Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

Science.gov (United States)

Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

2017-12-01

Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

[Efficacy of MVP chemotherapy combined with concurrent radiotherapy for advanced non-small cell lung cancer].

Science.gov (United States)

Qiao, Tiankui; Zhou, Daoan; Chen, Wei; Wang, Xianglian

2004-12-20

To observe the effects of MVP chemotherapy combined with concurrent radiotherapy for stage IIIB-IV non-small cell lung cancer. Sixty-two patients with stage IIIB-IV non-small cell lung cancer were randomized into two groups, concurrent radiochemotherapy group and MVP che-motherapy group. All patients in two groups were treated with MVP regimen (mitomycin C 6 mg/m² on day 1, vindesine 2 mg/m² on days 1, 8, and cisplatin 80-100 mg/m²). Patients in concurrent radiochemotherapy group received concurrent radiotherapy (46-56 Gy in 5-6 weeks). All patients received 2-4 cycles of MVP chemotherapy. The response rate was 48.4% and 19.4% in concurrent radiochemotherapy group and MVP group respectively (P MVP group.. The results show that efficacy of MVP chemotherapy combined with concurrent radiotherapy is significantly higher than that of MVP chemotherapy alone for advanced non-small cell lung cancer.

Progress in Tissue Specimens Alternative for the Driver Genes Testing of Non-small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Yan SUN

2015-06-01

Full Text Available Target treatment based on driver genes in advanced non-small cell lung cancer is very important currently. Tumor tissues is the gold standard for driver genes testing. However, most of patients could not get the gene information for lack of enough tissues. To explore the tissue specimens alternatives is a hot spot in clinical work. This report reviews the tissue specimen alternatives of driver gene testing in non-small cell lung cancer.

Treatment of stage III non-small cell lung cancer and limited-disease small-cell lung cancer

NARCIS (Netherlands)

El Sharouni, S.Y.

2009-01-01

This thesis concerns the treatment of stage III non-small cell lung cancer (NSCLC) and limited disease small-cell lung cancer (SCLC). We described a systematic review on the clinical results of radiotherapy, combined or not with chemotherapy, for inoperable NSCLC stage III with the aim to define the

Radiotherapy for stage I-II non-small cell lung cancer

International Nuclear Information System (INIS)

Okamoto, Yoshiaki; Murakami, Masao; Mizowaki, Takashi; Nakajima, Toshifumi; Kuroda, Yasumasa

1999-01-01

Surgery has been regarded as the standard treatment for patients with non-small cell lung cancer in the early stage, while radiotherapy has become an effective alternative for medically inoperable patients and those who refuse surgery. We reviewed the records of 31 patients with stage I-II non-small cell lung cancer treated by radiotherapy between 1980 and 1997. There were 15 patients in stage I and 16 in stage II. The variables analyzed for influence on cause-specific survival and loco-regional control were: age, performance status, clinical stage, tumor size, tumor site, radiation field, radiation dose, and combination with chemotherapy. The overall and cause-specific 1-, 2-, 3-, and 5-years survival rates were 71% and 77%; 63% and 73%; 34% and 48%; and 17% and 32%, respectively. Five-year survival rate for patients with peripheral tumor in the lung was 72%, with 70% loco-regional control, while the 5-year survival rate of patients whose tumor originated in the central region was 20%, with 25% loco-regional control. These differences had marginal significance on univariate analysis (P=0.07), but only tumor site (central vs peripheral) showed marginal significant influence on cause-specific survival (P=0.08) and loco-regional control (P=0.07) on multivariate analysis. There were no fatal complications, including radiation-induced myelopathy. The present series showed satisfactory results with definitive radiotherapy for patients with medically inoperable stage I-II non-small cell lung cancer, with results similar to those in recent reports of radiotherapy. The only significant variable was that patients with peripheral tumors had a better prognosis than patients with central tumors. (author)

Epigenetic silencing of MicroRNA-503 regulates FANCA expression in non-small cell lung cancer cell.

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Li, Ning; Zhang, Fangfang; Li, Suyun; Zhou, Suzhen

2014-02-21

It is reported that MicroRNA-503 (miR-503) regulates cell apoptosis, and thus modulates the resistance of non-small cell lung cancer cells (NSCLC) to cisplatin. However, the exact role of miR-503 in NSCLC remains unknown. In the present study, the level of miR-503 expression in NSCLC was evaluated using realtime PCR, and the DNA methylation status within miR-503 promoter was analyzed by Combined Bisulfite Restriction Analysis (COBRA) or bisulfite-treated DNA sequencing assays (BSP). We found that the expression of miR-503 was significantly decreased in NSCLC tissues compared to normal tissues. A statistically significant inverse association was found between miR-503 methylation status and expression of the miR-503 in tumor tissues (PFANCA) gene and represses its expression at the transcriptional level. Taken together, our results suggest that miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin at least in part by targeting FANCA. Copyright © 2014 Elsevier Inc. All rights reserved.

Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: a phase I study

International Nuclear Information System (INIS)

Order, Stanley E.; Siegel, Jeffry A.; Principato, Robert; Zeiger, Louis E.; Johnson, Elizabeth; Lang, Patricia; Lustig, Robert; Wallner, Paul E.

