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Objective: This article is a Meta-analysis aiming to systematically evaluate the difference in efficacy of immune checkpoint inhibitor in patients with non-small cell lung cancer (NSCLC) by age., Methods: We performed a Meta-analysis of published randomized controlled trials concerning for patients with NSCLC by age. We compared overall survival among three groups (age <65 years, age 65-75 years, age ≥75 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected and pooled., Results: A total of 10,291 patients from 17 RCTs were included. In the group under age 65 years, immune checkpoint inhibitor can significantly prolong the overall survival of patients with NSCLC (HR = 0.73, 95% CI: 0.66∼0.81, P < 0.00001). In the age 65-75 years group, immune checkpoint inhibitors prolonged overall survival in patients with NSCLC (HR = 0.78, 95% CI:0.71∼0.84, P < 0.00001). However, it has no significant effect on the overall survival of NSCLC patients (HR = 0.88, 95% CI:0.72∼1.08, P > 0.05) in the group older than 75 years., Conclusions: Immune checkpoint inhibitors prolonged the overall survival of NSCLC patients in the age <65 years group and the age 65-75 years group, but in the age ≥75 years group, there was no significant effect on overall survival. This may be related to innate immune and adaptive immune dysregulation due to "immunosenescence" in older patients., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

The occurrence of malignant mesothelioma is related to exposure of asbestos. And many researchers have conducted in-depth analysis of the molecular changes of mesothelioma, showed that its molecular characteristics were chromosome changes, including chromosome rearrangement, gene mutation and gene deletion. Recent studies have strengthened our understanding of molecular characterization of mesothelioma, such as targeted mutations of tumor suppressor genes, differential gene expression, changes of miRNA and signal pathways. It is of great significance for the early diagnosis, clinical treatment and prognosis of malignant mesothelioma to explore the pathogenesis and development of malignant mesothelioma. This article reviews the research progress on the pathogenesis and carcinogenesis-related molecules of malignant mesothelioma.

Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, characterized by insidious onset, strong local invasiveness, short survival period, and poor prognosis. Clinical diagnosis is of paramount importance for the treatment and prognosis of MPM. Currently, the gold standard for diagnosing MPM is the results of histopathological examinations. Immunohistochemistry (IHC) is an effective auxiliary method in pathological diagnosis. Preliminary examinations can use two positive markers and two negative markers to distinguish pleural metastatic tumors, with additional antibodies selected based on differential diagnosis. The combined use of IHC markers plays a crucial role in the differential diagnosis between MPM and other tumors. This article primarily introduces commonly used IHC markers in MPM and the research progress of novel IHC markers in screening and differential diagnosis, aiming to provide reference for the clinical diagnosis and treatment of MPM.

Purpose: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study., Methods: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety., Results: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively., Conclusion: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified., Clinical Trial Number: NCT02474355., (© 2023. The Author(s).)

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8 + T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity., (© 2023. The Author(s).)

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC., Significance: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers., (©2022 American Association for Cancer Research.)

Background: DNA replication alteration is a hallmark of patients with lung adenocarcinoma (LUAD) and is frequently observed in LUAD progression. Origin recognition complex (ORC) 1, ORC2, ORC3, ORC4, ORC5, and ORC6 form a replication-initiator complex to mediate DNA replication, which plays a key role in carcinogenesis, while their roles in LUAD remain poorly understood., Methods: The mRNA and protein expression of ORCs was confirmed by the GEPIA, HPA, CPTAC, and TCGA databases. The protein-protein interaction network was analyzed by the GeneMANIA database. Functional enrichment was confirmed by the Metascape database. The effects of ORCs on immune infiltration were validated by the TIMER database. The prognostic significance of ORCs in LUAD was confirmed by the KM-plot and GENT2 databases. DNA alteration and protein structure were determined in the cBioProtal and PDB databases. Moreover, the protein expression and prognostic value of ORCs were confirmed in our LUAD data sets by immunohistochemistry (IHC) staining., Results: ORC mRNA and protein were significantly increased in patients with LUAD compared with corresponding normal tissue samples. The results of IHC staining analysis were similar result to those of the above bioinformatics analysis. Furthermore, ORC1 and ORC6 had significant prognostic values for LUAD patients. Furthermore, the ORC cooperatively promoted LUAD development by driving DNA replication, cellular senescence, and metabolic processes., Conclusion: The ORC, especially ORC1/6, has important prognostic and expression significance for LUAD patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized., Methods: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation., Results: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference., Conclusions: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP., (© 2022. The Author(s).)

Interstitial lung disease combined with lung cancer (ILD-LC) has attracted more and more attention. Interstitial lung disease (ILD) is an independent risk factor of lung cancer. ILD and lung cancer have common pathogenesis of promoting fibrosis and promoting cancer, so they are not only comorbidities. This review updated the epidemiology, pathogenesis and incidence and risk factors of treatment-induced acute exacerbation(including surgery, chemotherapy, and radiotherapy)in ILD-LC. The purpose is to improve the understanding, individual management and quality of life of patients in ILD-LC.

