metastases. RESULTS: Serum DKK1 levels in patients with osseous metastases were significantly higher than in the other 2 groups (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 pg/ml (area under curve 0.791, 95% confidence interval 0.739-0.843, sensitivity 77.1% and specificity 71.4%). Of interest, serum DKK1 correlated with the number of bone lesions (P = 0.042) and associated with the poor survival in NSCLC patients with osseous metastases (P = 0.029). CONCLUSIONS: Our data shows that serum DKK1 can be used for the detection of NSCLC bone metastases. More importantly this is the first report to show that serum DKK1 is a good predictor of poor prognosis in NSCLC patients with bone metastases.

Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells.

PURPOSE: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer. MATERIALS AND METHODS: Z'-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay. RESULTS: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC50 values of 297 nmol/L, 1.31 µmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment. CONCLUSION: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.

Sonographic Features of Endobronchial Ultrasound in Differentiation of Benign Lymph Nodes.

Endobronchial ultrasound (EBUS) features have been found to be a useful tool in differentiating malignant from benign lymph nodes, but the use of these features to distinguish benign intrathoracic lymphadenopathies, including tuberculosis, sarcoidosis and reactive lymphadenitis, has not been established. The goal of this study was to evaluate the use of EBUS features in predicting tuberculosis, sarcoidosis, and non-specific inflammation. One hundred eighty-eight patients with suspected benign lymphadenopathy were included in the study. The EBUS features studied were short axis, shape, calcification, central hilar structure, necrosis sign, margins, echogenicity, clustered formation and vascular patterns. The sonographic findings were confirmed by clinicopathologic results. EBUS-Guided transbronchial needle aspiration was performed on 452 lymph nodes. Thirty-seven tuberculous nodes, 193 sarcoid nodes and 150 reactive nodes were retrospectively analyzed. Excluded were 72 nodes. Multivariate analysis revealed that presence of the necrosis sign and absence of the clustered formation are independent factors predictive of tuberculous nodes. Short axis >1 cm, absence of central hilar structure, distinct margins, presence of clustered formation and non-hilar perfusion were predictive of sarcoid nodes. Presence of central hilar structure, absence of clustered formation and vascular pattern (hilar perfusion or avascularity) were predictive of reactive lymphadenitis. The sum score model of these combined predictive factors indicated that the best diagnostic accuracies for predicting tuberculous nodes, sarcoid nodes and reactive lymphadenitis were 77.1%, 89.2% and 87.1%, respectively. Sonographic features could be helpful in differentiating the type of benign intrathoracic lymphadenopathy during EBUS examination.

Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer.

OBJECTIVE: The aim of this study was to assess the effectiveness and accuracy of blood-based circulating-free tumor DNA on testing epidermal growth factor receptor (EGFR) gene mutations. METHODS: In total, 219 non-small cell lung cancer patients in stages III-IV were enrolled into this study. All patients had tissue samples and matched plasma DNA samples. EGFR gene mutations were detected by the Amplification Refractory Mutation System (ARMS). We compared the mutations in tumor tissue samples with matched plasma samples and determined the correlation between EGFR mutation status and clinical pathologic characteristics. RESULT: The overall concordance rate of EGFR mutation status between the 219 matched plasma and tissue samples was 82% (179/219). The sensitivity and specificity for the ARMS EGFR mutation test in the plasma compared with tumor tissue were 60% (54/90) and 97% (125/129), respectively. The positive predictive value was 93% (54/58) and the negative predictive value was 78% (125/161). The median overall survival was longer for those with EGFR mutations than for those without EGFR mutations both in tissue samples (23.98 vs. 12.16months; P<0.001) and in plasma (19.96 vs. 13.63months; P=0.009). For the 68 patients treated with EGFR- tyrosine kinase inhibitors (TKIs), the median progression-free survival (PFS) was significantly prolonged in the EGFR mutant group compared to the non-mutation group in tumor tissue samples (12.26months vs. 2.40months, P<0.001). In plasma samples, the PFS of the mutant group was longer than that of the non-mutant group. However, there was no significant difference between the two groups (10.88months vs. 9.89months, P=0.411). CONCLUSIONS: The detection of EGFR mutations in plasma using ARMS is relatively sensitive and highly specific. However, EGFR mutation status tested by ARMS in plasma cannot replace a tumor tissue biopsy. Positive EGFR mutation results detected in plasma are fairly reliable, but negative results are hampered by a high rate of false negatives.