1996-01-01

Purpose: Selective high-dose radiation of solid tumors has been a goal of radiation oncology. The physiological barriers of solid tumors (high interstitial tumor pressure, reduced tumor vascularity, and poor perfusion) have been major barriers in achieving significant tumor dose of systemically infused radioconjugates. Direct tumor infusional brachytherapy overcomes these barriers and leads to selective high tumor doses. Methods and Materials: The development of interstitial tumor infusion of macroaggregated albumin (MAA) followed by colloidal chromic phosphate 32 P has overcome solid tumor obstacles in 47 patients with nonresectable pancreatic cancer in a Phase I dose escalation study. The colloidal 32 P infusion was followed by external radiation and five fluorouracil. Results: Of the 28 patients with cancer limited to the pancreas, 15 of 16 patients retained 86-100% (mean 96%) of the infused colloidal 32 P isotope. While the other 12 patients had partial shunting to the liver, shunting to the liver was due to high interstitial resistance with tumor dose deposition of 17-88% (mean 52%). Of the 19 patients with metastatic pancreas cancer, colloidal 32 P tumor deposition ranged from 22 to 100% of the infused dose (mean 79%). The less than optimal tumor deposition led to our increasing the MAA from 600,000 to 1.5-2.5 million particles. Interstitial dexamethasone 2 mg and later 4 mg was infused first and prevented liver shunting by somehow reducing tumor resistance. The median survival in 28 Phase I patients with nonresectable pancreas cancer without metastasis, was 12 months. No significant toxicity occurred when treatment was limited to two infusions with as much as 30 mCi each. The maximum tumor dose was 17,000 Gy (1.700,000 cGy). In 19 non-resectable pancreatic cancer patients with metastasis, a 6.9 months median survival was observed. Conclusions: Infusional brachytherapy is an outpatient procedure that delivers high-dose radiation selectively to pancreatic

Radiosensitization of C225 on human non-small cell lung cancer cell line H-520

International Nuclear Information System (INIS)

Zhang Yingdong; Wang Junjie; Liu Feng; Zhao Yong

2008-01-01

Objective: To investigate the efficacy of C225 (cetuximab), a chimeric human-mouse anti-epithelial growth factor receptor monoclonal antibody, combined with 60 Co gamma irradiation against human non-small cell lung cancer cell line H-520. Methods: H-520 cells were treated either with different dose of 60 Co irradiation (1,2,4,6,8 and 10 Gy)alone or together with C225 (100 nmol/L). Colony forming capacity was determined to create the survival curve 10 days after the treatment. Cells in different groups were harvested 72 hours after irradiation for apoptosis analysis or 48 hours after irradiation for cell cycle analysis by flow cytometry assay. Results: The clone number in combinational treatment group was less than that in irradiation only group, which suggested that the cell survival rate in the combinational treatment group was significantly decreased comparing with irradiation only group (F=6.36, P O + G 1 phases for C225 treatment, in G 2 + M phases for 60 Co irradiation, and in both G 0 + G 1 and G 2 + M phases for C225 in combination with 60 Co irradiation. Conclusions: C225 has radiosensitizing effects on H-520 cells, which may through the enhancement of 60 Co irradiation-induced cell death and cell cycle arrest. This study provides a supportive evidence for clinical treatment in non-small cell lung cancer. (authors)

Vorinostat increases carboplatin and paclitaxel activity in non-small cell lung cancer cells

OpenAIRE

Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Kanterewicz, Beatriz; Balius, Trent; Belani, Chandra P.; Hershberger, Pamela A.

2010-01-01

We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 h of continuous drug exposure. Vorinostat (1 µM) inhibited growth by: 17±7% in A549, 28±6% in 128-88T, 39±8% in Calu1, and 41±7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel le...

Effects of icotinib on advanced non-small cell lung cancer with different EGFR phenotypes.

Science.gov (United States)

Pan, Huiyun; Liu, Rong; Li, Shengjie; Fang, Hui; Wang, Ziwei; Huang, Sheng; Zhou, Jianying

2014-09-01

Icotinib is the first oral epidermal growth factor receptor (EGFR) tyrosine kinase receptor inhibitor, which has been proven to exert significant inhibitory effects on non-small cell lung cancer in vitro. Clinical evidence has showed that the efficacy of Icotinib on retreating advanced non-small cell lung cancer is comparable to Gefitinib. However, different phenotypes of EGFR can affect the therapeutic outcomes of EGFR tyrosine kinase receptor inhibitor. Therefore, our study focused on efficacy and safety of Icotinib in patients with advanced non-small cell lung cancer of different EGPR phenotypes. Clinical data of patients with advanced non-small cell lung cancer who received Icotinib treatment from August, 2011 to May, 2013 were retrospectively analyzed. Kaplan-Meier analysis was used for survival analysis and comparison. 18 wild-type EGFR and 51 mutant type were found in a total of 69 patients. Objective response rate of patients with mutant type EGFR was 54.9 % and disease control rate was 86.3 %. Objective response rate of wild-type patients was 11.1 % (P = 0.0013 vs mutant type), disease control rate was 50.0 % (P = 0.0017). Median progression-free survival (PFS) of mutant type and wild-type patients were 9.7 and 2.6 months, respectively (P Icotinib included rash, diarrhea, itching skin with occurrence rates of 24.6 % (17/69), 13.0 % (9/69), and 11.6 % (8/69), respectively. Most adverse reactions were grade I-II. Icotinib has great efficacy in EGFR mutated patients, making it an optimal regimen to treat EGFR mutated patients. Furthermore, most of adverse reactions associated with Icotinib treatment were tolerable.

Non-small cell lung cancer in never smokers: a clinical entity to be identified.

Science.gov (United States)

Santoro, Ilka Lopes; Ramos, Roberta Pulcheri; Franceschini, Juliana; Jamnik, Sergio; Fernandes, Ana Luisa Godoy

2011-01-01

It has been recognized that patients with non-small cell lung cancer who are lifelong never-smokers constitute a distinct clinical entity. The aim of this study was to assess clinical risk factors for survival among never-smokers with non-small cell lung cancer. All consecutive non-small cell lung cancer patients diagnosed (n = 285) between May 2005 and May 2009 were included. The clinical characteristics of never-smokers and ever-smokers (former and current) were compared using chi-squared or Student's t tests. Survival curves were calculated using the Kaplan-Meier method, and log-rank tests were used for survival comparisons. A Cox proportional hazards regression analysis was evaluated by adjusting for age (continuous variable), gender (female vs. male), smoking status (never- vs. ever-smoker), the Karnofsky Performance Status Scale (continuous variable), histological type (adenocarcinoma vs. non-adenocarcinoma), AJCC staging (early vs. advanced staging), and treatment (chemotherapy and/or radiotherapy vs. the best treatment support). Of the 285 non-small cell lung cancer patients, 56 patients were never-smokers. Univariate analyses indicated that the never-smoker patients were more likely to be female (68% vs. 32%) and have adenocarcinoma (70% vs. 51%). Overall median survival was 15.7 months (95% CI: 13.2 to 18.2). The never-smoker patients had a better survival rate than their counterpart, the ever-smokers. Never-smoker status, higher Karnofsky Performance Status, early staging, and treatment were independent and favorable prognostic factors for survival after adjusting for age, gender, and adenocarcinoma in multivariate analysis. Epidemiological differences exist between never- and ever-smokers with lung cancer. Overall survival among never-smokers was found to be higher and independent of gender and histological type.