Objective: Depression is positively correlated with the high incidence and low survival rate of cancers, while more cancer patients suffer depression. However, the interaction between depression and cancer, and possible underline mechanisms are unclear., Methods: Chronic unpredictable mild stress (CUMS) was used to induce depression, and smoke to induce lung cancer in lung cancer vulnerable AJ mice. After 8 weeks, sucrose preference and forced swimming behaviors were tested. Blood corticosterone concentration, and levels of cytokines, lung cancer-related factors, brain-derived neurotrophic factor (BDNF) and apoptosis-related factors in the lung, amygdala and hippocampus were measured., Results: Compared to control group, CUMS or smoke decreased sucrose consumption and increased immobility time, which were deteriorated by stress+smoke. CUMS, smoke or both combination decreased mononuclear viability and lung TNF-α concentration, increased serum corticosterone and lung interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-12 and HSP-90α concentrations. Furthermore, stress+smoke caused more increase in corticosterone and IL-10, but decreased TNF-α. In parallel, in the lung, Bcl-2/Bax and lung cancer-related factors CDK1, CDC20, P38α etc were significantly increased in stress+smoke group. Moreover, CUMS decreased BDNF, while CUMS or smoke increased TrkB and P75 concentrations, which were exacerbated by stress+smoke. In the amygdala, except for CUMS largely increased Bax/Bcl-2 and decreased TrkB, each single factor decreased BDNF and IL-10, but increased P75, IL-1β, IL-12, TNF-α concentrations. Changes in Bax/Bcl-2, IL-10 and TNF-α were further aggravated by the combination. In the hippocampus, except for CUMS largely increased P75 concentration, each single factor significantly increased Bax/Bcl-2 ratio, IL-1β and TNF-α, but decreased BDNF, TrkB and IL-10 concentrations. Changes in Bax, Bax/Bcl-2, IL-10 and TNF-α were further aggravated by the combination., Conclusion: These results suggest that a synergy between CUMS and smoke exposure could promote the development of depression and lung cancer, through CUMS increased the risk of cancer occurrence, and conversely lung cancer inducer smoke exposure deteriorated depressive symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC)., Methods: A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice., Results: Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045)., Conclusions: Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC., (© 2022. The Author(s).)

Objective: Investigate the current situation of lung cancer cough diagnosis and treatment and the awareness of related issues among Chinese medical providers. Methods: Doctors, nurses, pharmacists from the oncology department, respiratory department, or general department were investigated using an electronic questionnaire from January 29 to March 29, 2021. There were 25 questions about lung cancer in the questionnaire. The questionnaire was including the most common accompanying symptoms in patients with lung cancer, the incidence of lung cancer-related cough, the assessment of the proportion of central antitussive drugs, and the commonly used central antitussives. Results: Questionnaires from 2 424 medical providers were collected from 402 hospitals in 21 provincial administrative units. Cough was the most common symptom in lung cancer. Most physicians believed that the incidence of lung cancer-related cough was 51%~75%, while the proportion of patients satisfied with the treatment was only 11%~20%. The evaluation of lung cancer-related cough was seriously insufficient. The leading cause of lung cancer-related cough was tumors. And the main problem was the inadequate antitussive effect of drugs in lung cancer-related cough management. The proportion of central antitussive medication usage in the secondary and tertiary hospitals was 93.9% and 92.0%, significantly higher than 75.0% in Primary hospitals (χ²=8.390, P =0.015). The proportion of the physicians who underhanded that codeine is at risk of addiction was 76.6% and 72.0% in the secondary and tertiary hospitals, which were significantly higher than 53.9% in Primary hospitals (χ²=9.240, P =0.010). In different occupations, the proportions of doctors and pharmacists who knew the risk of addicting to codeine were 73.0% and 82.6%, which were significantly higher than the 66.4% of nurses (χ²=21.200, P< 0.001). The Chinese medical providers were lack of training about the basic knowledge of using central antitussive medication. Conclusions: The proportion of patients who were satisfied with the effect of cough treatment is low. The medical staff did not have enough awareness of this. There was an urgent need to develop a consensus and standardize lung cancer cough diagnosis and treatment in China.