Serum GRP78 as a Tumor Marker and Its Prognostic Significance in Non-Small Cell Lung Cancers: A Retrospective Study

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Xiao Ma

2015-01-01

Full Text Available Introduction. Glucose-regulated protein 78 (78 kDa, GRP78, which is also known as immunoglobulin heavy chain binding protein (BIP, is a major chaperone in the endoplasmic reticulum (ER. The expression and clinical significance of GRP78 in the serum of non-small cell lung cancer patients have not yet been clearly described. The aims of the present study were to investigate the expression of GRP78 in the serum of non-small cell lung cancer patients, the relationships with clinicopathological parameters, and the potential implications for survival. Patients and Methods. A total of 163 peripheral blood samples from non-small cell lung cancer patients were prospectively collected at the Department of Thoracic Surgery, Fudan University Shanghai Cancer, China. Clinical characteristics data, including age, gender, stage, overall survival (OS time, and relapse-free survival (RFS time, were also collected. Serum GRP78 levels were measured using a commercially available ELISA kit. The associations between GRP78 levels and clinicopathological characteristics and survival were examined using Student’s t-test, Kaplan-Meier, or Cox regression analyses. Results. The mean ± standard error (SE value of GRP78 was 326.5 ± 49.77 pg/mL. This level was significantly lower compared with the level in late-stage non-small cell lung cancer patients (1227 ± 223.6, p=0.0001. There were no significant correlations with the clinicopathological parameters. No significant difference was found between high GRP78 expression and low GRP78 expression with regard to RFS (p=0.1585. However, the OS of patients with higher GRP78 expression was significantly poorer (p=0.0334. Conclusions. GRP78 was expressed in non-small cell lung cancer patients and was highly enriched in late-stage lung cancer. GRP78 may have an important role in the carcinogenesis of non-small cell lung cancer and may be a prognostic marker for non-small cell lung cancer.

Molecular Modeling, Docking, Dynamics and simulation of Gefitinib and its derivatives with EGFR in Non-Small Cell Lung Cancer.

Science.gov (United States)

Reddy, Pulakuntla Swetha; Lokhande, Kiran Bharat; Nagar, Shuchi; Reddy, Vaddi Damodara; Murthy, P Sushma; Swamy, K Venkateswara

2018-02-27

Gefitinib (lressa) is the most prescribed drug, highly effective to treat of non-small cell lung cancer; primarily it was considered targeted therapy is a kinase inhibitor. The non-small cell lung cancer caused by the mutation in the Epithelial Growth Factor Receptor (EGFR) gene, Iressa works by blocking the EGFR protein that helps the cancer cell growth. EGFR protein has lead to the development of anticancer therapeutics directed against EGFR inhibitor including Gefitinib for non-small cell lung cancer. To explore research on Gefitinib and its derivatives interaction with crystal structure EGFR to understand the better molecular insights interaction strategies. Molecular modeling of ligands (Gefitinib and its derivatives) was carried out by Avogadro software till atomic angle stable confirmation obtained. The partial charges for the ligands were assigned as per standard protocol for molecular docking. All docking simulations were performed with AutoDockVina. Virtual screening carried out based on binding energy and hydrogen bonding affinity. Molecular dynamics (MD) and Simulation EGFR was done using GROMACS 5.1.1 software to explore the interaction stability in a cell. The stable conformation for EGFR protein trajectories were captured at various time intervals 0-20ns. Few compounds screen based on high affinity as the inhibitor for EGFR may inhibit the cell cycle signalling in non-small cell lung cancer. These result suggested that a computer aided screening approach of a Gefitinib derivatives compounds with regard to their binding to EGFR for identifying novel drugs for the treatment of non-small cell lung cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Phase 1 Trial of an Immune Checkpoint Inhibitor plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer

Science.gov (United States)

2017-10-01

with Inoperable Stage I Non-Small Cell Lung Cancer PRINCIPAL INVESTIGATOR: Karen Kelly, MD CONTRACTING ORGANIZATION: University of California...Inhibitor plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer 5b. GRANT NUMBER W81XWH-15-2-0063...immune checkpoint inhibitor MPDL3280A (atezolizumab) in early stage inoperable non-small cell lung cancer . The trial is comprised of a traditional 3 + 3

Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway

International Nuclear Information System (INIS)

Mi, Shanwei; Xiang, Gang; Yuwen, Daolu; Gao, Jian; Guo, Wenjie; Wu, Xuefeng; Wu, Xudong; Sun, Yang; Su, Yongqian; Shen, Yan; Xu, Qiang

2016-01-01

Resistance to cisplatin is a major obstacle for the success of non-small cell lung cancer therapy. The mechanisms underlying cisplatin resistance are not fully understood. In this study, we found that the increase of basal auotophagy accompanied the development of cisplatin resistance. Meanwhile the blockade of the Akt/mTOR pathway occurred in the process. Inhibition of this pathway was induced by cisplatin treatment in the resistant non-small cell lung carcinoma cells. Andrographolide, a natural diterpenoid, promoted the activation of the Akt/mTOR signaling by downregulating PTEN and suppressed autophagy, which subsequently resensitized the resistant cells to cisplatin-mediated apoptosis. Cisplatin treatment in combination with andrographolide significantly prevented the growth of the resistant cells in vivo. These results highlight the involvement of autophagy in cisplatin-resistance development and suggest that inhibition of autophagy via tuning the Akt/mTOR signaling could be a promising strategy in the therapy for cisplatin-resistant non-small cell lung cancer. - Highlights: • The increase of basal auotophagy accompanied the development of cisplatin resistance in NSCLC cells. • Cisplatin induced the blockade of the Akt/mTOR pathway. • Andrographolide promoted the activation of the Akt/mTOR signaling. • Andrographolide downregulated PTEN expression. • Cisplatin treatment in combination with andrographolide resensitized the resistant cells to cisplatin.

Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway

Energy Technology Data Exchange (ETDEWEB)

Mi, Shanwei; Xiang, Gang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Yuwen, Daolu [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Gao, Jian; Guo, Wenjie; Wu, Xuefeng; Wu, Xudong; Sun, Yang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Su, Yongqian [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Shen, Yan, E-mail: shenyan@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China)

2016-11-01

Resistance to cisplatin is a major obstacle for the success of non-small cell lung cancer therapy. The mechanisms underlying cisplatin resistance are not fully understood. In this study, we found that the increase of basal auotophagy accompanied the development of cisplatin resistance. Meanwhile the blockade of the Akt/mTOR pathway occurred in the process. Inhibition of this pathway was induced by cisplatin treatment in the resistant non-small cell lung carcinoma cells. Andrographolide, a natural diterpenoid, promoted the activation of the Akt/mTOR signaling by downregulating PTEN and suppressed autophagy, which subsequently resensitized the resistant cells to cisplatin-mediated apoptosis. Cisplatin treatment in combination with andrographolide significantly prevented the growth of the resistant cells in vivo. These results highlight the involvement of autophagy in cisplatin-resistance development and suggest that inhibition of autophagy via tuning the Akt/mTOR signaling could be a promising strategy in the therapy for cisplatin-resistant non-small cell lung cancer. - Highlights: • The increase of basal auotophagy accompanied the development of cisplatin resistance in NSCLC cells. • Cisplatin induced the blockade of the Akt/mTOR pathway. • Andrographolide promoted the activation of the Akt/mTOR signaling. • Andrographolide downregulated PTEN expression. • Cisplatin treatment in combination with andrographolide resensitized the resistant cells to cisplatin.

Non-small cell lung cancer in never smokers: a clinical entity to be identified

Directory of Open Access Journals (Sweden)

Ilka Lopes Santoro

2011-01-01

Full Text Available OBJECTIVES: It has been recognized that patients with non-small cell lung cancer who are lifelong never-smokers constitute a distinct clinical entity. The aim of this study was to assess clinical risk factors for survival among neversmokers with non-small cell lung cancer. METHODS: All consecutive non-small cell lung cancer patients diagnosed (n = 285 between May 2005 and May 2009 were included. The clinical characteristics of never-smokers and ever-smokers (former and current were compared using chi-squared or Student's t tests. Survival curves were calculated using the Kaplan-Meier method, and log-rank tests were used for survival comparisons. A Cox proportional hazards regression analysis was evaluated by adjusting for age (continuous variable, gender (female vs. male, smoking status (never- vs. ever-smoker, the Karnofsky Performance Status Scale (continuous variable, histological type (adenocarcinoma vs. non-adenocarcinoma, AJCC staging (early vs. advanced staging, and treatment (chemotherapy and/or radiotherapy vs. the best treatment support. RESULTS: Of the 285 non-small cell lung cancer patients, 56 patients were never-smokers. Univariate analyses indicated that the never-smoker patients were more likely to be female (68% vs. 32% and have adenocarcinoma (70% vs. 51%. Overall median survival was 15.7 months (95% CI: 13.2 to 18.2. The never-smoker patients had a better survival rate than their counterpart, the ever-smokers. Never-smoker status, higher Karnofsky Performance Status, early staging, and treatment were independent and favorable prognostic factors for survival after adjusting for age, gender, and adenocarcinoma in multivariate analysis. CONCLUSIONS: Epidemiological differences exist between never- and ever-smokers with lung cancer. Overall survival among never-smokers was found to be higher and independent of gender and histological type.

Molecular biologic study about the non-small cell lung carcinoma (2) : p53 gene alteration in non-small cell lung carcinoma

International Nuclear Information System (INIS)

Park, Jong Ho; Zo, Jae Ill; Paik, Hee Jong; Kim, Mi Hee

1996-12-01

The main purpose of this research was to identify of the p53 and 3p gene alteration in non-small cell lung cancer patients residing in Korea. Furthermore, we analyzed the relationship between the p53 and 3p gene alterations and the clinicopathologic results of lung cancer patients. And we have investigated the role of PCR-LOH in analyzing tumor samples for LOH of defined chromosomal loci. We have used the 40 samples obtained from the lung cancer patients who were diagnosed and operated curatively at Korea Cancer Center Hospital. We have isolated the high molecular weight. DNA from the tumors and normal tissues. And we have amplified the DNA with PCR method and used the microsatellite assay method to detect the altered p53 and 3p gene. The conclusions were as follow: 1) The 3p gene alteration was observed in 9/39 (23.1%) and p53 gene alteration was observed in 15/40 (37.5%) of resected non-small cell lung cancer. 2) There was no correlations between the 3p or p53 gene alterations and prognosis of patients, but further study is necessary. 3) PCR-LOH is a very useful tool for analyzing small amount of tumor samples for loss of heterozygosity of defined chromosomal loci. (author). 10 refs

Effectiveness of palliative radiotherapy in patients with non-small cell lung cancer

International Nuclear Information System (INIS)

Chmielewska, E.; Jaskiewicz, P.