Objectives : Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods : We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results : Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions : The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective: To investigate the clinicopathological and molecular characteristics of pulmonary enteric adenocarcinoma (PEAC). Methods: The clinical and pathological data of 19 cases of PEAC in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively collected from 2015 to 2019. Immunohistochemistry (IHC) was used to detect the relevant immunophenotypes, amplification refractory mutation system (ARMS) and fluorescence in situ hybridization (FISH) were used to detect the expression of EGFR, KRAS and ALK genes. The patients were followed up, and the relevant literature was reviewed and analyzed. Results: There were 19 cases, including 10 males and 9 females, with a mean age of 58 years (range 33-71 years). Microscopically, the tumors showed moderately to highly differentiated adenoid and/or papillary growth patterns. The tumor cells were highly columnar and sometimes showed pseudostratification. Inflammatory necrosis and scattered nuclear fragmentation were seen in some glandular lumens. IHC showed variable expression of CK7 (19/19), TTF1 (8/19), Napsin A (6/19), villin (17/19), CK20 (16/19) and CDX2 (10/19). Molecular testing showed KRAS mutation in nine cases (9/19), EGFR mutation in one case (1/19), and positive ALK split signal in one case (1/19). In the literature, the reported mutation rate of KRAS in PEAC was much higher than that of EGFR and ALK. All 19 cases underwent surgical resection and 11 cases were subjected to chemotherapy or radiotherapy. Conclusions: PEAC is a rare variant of invasive pulmonary adenocarcinoma, and has similar histological and cytological features to that of colorectal adenocarcinoma. However, detailed medical history, histologic heterogeneity, an IHC combination of CK7(+)/villin(+) and high KRAS mutation rate are the key points of diagnosis. The prognosis needs long-term follow-up and big data statistics.

Background: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented., Methods: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded., Results: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy., Conclusions: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC., (© 2019 American Cancer Society.)

Objectives: This study investigated factors associated with (i) the likelihood of receiving a gene aberration test and (ii) the choice of treatment between chemotherapy and targeted therapy in patients with non-small cell lung cancer (NSCLC) in China., Materials and Methods: This cross-sectional study analyzed data previously extracted from the medical charts of patients with unresectable Stage IIIB/IV nonsquamous NSCLC discharged from one of 12 tertiary hospitals in China between August 2015 and March 2016. Logistic regressions were applied to investigate factors associated with receiving a gene aberration test and the treatment decision., Results: Data from 932 patients were analyzed. Patients were less likely to have a gene aberration test if they had a histologic subtype other than adenocarcinoma or a hospital waiting time for test results of >5 days. Patients were more likely to receive tyrosine kinase inhibitor (TKI) treatment than chemotherapy if they had a positive result for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase gene aberration testing. EGFR positive patients were more likely to receive TKI treatment than chemotherapy if they did not have insurance for TKI or pemetrexed treatment, and more likely to receive chemotherapy than TKI treatment if they had a waiting time for test results of >5 days. EGFR wild-type/unknown patients receiving chemotherapy were more likely to receive pemetrexed if they attended a hospital in a developed area or had insurance for pemetrexed., Conclusion: In this real-world setting in China, the choice of first-line treatment for advanced NSCLC was appropriately guided by gene aberration testing for most patients. However, gene aberration testing and the treatment decision were influenced by practical factors such as hospital location, the waiting time for test results, and insurance coverage, which should be addressed to ensure optimal patient care., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To evaluate progressive changes in quantitative CT features of the non-solid component of ground-glass nodules (GGNs) from baseline to follow-up to differentiate invasive (minimally invasive adenocarcinoma [MIA] and invasive adenocarcinoma [IA]) GGNs from benign or pre-invasive (adenocarcinoma in situ [AIS]) lesions., Materials and Methods: Patients with a GGN detected at baseline and follow-up computed tomography (CT), examined by tissue sampling were included in the study. The diameter and mean, maximum, minimum CT density and density deviation from the non-solid component of whole GGNs were measured. Progression of these features over time was analysed by linear regression analysis. Multivariate receiver operating characteristics analyses of combined measures created by a logistic regression model were performed to evaluate diagnostic performance for invasive GGNs., Results: Sixty-one patients (24 males) with 70 GGNs were included. Fifteen GGNs were benign, six AIS, 38 MIA, and 11 IA. The mean diameter of all histological subtypes increased from baseline to follow-up, the largest increase was found in the MIA group (p<0.001). For MIA and IA, the mean, maximum, minimum density, and density deviation had a positive correlation over time, whilst benign and pre-invasive GGNs showed a negative correlation for these features. A diagnostic model based on three GGN features (increasing in diameter, mean density, and density deviation) identified invasive GGNs with a sensitivity, specificity and area under the receiver operating characteristic (ROC) curve (AUC) of 83.7%, 61.9%, and 0.786, respectively (p<0.001)., Conclusion: In GGN follow-up, the diameter of benign and AIS, and invasive GGNs significantly increased. Additional analysis of mean density and density deviation in the non-solid component may help to identify invasive GGNs., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objectives: Limited understanding exists of epidermal growth factor receptor (EGFR) mutation frequency in less common subgroups of advanced non-small-cell lung cancer (aNSCLC) (e.g. squamous cell carcinoma [SCC]), and to what extent local practices exclude patients from EGFR testing based on their clinical characteristics., Materials and Methods: IGNITE (non-comparative/-interventional; NCT01788163) was conducted in 90 centres (Asia-Pacific/Russia). Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly-diagnosed/recurrent disease after resection; ineligible for curative treatment. Patients provided a tissue/cytology (all) and a blood plasma (China/Russia/South Korea/Taiwan) sample. Primary endpoint: EGFR mutation frequency in aNSCLC patients (adenocarcinoma [ADC]/non-ADC), as per local practices., Results: 3382 patients were enrolled. EGFR mutation frequencies for evaluable tissue/cytology samples in Asia-Pacific and Russian patients: 49.3% (862/1749) and 18.0% (90/500) for ADC tumours; 14.1% (74/525) and 3.7% (15/402) for non-ADC; 9.9% (40/403) and 3.7% (13/349) for SCC. Of Russian patients with SCC tumours harbouring common, activating EGFR mutations, 6/9 were never-/former-smokers. Mutation status concordance between 2581 matched tissue/cytology and plasma samples: 80.5% (sensitivity 46.9%, specificity 95.6%)., Conclusion: EGFR mutation testing should be considered in all Asian aNSCLC patients. Also, as activating EGFR mutations were observed in a small number of Caucasian squamous NSCLC patients, testing here may be appropriate, particularly in those with no/remote smoking history. Circulating free tumour-derived DNA is feasible for mutation analysis employing well-validated and sensitive methods, when tumour samples are unavailable., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China., Methods: Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment. Patient data (demographics, NSCLC histologic type, Eastern Cooperative Oncology Group [ECOG] Performance Status [PS], gene aberration test and results [if performed], and first-line anticancer treatment regimen) were extracted from medical charts and entered into Medical Record Abstraction Forms (MERAFs), which were collated for analysis., Results: Overall, 1041 MERAFs were collected and data from 932 MERAFs were included for analysis. Patients with unresectable Stage IIIB/IV nonsquamous NSCLC had a median age of 59 years, 56.4% were male, 58.2% were never smokers, 95.0% had adenocarcinoma, and 92.9% had an ECOG PS ≤1. A total of 665 (71.4%) patients had gene aberration tests; 46.5% (309/665) had epidermal growth factor receptor (EGFR) gene mutations, 11.5% (48/416) had anaplastic lymphoma kinase (ALK) gene fusions, and 0.8% (1/128) had a c-ros oncogene 1 gene fusion. The most common first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was chemotherapy (72.5%, 676/932), followed by tyrosine kinase inhibitors (TKIs; 26.1%, 243/932), and TKIs plus chemotherapy (1.4%, 13/932). Most chemotherapy regimens were platinum-doublet regimens (93.5%, 631/676) and pemetrexed was the most common nonplatinum chemotherapy-backbone agent (70.2%, 443/631) in platinum-doublet regimens. Most EGFR mutation-positive patients (66.3%, 205/309) were treated with EGFR-TKIs., Conclusions: Findings from our survey of 12 tertiary hospitals throughout China showed an increased rate of gene aberration testing, compared with those rates reported in previous surveys, for patients with advanced nonsquamous NSCLC. In addition, pemetrexed/platinum-doublet chemotherapy was the predominant first-line chemotherapy regimen for this population. Most patients were treated based on their gene aberration test status and results.