2001-01-01

Lung cancer is the most frequent malignant neoplasm in Poland. During the last 25 years it has become the first reason of death of men and the second of women in Poland. Patients with non-small cell lung cancer constitute 75% of all lung cancer patients. The therapy of choice for the advanced, non-small cell lung cancer is radiotherapy with palliative assumption. Many papers indicate that this therapy has no influence on long-term survival, hence it is aimed at reducing the symptoms. The therapy brings relief to 70-80% of patients. At present no other method with similar effectiveness is known. The aim of the is study was to assess the effectiveness of palliative radiotherapy as a treatment of the advanced, non-small cell lung cancel, applied as a remedy for the symptoms resulting from the growth of a lung tumour: Improvement of the quality of life and long-term survivals were assessed and prognostic factors were analysed. Between 1990 and 1995, 2330 patients with lung cancer attended the Outpatient Clinic of the Maria Sklodowska-Curie Memorial Cancer Center in Warsaw. There were 1948 patients with the non-small cell lung cancer. From this group 832 patients were qualified to palliative radiotherapy that included the primary tumour. The documentation was found for 803 patients and this group was analysed. The group constituted of 115 women (14.3%) and 688 men (85.7%), aged 28 to 91 (mean 61). In the majority of cases a significant advancement of the disease was found: stage III A in 388 patients (48.3%) and stage III B in 358 patients (44.6%). Retrospective analysis of the results of the treatment was carried out. The material contained information on 803 patients. The basis for the analysis was the survival time. It was measured from the starting date of the irradiation to the date of death or the date of the last available information that the patient lives. The survival probability was calculated with the Kaplan-Meier method. Multidimensional analysis of the

Factors predicting radiation pneumonitis in locally advanced non-small cell lung cancer

International Nuclear Information System (INIS)

Kim, Myung Soo; Lee, Ji Hae; Ha, Bo Ram; Lee, Re Na

2011-01-01

Thoracic radiotherapy is a major treatment modality of stage III non-small cell lung cancer. The normal lung tissue is sensitive to radiation and radiation pneumonitis is the most important dose-limiting complication of thoracic radiation therapy. This study was performed to identify the clinical and dosimetric parameters related to the risk of radiation pneumonitis after definitive radiotherapy in stage III non-small cell cancer patients. The medical records were reviewed for 49 patients who completed definitive radiation therapy for locally advanced non-small cell lung cancer from August 2000 to February 2010. Radiation therapy was delivered with the daily dose of 1.8 Gy to 2.0 Gy and the total radiation dose ranged from 50.0 Gy to 70.2 Gy (median, 61.2 Gy). Elective nodal irradiation was delivered at a dose of 45.0 Gy to 50.0 Gy. Seven patients (14.3%) were treated with radiation therapy alone and forty two patients (85.7%) were treated with chemotherapy either sequentially or concurrently. Twenty-five cases (51.0%) out of 49 cases experienced radiation pneumonitis. According to the radiation pneumonitis grade, 10 (20.4%) were grade 1, 9 (18.4%) were grade 2, 4 (8.2%) were grade 3, and 2 (4.1%) were grade 4. In the univariate analyses, no clinical factors including age, sex, performance status, smoking history, underlying lung disease, tumor location, total radiation dose and chemotherapy were associated with grade ≥2 radiation pneumonitis. In the subgroup analysis of the chemotherapy group, concurrent rather than sequential chemotherapy was significantly related to grade ≥2 radiation pneumonitis comparing sequential chemotherapy. In the univariate analysis with dosimetric factors, mean lung dose (MLD), V20, V30, V40, MLDipsi, V20ipsi, V30ipsi, and V40ipsi were associated with grade ≥2 radiation pneumonitis. In addition, multivariate analysis showed that MLD and V30 were independent predicting factors for grade ≥2 radiation pneumonitis. Concurrent

Eosinophilia after radiotherapy for non-resected cervical cancer

International Nuclear Information System (INIS)

Murohashi, Ikuo; Kawase, Yoshiko; Bessho, Masami; Nara, Nobuo

1982-01-01

The behaviors of peripheral eosinophils during radiotherapy were examined in 200 cases of non-resected cervical cancer. Before irradiation, the mean absolute eosinophil count had been 170 +- 168/mm 3 , and eosinophilia (more than 500/mm 3 ) had been observed in 11 cases (5.5%). Postirradiation eosinophilia occurred in 126 cases (63%). The mean period between institution of irradiation and the peak of the eosinophil count was 27.8 days. The mean highest eosinophil count was 691 +- 437/mm 3 , and the mean bone marrow dose in this period was 906 rad. Comparisons of the eosinophil count according to the stage showed no significant differences. (Chiba, N.)

A Systematic Overview of Radiation Therapy Effects in Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Sirzen, Florin; Kjellen, Elisabeth; Soerenson, Sverre; Cavallin-Staahl, Eva

2003-01-01

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately. This synthesis of the literature on radiation therapy for non-small cell lung cancer (NSCLC) is based on data from 4 meta-analyses and 31 randomized trials. Moreover, data from 12 prospective studies, 12 retrospective studies and 6 other articles were used. In total, 65 scientific articles are included, involving 18,310 patients. The results were compared with those of a similar overview from 1996 including 28,172 patients. The conclusions reached can be summarized as follows: Extensive clinical experience indicates that radiotherapy for medically inoperable patients or patients refusing surgery with NSCLC stage I/II prolongs survival, 15-20% of these patients reaching long-term (5-year) survival. However, no randomized trials have addressed this issue. There is strong evidence that postoperative radiotherapy in radically resected stage I/II NSCLC does not prolong survival compared with observation alone. There is some evidence that continuous hyperfractionated accelerated radiotherapy (CHART) is associated with increased survival compared to conventional radiotherapy in locally advanced NSCLC and also in medically unfit patients with stage I/II NSCLC. However, the benefit is limited to squamous cell histology. There is strong evidence that combined modality treatment with platinum-based chemotherapy and radiotherapy, either neoadjuvant or concomitant, is superior to radiotherapy alone in terms of survival in locally advanced unresectable NSCLC and should be the standard of care in patients with good performance status. There is some evidence that concomitant chemo-radiotherapy is associated with increased survival compared with sequential chemo-radiotherapy, albeit at the price of increased toxicity. Comment: Combined chemo

Customising chemotherapy in advanced nonsmall cell lung cancer: daily practice and perspectives

DEFF Research Database (Denmark)

Vilmar, A C; Sorensen, J B

2011-01-01

Treating patients with advanced nonsmall cell lung cancer (NSCLC) is a daunting task but during recent years new options have emerged. By tailoring treatment using either information on histological subtypes of NSCLC or biomarkers it is now possible to improve outcome and maintain stable quality...