Objective: The purpose of this study was to explore the mechanism of microRNA-224 (miR-224) in NSCLC., Patients and Methods: Quantitative RT-PCR (qRT-PCR) was used to evaluate expression levels of miR-224. The association of miR-224 with the clinicopathologic features of NSCLC was evaluated in 56 patients. The roles of miR-224 in cell proliferation were analyzed in vivo and in vitro with pre-miR-224 transfected cells. Also, the regulation of RASSF8 by miR-224 was evaluated by qRT-PCR, Western blotting and luciferase reporter assays., Results: In this study, we identified miR-224 to be significantly up-regulated in NSCLC tissues and associated with tumor size. Increased miR-224 expression promotes NSCLC cell proliferation by down-regulating RASSF8 at the mRNA and protein levels. The AKT pathway was found aberrantly activated after over-expression of miR-224. RASSF8 was identified as a direct target of miR-224 by bioinformatics analysis and luciferase reporter assay., Conclusions: The miR-224 played an oncogenic role in the proliferation of NSCLC by direct targeting RASSF8, and it is suggested that miR-224 may be a potential therapeutic target for NSCLC.

The echinoderm microtubule associated protein like 4‑anaplastic lymphoma kinase (EML4‑ALK) fusion is almost mutually exclusive to epidermal growth factor receptor (EGFR) or K‑RAS mutation in non‑small cell lung cancer (NSCLC), and it is extremely rare for patients to exhibit both mutations. The present study reported the case of a 71-year‑old female diagnosed with adenocarcinoma, exhibiting mutations in EGFR and EML4‑ALK. The present study treated this patient with EGFR‑TK inhibitors, as the first line therapy, and gefitinib therapy revealed a good response until now. In addition, previously reported cases and associated literature were reviewed. The present study provided a greater understanding of the molecular biology and optimal treatment for patients with NSCLC with >1 driver mutation.