MicroRNA-944 Affects Cell Growth by Targeting EPHA7 in Non-Small Cell Lung Cancer

OpenAIRE

Minxia Liu; Kecheng Zhou; Yi Cao

2016-01-01

MicroRNAs (miRNAs) have critical roles in lung tumorigenesis and development. To determine aberrantly expressed miRNAs involved in non-small cell lung cancer (NSCLC) and investigate pathophysiological functions and mechanisms, we firstly carried out small RNA deep sequencing in NSCLC cell lines (EPLC-32M1, A549 and 801D) and a human immortalized cell line 16HBE, we then studied miRNA function by cell proliferation and apoptosis. cDNA microarray, luciferase reporter assay and miRNA transfectio...

Seizure outcomes in non-resective epilepsy surgery: An update

Science.gov (United States)

Englot, Dario J.; Birk, Harjus; Chang, Edward F.

2016-01-01

In approximately 30% of patients with epilepsy, seizures are refractory to medical therapy, leading to significant morbidity and increased mortality. Substantial evidence has demonstrated the benefit of surgical resection in patients with drug-resistant focal epilepsy, and in the present journal, we recently reviewed seizure outcomes in resective epilepsy surgery. However, not all patients are candidates for or amenable to open surgical resection for epilepsy. Fortunately, several non-resective surgical options are now available at various epilepsy centers, including novel therapies which have been pioneered in recent years. Ablative procedures such as stereotactic laser ablation and stereotactic radiosurgery offer minimally invasive alternatives to open surgery with relatively favorable seizure outcomes, particularly in patients with mesial temporal lobe epilepsy. For certain individuals who are not candidates for ablation or resection, palliative neuromodulation procedures such as vagus nerve stimulation, deep brain stimulation, or responsive neurostimulation may result in a significant decrease in seizure frequency and improved quality of life. Finally, disconnection procedures such as multiple subpial transections and corpus callosotomy continue to play a role in select patients with an eloquent epileptogenic zone or intractable atonic seizures, respectively. Overall, open surgical resection remains the gold standard treatment for drug-resistant epilepsy, although it is significantly under-utilized. While non-resective epilepsy procedures have not replaced the need for resection, there is hope that these additional surgical options will increase the number of patients who receive treatment for this devastating disorder - particularly individuals who are not candidates for or who have failed resection. PMID:27206422

Results of surgical treatment of T4 non-small cell lung cancer

NARCIS (Netherlands)

Pitz, CCM; de la Riviere, AB; van Swieten, HA; Westermann, CJJ; Lammers, JWJ; van den Bosch, JMM

2003-01-01

Objective: Because of location and invasion of surrounding structures, the role of surgical treatment for T4 tumors remains unclear. Extended resections carry a high mortality and should be restricted for selected patients. This study clarifies the selection process in non-small cell T4 tumors with

Approach for oligometastasis in non-small cell lung cancer.

Science.gov (United States)

Suzuki, Hidemi; Yoshino, Ichiro

2016-04-01

Non-small cell lung cancer (NSCLC) harboring a limited number of distant metastases, referred to as the oligometastatic state, has been indicated for surgery for the past several decades. However, whether the strategy of surgical treatment results in a survival benefit for such patients remains controversial. Experientially, however, thoracic surgeons often encounter long-term survivors among surgically resected oligometastatic NSCLC patients. In this article, the current situation of surgical approach and potential future perspective for oligometastatic NSCLC are reviewed.

Decision support systems for incurable non-small cell lung cancer: A systematic review

NARCIS (Netherlands)

Révész, D. (D.); Engelhardt, E.G. (E. G.); Tamminga, J.J. (J. J.); F.M.N.H. Schramel (Franz); B.D. Onwuteaka-Philipsen (Bregje); E.M.W. van de Garde (Ewoudt); E.W. Steyerberg (Ewout); Jansma, E.P. (E. P.); H.C. de Vet (Henrica C); V.M.H. Coupé (Veerle)

2017-01-01

textabstractBackground: Individually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to

Decision support systems for incurable non-small cell lung cancer : a systematic review

NARCIS (Netherlands)

Révész, D; Engelhardt, E G; Tamminga, J J; Schramel, Franz M N H; Onwuteaka-Philipsen, B.D.; van de Garde, E M W; Steyerberg, E.W.; Jansma, E P; de Vet, Henrica C W; Coupé, V.M.H.

2017-01-01

BACKGROUND: Individually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to balance

Non-randomized therapy trial to determine the safety and efficacy of heavy ion radiotherapy in patients with non-resectable osteosarcoma

Directory of Open Access Journals (Sweden)

Bischof Marc

2010-03-01

Full Text Available Abstract Background Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT/heavy ion therapy (HIT may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results. Methods/Design This is a monocenter, single-arm study for patients ≥ 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E with 45 Gy PT (proton therapy and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 × 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial. Discussion The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response

MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

Directory of Open Access Journals (Sweden)

Debin Ma

2015-09-01

Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

SU-E-T-427: Cell Surviving Fractions Derived From Tumor-Volume Variation During Radiotherapy for Non-Small Cell Lung Cancer: Comparison with Predictive Assays

Energy Technology Data Exchange (ETDEWEB)

Chvetsov, A; Schwartz, J; Mayr, N [University of Washington, Seattle, WA (United States); Yartsev, S [London Health Sciences Centre, London, Ontario (Canada)