Purpose: Genetic polymorphisms of ribonucleotidereductase M1 (RRM1) was a DNA repair gene, which may affect patients' response to platinum-based chemotherapy or gemcitabine-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNPs) of RRM1 can be used to predict overall survival (OS), progression free survival and response in nonsmall cell lung cancer (NSCLC) patients treated with platinum-based regimens as first-line chemotherapy., Subjects and Methods: The genotypes of four tagSNPs (RRM1 -316C > A, RRM1 -269C > A, RRM1 -702G > A and RRM1 -585T > G) were determined by SNaPshot detection technology and sequencing approaches in 184 advanced NSCLC patients by using peripheral blood., Results: The overall response rate for 178 patients was 40.2% and the disease control rate was 90.2%. In patients who had ever smoked, a significant correlation was observed between the genotype of RRM1 -269C > A and response (P = 0.046). There was a significant difference in response according to the genotype of RRM1 -702G > A (P = 0.043). Using Log-rank test, we found that patients with the allelotype (CC) of RRM1 -269C > A had a shorter OS (P = 0.006) than the allelotype (CA + AA)., Conclusion: The genotype of RRM1 -269C > A was significantly associated with platinum-based chemotherapy sensitivity in smoking patients and can be used to predict OS in advanced NSCLC patients who received platinum-based chemotherapy or gemcitabine-based chemotherapy. And the genotype of RRM1 -702G > A can serve as a biomarker for chemotherapy sensitivity in advanced NSCLC patients.

Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma. This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1-14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry. In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7). This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.

Background: Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL., Methods: Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival., Results: The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively., Conclusions: The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as erlotinib and gefitinib are targeted drugs for the kinase domain of EGFR. They are widely used for the treatment of non-small cell lung cancer (NSCLC). The EGFR exon 19 deletion mutation and the L858R mutation in exon 21 comprise approximately 90% of the somatic mutations in NSCLC patients that respond to EGFR TKI. Several recent studies have also reported that small cell lung cancer (SCLC) patients with EGFR mutations responded to gefitinib. Further study, however, has been limited due to the difficulty obtaining tumor specimens from SCLC patients., Objectives: The aim of this study was to explore the EGFR mutation status in SCLC patients by plasma analysis., Material and Methods: Plasma samples from SCLC patients were collected for mutant-enriched liquidchip (MEL) analysis to identify the EGFR mutations in exon 19 and 21., Results: The exon 19 deletion mutation was detected in one out of 35 patients (a female non-smoker). No exon 21 mutations were found., Conclusions: A prevalence of EGFR mutations in SCLC is rare, and occurs most frequently in females and nonsmokers.

Purpose: Capecitabine (CAP), a prodrug, needs to be converted to 5-fluorouracil by several key enzymes, including thymidine phosphorylase (TP). To improve the therapeutic index, potentiation of antitumor activity of CAP is required. In this study, we explored whether lidamycin (LDM), an enediyne anticancer antibiotic, can induce synergistic antitumor effects in combination with CAP in murine breast cancer in vitro and in vivo., Methods: Using MTT, cell migration and invasion, siRNA knockdown, and Western blot assays, the in vitro synergistic effects of LDM plus CAP on 4T1(LUC) cells were evaluated, and the mechanism of this synergy was explored. For in vivo model of orthotopic implantation model of 4T1(LUC) cells, optical molecular imaging system was utilized to evaluate the growth of primary tumor and metastasis. To further understand the mechanism of action of the LDM/CAP combination, immunohistochemistry analysis was carried out to detect thymidine phosphorylase induction and ERK signaling., Results: As determined by MTT and transwell assay, LDM enhanced the inhibitory effects of CAP on cancer cell proliferation, migration, and invasion. Western blot showed that this synergistic effect was attributed to the up-regulated expression of TP induced by LDM. Knocking down TP impaired the synergistic anti-proliferative effect of LDM and CAP. Furthermore, our data suggested that LDM-induced up-regulation of TP both in vitro and in vivo is associated with ERK activation, because the inhibition of ERK activity by ERK inhibitor U0126 abrogated LDM-induced TP up-regulation. In animal models, LDM plus CAP potently inhibited primary tumor growth as well as lung metastasis compared with control or single-agent-treated group., Conclusions: LDM can potentiate the antitumor effects of CAP on breast cancer line. The synergistic effects suggest that the combination of LDM and CAP is an innovative antitumor strategy for breast cancer therapy.

Objective: To observe the clinical efficacy and safety of pemetrexed or gemcitabine combined with carboplatin as the first-line therapy in elderly patients with advanced non-small cell lung cancer (NSCLC)., Methods: Seventy patients aged 70 years or over with stage IIIb-IV NSCLC were equally and randomly divided into pemetrexed plus cisplatin group (PC) and gemcitabine plus carboplatin group (GC). Patients in the PC group received pemetrexed (PEM) 500 mg/m(2) on day 1, and carboplatin (CBP) AUC5 on day 1 for 21-day cycle. Patients in the GC group received gemcitabine 1000 mg/m(2) on days 1 and 8, CBP AUC5 on day 1 for a 21-day cycle., Results: In the PC and GC groups, CR 0 and 0, PR 10 and 8, response rates 28.6% and 22.9% were observed, respectively. There was no statistically significant difference between the two groups (χ(2) = 0.299, P = 0.584). The 1-year and 2-year survival rates of the PC and GC groups were 48.6% vs. 45.7% and 11.4% vs. 11.4%, respectively, with a median survival of 11.00 and 10.00 months, without a statistically significant difference between the two groups (χ(2) = 0.01, P = 0.919). Regarding toxicities, the incidences of neutropenia/thrombocytopenia, nausea and vomiting (grade III ∼ IV) in the GC group were significantly higher than those in the PC group (P < 0.05). According to the observer scale of lung cancer symptoms, the post-treatment scores improved in both the two groups, and with no significant difference between them (P > 0.05)., Conclusions: PC and GC show similar efficacy for elderly NSCLC patients, however, the toxicities in PC patients are lower than those in GC patients. Thus, pemetrexed combined with carboplatin is an effective chemotherapeutic regimen for advanced NSCLC in elderly patients.

Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC)., Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods., Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival., Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum.

Objective: To study Chinese medicine (CM) signs and symptoms of urethane-induced lung cancer in mice, and observe the effect of Aconiti Lateralis Radix Praeparata and Taraxaci Herba on symptoms in mice and tumor progress., Method: The mice were intraperitoneally injected with urethane twice a week for consecutively five weeks to establish a lung cancer model. The changes in their appearance, body temperature and auricle microcirculation were observed in carcinogenic process. CM signs and symptoms of urethane-induced lung cancer in mice were evaluated with energy metabolism, erythrocytic ATP emzymatic activity and hemorrheological index. During the tumor model was induced, Aconiti Lateralis Radix Praeparata and Taraxaci Herba were used to treat the mice and observe their effect on symptoms in mice and tumor progress., Result: During urethane was used to induce lung cancer, the mice had gradually become chill, lazy, hunched, with reduction in temperature, cyanosis in auricle and tail. Meanwhile, their energy metabolism and erythrocytic ATP enzymatic activity reduced, whereas their whole blood viscosity and erythrocytic aggregate index increased. Taraxaci Herba showed an effect on enhancing above symptoms and signs but had no effect on tumor progress. Aconiti Lateralis Radix Praeparata showed an effect on reducing above symptoms and signs and preventing tumor progress., Conclusion: Mice with urethane-induced lung cancer show CM signs and symptoms of congealing cold with blood stasis. The treatment with Aconiti Lateralis Radix Praeparata can alleviate symptoms and signs in mice and prevent tumor progress.

Purpose: The GNAS1 gene is linked to proapoptotic signaling and correlates closely with clinical outcomes in many human cancers. The aim of this study was to evaluate whether the T393C polymorphism of the GNAS1 gene could be used as a chemotherapy sensitivity and prognosis predictive marker of advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum (GP)., Methods: In this study, we performed the PCR-restriction fragment length polymorphism assay to examine the genotypes of the GNAS1 T393C polymorphism in 131 peripheral blood DNA specimens from advanced NSCLC patients with GP treatment., Results: The frequencies of the CC, CT, and TT genotypes in 131 advanced NSCLC cases were 25.2, 47.4, and 26.7%, respectively. The favorable TT genotype was significantly correlated with better overall survival (OS; P < 0.05) and longer progress-free survival (PFS; P < 0.05) compared with the CT or CC genotype. In the multivariate Cox proportional hazards model, the GNAS1 T393C polymorphism was independently associated with overall survival after adjusting the clinicopathological factors (P < 0.05)., Conclusions: This study suggests that the TT genotype of the GNAS1 T393C polymorphism could be an independent prognostic marker to predict chemotherapy sensitivity, favorable OS and PFS in advanced NSCLC patients with GP treatment.

Malignant tumors in the tonsils are usually primary. Metastases to the tonsils are extremely rare, with nearly one hundred cases reported. Herein we present an unusual case of palatine tonsillar metastasis of non-small cell lung cancer during chemotherapy. The patient was a 39-year-old man who was diagnosed as non-small lung cancer with IIIA4 staging and poor differentiated histology. After two cycles of vinorelbine and cisplatin based chemotherapy, a big mass was developed in the right palatine tonsil which was pathologically confirmed as the metastasis from the lung. There was no hemorrhage and complains except moderate foreign body sensations. No cervical lymphadenopathy and distal metastases to other organs such as brain and liver was found. Because of poor overall performance status, no radiotherapy was given. The disease progressed after docetaxel treatment. To the best of our knowledge, this is the first case with palatine tonsillar metastasis from non-small lung cancer during induction chemotherapy.

To know the incidence of epidermal growth factor receptor (EGFR) mutations in small cell lung cancer (SCLC) patients who received surgical resection in mainland China. xTAG technology was used to detect the EGFR exon 19 and exon 21 mutations of 40 patients with SCLC who received surgical treatment in Zhejiang Cancer Hospital from 1998 to 2010. 2 of 40 cases were found with mutations in exon 19 of the EGFR gene. The mutation in exon 19 of the EGFR gene is in a female and non smoking patient which pathology is SCLC combined adenocarcinoma, and the other is male and smoking patient which pathology is SCLC combined squamous cell carcinoma. The EGFR mutation is rare in SCLC patients, and EGFR mutation might occur more often in combined SCLCs than conventional patients.