2014-06-01

Purpose: To show that a distribution of cell surviving fractions S{sub 2} in a heterogeneous group of patients can be derived from tumor-volume variation curves during radiotherapy for non-small cell lung cancer. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage (MV) computed tomography (CT). Statistical distributions of cell surviving fractions S{sup 2} and cell clearance half-lives of lethally damaged cells T1/2 have been reconstructed in each patient group by using a version of the two-level cell population tumor response model and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Non-small cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractions S{sub 2} for non-small cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sup 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Comparison of the reconstructed cell surviving fractions with patient survival data shows that the patient survival time decreases as the cell surviving fraction increases. Conclusion: The data obtained in this work suggests that the cell surviving fractions S{sub 2} can be reconstructed from the tumor volume

SU-E-T-427: Cell Surviving Fractions Derived From Tumor-Volume Variation During Radiotherapy for Non-Small Cell Lung Cancer: Comparison with Predictive Assays

International Nuclear Information System (INIS)

Chvetsov, A; Schwartz, J; Mayr, N; Yartsev, S

2014-01-01

Purpose: To show that a distribution of cell surviving fractions S 2 in a heterogeneous group of patients can be derived from tumor-volume variation curves during radiotherapy for non-small cell lung cancer. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage (MV) computed tomography (CT). Statistical distributions of cell surviving fractions S 2 and cell clearance half-lives of lethally damaged cells T1/2 have been reconstructed in each patient group by using a version of the two-level cell population tumor response model and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Non-small cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractions S 2 for non-small cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S 2 reconstructed from tumor volume variation agree with the PDF measured in vitro. Comparison of the reconstructed cell surviving fractions with patient survival data shows that the patient survival time decreases as the cell surviving fraction increases. Conclusion: The data obtained in this work suggests that the cell surviving fractions S 2 can be reconstructed from the tumor volume variation curves measured

Study on the relationship between serum concentration of CYFRA21-1 and pathological staging in patients with non-small cell lung cancer

International Nuclear Information System (INIS)

Shang Wenjun; Zhou Yaohong; Wang Xiaoli; Wu Yizhi; Li Jun

2010-01-01

Objective: To study the relationship between of serum concentrations of CYFRA21-1 and to pathological staging in patients with non-small cell lung cancer. Methods: Serum concentrations of CYFRA21-1 were determined with IRMA in 224 patients with non-small cell lung cancer. Results: The serum CYFRA21-1 levels in patients with non-small cell lung carcinoma increased gradually as the tumor size enlarged. Levels in patients of T2 and T3 stages were significantly higher than those in patients of T1 stage, but the difference between those in patients of T2 stage and T3 stage were not significant. The serum CYFRA21-1 levels also increased as the number of lymph nodes with metastasis increased. Differences of serum levels of CYFRA21-1 in patients of consecutive lymph node stages were all significant. Conclusion: Preoperative detection of the serum concentration of CYFRA21-1 in patient with non-small cell lung cancer has important clinical significance on the judgement of T, N stages. (authors)

A new in vitro screening system for anticancer drugs for the treatment of non-small cell lung cancer

International Nuclear Information System (INIS)

Hanauske, U.; Hanauske, A.R.; Clark, G.M.; Tsen, D.; Buchok, J.; Hoff, D.D. von

1989-01-01

We have evaluated a semiautomated radiometric assay (BACTEC 460 system) for screening of activity of anticancer drugs against human non-small cell lung cancer cell lines. Cells from seven cell lines were exposed to standard antineoplastic agents at four different concentrations using a 1-h incubation. Alpha 2-interferon was tested using a continuous incubation. In vitro drug activity was analyzed as a function of the clinically achievable serum concentration. Our results indicate that two cell lines (CALU-3, SK-MES-1) exhibit in vitro drug sensitivity patterns closest to those observed in clinical studies. These two cell lines might therefore be most useful for screening new anticancer compounds for activity against non-small cell lung cancer. The radiometric assay is a semiautomated system which has advantages over other, more time-consuming screening systems

Therapeutic effect analysis of three dimensional conformal radiotherapy non-small cell lung cancer

International Nuclear Information System (INIS)

Yao Zhijun; Cao Yongzhen; Zhang Wenxue; Liang Feng

2012-01-01

Objective: To analyse the treatment effect of non-small cell lung cancer of three dimensional conformal radiotherapy (3D-CRT) and to study the effect of patient survival related factors. Methods: Retrospective analysis was mack for 136 cases of non-small cell lung cancer, all accept 3D-CRT, through the case data collection and long-term follow-up, using the single factor and multiple factor analysis survival time and its influencing factors. Results: The recent curative effects of 136 cases of patients with three dimensional conformal radiotherapy: Complete response (CR) 14.7% (20/136), partial response (PR) 60.3 (82/136), stable disease(SD) 19.9% (27/136), progression disease (PD) 5.1% (7/136), total effective rate is 75% (102/136). One, two, three, five year survival rate is 79.4%, 45.4%, 22.1%, 12.5%. Side effects: Class 1 radiated esophagitis 35 cases, Class 2 radiated esophagitis 16 cases, Class 3 and above radiated esophagitis 0 case. Class I radiated pneumonia 20 cases, Class 2 radiated pneumonia 9 cases, Class 3 radiated pneumonia 0 case. Single factor analysis shows the influence of gender, age, pathology, phase, dose, and first-phase curative effect to the survival time are of a statistical significance, Multiple factor analysis showed KPS score, phase, dose, first-phase curative effect are the survival time independent factors. Conclusion: 3D-CRT for patients with non-small cell lung carcinoma is a safe, effective treatment method, Side effects are relatively low, and the patients survival time is long after radiotherapy. (authors)

Radiation therapy alone for early stage non-small cell carcinoma of the lung

International Nuclear Information System (INIS)