Objective: To explore a chemotherapeutic regimen suitable for non-small cell lung cancer (NSCLC) in elderly patients., Methods: A total of 68 elderly patients with NSCLC (stage IIIb/IV) were equally and randomly divided into single-agent and combined groups. Patients in single-agent group received gemcitabine 1000 mg/m(2) at Days 1 and 8 for a 21-day cycle. Those in combined group received gemcitabine 1000 mg/m(2) at Days 1 and 8 in combination carboplatin AUC5 at Day 2 for a 21-day cycle. The drugs were intravenously administered. All patients received 3 cycles of treatment., Results: In single-agent and combined groups, CR 1 and 1, PR 12 and 13, response rates 38% and 41% were respectively observed. There was no statistically significant difference between two groups (P > 0.05). The 1-year and 2-year survival rates of single-agent and combined groups were 31% vs 32% and 12% vs 14% with a median survival of 9.9 and 9.8 months without a statistically significant difference (P > 0.05). The rates of leucopenia and thrombocytopenia (III-IV degree) were 47% and 38% in combined group and they were higher than 24% and 15% in single-agent group with a statistically significant difference (P < 0.05). The observer scale of lung cancer symptom scale showed that the post-treatment scores of appetite, fatigue and pain significantly improved in single-agent group while no improvement was observed in combined group. Also the scores of appetite, fatigue and pain of single-agent group were higher than those of combined group after chemotherapy (P < 0.05)., Conclusion: Single-agent gemcitabine regimen is more suitable for advanced NSCLC in elderly patients.

Gefitinib has been approved for the treatment of patients with non-small cell lung cancer. However, its efficiency is limited by the development of drug resistance. Additional treatments for cases of non-small cell lung cancer relapsing with treatment with gefitinib are urgently required. To investigate the mechanisms of acquired resistance to gefitinib, we established PC-9-ZD, a human lung cancer cell line resistant to gefitinib after long-term exposure to the drug. PC-9-ZD cells showed more resistance to gefitinib than their parental PC-9 cells. We show that gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities, which result in impaired cell cycle progression through G1 arrest only in parental PC-9 cells, in which it inhibits growth. Our present data suggested that after long-term exposure to gefitinib, the survival of PC-9-ZD cells with heightened levels of p-Akt and reduced levels of p21 resisted further gefitinib-induced inhibition of cell growth. To explore a new strategy to improve the efficacy of gefitinib, we treated the cells with tumor necrosis factor-alpha (TNF-alpha) and found that the cells with acquired resistance to gefitinib showed increasing sensitivity to TNF-alpha, which correlated with the low activation level of nuclear factor (NF)kappaB/p65 in PC-9-ZD cells. TNF-alpha treatment induced an elevated activated NFkappaB/p65, concomitant with induced p21 levels, which resulted in increased sensitivity to gefitinib in PC-9-ZD cells. Consistent with our earlier observation that p21 is induced in an NFkappaB/p65-dependent manner, we conclude that p21 plays an important role in mediating cell growth inhibition by gefitinib. Thus, we proposed that combined treatment with TNF-alpha/gefitinib is an efficient therapeutic strategy for tumors that develop resistance to gefitinib.

Background: Osteosarcoma (OSA) is the most frequent type of primary malignant bone tumor and is apt to occur in children and young adults. Pulmonary metastasis (OSPM) is the major reason for its fatal outcome. Osteocalcin (OC) is a major noncollagenous bone protein whose expression is limited almost exclusively to bone marrow and osteotropic tumors. OC is also known to express in cell lines with bone metastasis feathers. Gene therapy strategies with the OC promoter directing the replication of adenovirus in a tumor-specific manner are a potential modality for OSPM therapy., Methods: We detected OC mRNA expression by RNA in situ hybridization in OSA and OSPM samples from patients, and tested OC promoter transcriptional activity in OSA and non-OSA cell lines. Then we used a transcriptional replication-competent adenovirus, Ad-OC-E1a, to treat OSPM, and evaluated its tumor-specific replication and killing activities in vitro as well as anti-OSPM efficacy in vivo via systemic delivery., Results: OC mRNA was detected in all types of OSA tissues, including OSPM tissues. The transcriptional activity of the OC promoter was much higher in a OSPM cell line SAOS-2LM7 and primary OSA cell line MG63 than in non-OSA cell lines, including cell lines from breast cancer, colon cancer, and liver cancer. Ad-OC-E1a expressed E1a protein only in MG63 and SAOS-2LM7, which indicated that adenovirus E1a was under strict control by the OC promoter. Ad-OC-E1a demonstrated killing and viral replication activity close to wild-type adenovirus levels in MG63 and SAOS-2LM7, but the killing and viral replication activities were attenuated significantly in cells expressing low OC transcriptional activity. To test whether Ad-OC-E1a could be used to target human OSPM in vivo, SAOS-2LM7 pulmonary metastasis models in nude mice were induced and treated by tail-vein injection with Ad-OC-E1a. Compared to tumor nodules in the lung in groups treated with PBS or control virus, the quantity of metastasized tumor nodules decreased significantly. Adenovirus-infected cells were stained immunohistochemically only inside and around the OSPM nodules but spared normal lung tissue and other organs., Conclusions: These data demonstrated that OC promoter could direct adenovirus replication by controlling the E1a gene to target human OSPM in a tumor-specific manner, providing an efficient tool to develop a feasible therapeutic modality for OSPM., (Copyright 2006 John Wiley & Sons, Ltd.)

Objective: To study the clinical efficaly and safety of Tiepi Fengdou Granule (TFG) and Capsule (TFC) combined with chemotherapy and/or radiotherapy in treating lung cancer patients with Qi-Yin asthenia syndrome (QYAS)., Methods: Eighty patients were randomly assigned into 3 groups: the TFG group (32 cases), the TFC group (32 cases) and the Shengmai Capsule control group (16 cases). Changes of symptoms of QYAS, main symptoms of lung cancer, Karnofsky scoring as well as the blood routine test were observed., Results: The total effective rate of symptom improving in the TFG group and the TFC group was 81.2% and 93.3% respectively, showing insignificant difference between the 2 groups (P > 0.05), but both were higher than that in the Shengmai Capsule control group (50.0%, P < 0.05 and P < 0.01). Additionally, as compared with those before treatment, the neutrophil count increased and the lymphocytes count obviously decreased in the TFC group after treatment (all P < 0.05)., Conclusion: Both dose-forms of the remedies, TFC and TFG, have significant effects in treating lung cancer with QYAS, but with insignificant difference between them.

Objective: To evaluate the difference of efficacy, side-effects and quality of life in advanced non-small-cell lung cancer (NSCLC) patients treated with oxaliplatin plus vinorelbine or cisplatin plus vinorelbine., Methods: Eligible patients were randomly assigned to NL (oxaliplatin + vinorelbine) group and NP (cisplatin + vinorelbine) group in a 2:1 ratio. In the NL group, 70 evaluable cases were treated with oxaliplatin 130 mg/m(2) i.v. on day 2, and vinorelbine 25 mg/m(2) i.v. on days 1 and 8 in 21 days per cycle. In the NP group, 32 evaluable cases were treated with cisplatin 80 mg/m(2) i.v. divided to 2 - 3 days dosing, 21 days per cycle, and vinorelbine administered by the same way as in the NL group. The response rate, time to progression (TTP), one-year survival, side-effects and the quality of life were observed., Results: The response rate was 35.7% vs. 43.8% (P = 0.4), median TTP was 4.7 months vs. 5.5 months (P = 0.6), one-year survival rate was 38.5% vs. 58.6% (P = 0.07) in the NL and NP groups, respectively. Grade I-II neuro-sensory toxicity occurred significantly more frequent in NL group than in NP group (68.4% vs. 36.4%, P = 0.0017). However, Grade I-II granulocytopenia was significantly less occurred in NL group than in NP group (49.4% vs. 70.6%, P = 0.037). There was no statistically difference between the two groups regarding quality of life., Conclusion: Due to good efficacy and tolerability, the NL regimen offered a new candidate for treating advanced NSCLC.

Background & Objective: EP regimen[etoposide (VP-16) + cisplatin (DDP)] is a standard regimen for treatment of small cell lung cancer (SCLC), but the cure rate is still low. Teniposide (VM-26) is highly active single agent for SCLC as VP-16, and penetratable through blood-brain barrier. This clinical trial was designed to compare the efficacy and toxicity of teniposide plus cisplatin (VM-26 + DDP) regimen and EP regimen in treatment of SCLC, and the possible role of VM-26 on prevention of brain metastasis of SCLC., Methods: A total of 70 previously untreated SCLC patients without brain metastasis were included; 34 patients received VM-26 + DDP and 36 patients received EP. The characteristics of patients were comparable according to chi 2 test., Results: The overall response rate-was 76.5% for VM-26 + DDP group with 12 complete response (CR) and 14 partial response (PR), and 69.4% in the EP group with 12 CR and 13 PR (P = 0.595). The median duration of survival was 10.4 months for VM-26 + DDP group versus 9.8 months for EP group (P > 0.05). The 1, 2, and 5-year survival rates were 35.3%, 14.7%, 8.8% in the VM-26 + DDP group; and 38.9%, 13.9%, 8.3% in the EP group (P > 0.05, without statistical difference). The rate of brain metastasis was 5.9% for VM-26 + DDP group and 19.4% for EP group (P = 0.027, with statistical difference). The main toxicity was mylosuppression (I-II); there was no significant difference between the two groups (P > 0.05)., Conclusion: VM-26 + DDP is a highly active regimen for treatment of SCLC; there is no difference in the effectiveness and toxicity versus EP regimen; VM-26 is possibly effective in prevention of brain metastasis in SCLC patients.