Chun, Ha Chung; Lee, Myung Za

2002-01-01

To evaluate the outcome of early stage non-small cell lung cancer patients who were treated with radiation therapy along and define the optimal radiotherapeutic regimen for these patients. A retrospective review was performed on patients with sage I or II non-small cell carcinoma of the lung that were treated at our institution between June, 1987 and May, 2000. A total of 21 patients treated definitively with radiation therapy alone were included in this study. The age of the patients ranged from 53 to 81 years with a median of 66 years. All the patients were male. The medical reasons for inoperability were lack of pulmonary reserve, cardiovascular disease, poor performance status, old age, and patient refusal in the decreasing order. Pathological evidence was not adequate to characterize the non-small cell subtype in two patients. Of the remaining 19 patients, 16 had squamous cell carcinoma and 3 had adenocarcinoma. Treatment was given with conventional fractionation, once a day, five times a week. The doses to the primary site ranged from 56 Gy to 69 Gy. No patients were lost to follow-up. The overall survival rates for the entire group at 2, 3 and 5 years were 41, 30 and 21%, respectively. The cause specific survivals at 2, 3 and 5 years were 55, 36 and 25%, respectively. An intercurrent disease was the cause of death in two patients. The cumulative local failure rate at 5 years was 43%. Nine of the 21 patients had treatment failures after the curative radiotherapy was attempted. Local recurrences as the first site of failure were documented in 7 patients. Therefore, local failure alone represented 78% of the total failures. Those patients whose tumor sizes were less than 4 cm had a significantly better 5 year disease free survival than those with tumors greater than 4 cm (0% vs 36%). Those patients with a Karnofsky performance status less than 70 did not differ significantly with respect to actuarial survival when compared to those with a status greater than 70

Effect of informing the diagnosis on depressive state in patients with non-small cell lung cancer of stage Ⅲ

OpenAIRE

Wei WANG; Ping CHEN; Xianglin PI; Anlan WANG; Xiaoping WEN; Dong HUANG

2008-01-01

Background and objective As other tumors, unresectabe lung cancer can cause many psychological problems to the patients, such as depression and anxiety. The present paper aims to evaluate the status of depression before and after knowing the state of illness in patients with non-small cell lung cancer of stage Ⅲ. Methods 43 casesof newly diagnosed non-small cell lung cancer (NSCLC) with stage Ⅲ were enrolled in the study. All the patients were distributed into three groups and given different...

Non-resectable tumors of head and neck.Opportunities chemoradiotherapy

International Nuclear Information System (INIS)

Cjedakov, Yi.Je.; Semykoz, N.G.; Rogaljev, A.V.; Ostapenko, Yu.V.; Gonchar, O.G.; Bondar, A.V.; Gorovenko, R.Je.

2015-01-01

This article is concerned with the treatment of non-resectable epithelial tumors of the head and neck. It gives a detailed account of the experience of radiation therapy in combination with selective regional chemotherapy administration as a method of combined treatment. According to the study result the complete tumor response was demonstrated in 5.3 % cases, participial tumor response - in 80.4 %, stable disease - in 10.7 %, progression of the tumor process - in 3.6 %. The reported adheres events and their treatment details are described for all severity as per NCI-CTCAE. The performed analysis suggests the preliminary study treatment results and the advantages of the selected scheme

Indications and interventional options for non-resectable tracheal stenosis

Science.gov (United States)

Bacon, Jenny Louise; Patterson, Caroline Marie

2014-01-01

Non-specific presentation and normal examination findings in early disease often result in tracheal obstruction being overlooked as a diagnosis until patients present acutely. Once diagnosed, surgical options should be considered, but often patient co-morbidity necessitates other interventional options. Non-resectable tracheal stenosis can be successfully managed by interventional bronchoscopy, with therapeutic options including airway dilatation, local tissue destruction and airway stenting. There are common aspects to the management of tracheal obstruction, tracheomalacia and tracheal fistulae. This paper reviews the pathogenesis, presentation, investigation and management of tracheal disease, with a focus on tracheal obstruction and the role of endotracheal intervention in management. PMID:24624290

Exosomal proteins as prognostic biomarkers in non-small cell lung cancer

DEFF Research Database (Denmark)

Sandfeld-Paulsen, B; Aggerholm-Pedersen, N; Bæk, R

2016-01-01

BACKGROUND: Use of exosomes as biomarkers in non-small cell lung cancer (NSCLC) is an intriguing approach in the liquid-biopsy era. Exosomes are nano-sized vesicles with membrane-bound proteins that reflect their originating cell. Prognostic biomarkers are needed to improve patient selection...... Bonferroni correction. Results were adjusted for clinico-pathological characteristics, stage, histology, age, sex and performance status. CONCLUSION: We illustrate the promising aspects associated with the use of exosomal membrane-bound proteins as a biomarker and demonstrate that they are a strong...

Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data

Energy Technology Data Exchange (ETDEWEB)

Chvetsov, Alexei V., E-mail: chvetsov2@gmail.com; Schwartz, Jeffrey L.; Mayr, Nina [Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195-6043 (United States); Yartsev, Slav [London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, Ontario 46A 4L6 (Canada)

2014-06-15

Purpose: In our previous work, the authors showed that a distribution of cell surviving fractionsS{sub 2} in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractionsS{sub 2} and clearance half-lives of lethally damaged cells T{sub 1/2} have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractionsS{sub 2} for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sub 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Conclusions: The data obtained

TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/?-catenin signaling

OpenAIRE

Peng, Yun; Cao, Jun; Yao, Xiao-Yi; Wang, Jian-Xin; Zhong, Mei-Zuo; Gan, Ping-Ping; Li, Jian-Huang

2017-01-01

We investigated the effects of tumor suppressor candidate 3 (TUSC3) on autophagy in human non-small cell lung cancer (NSCLC) cells. A total of 118 NSCLC patients (88 males and 30 females) who underwent surgery at our institute were enrolled in the study. Immunohistochemical analysis revealed that TUSC3 protein expression was lower in NSCLC specimens than adjacent normal tissue. Correspondingly, there was greater methylation of TUSC3 in NSCLC than adjacent normal tissue. After transient transf...

[Mechanism and Prospect of Radiotherapy Combined with Apotatinib
in the Treatment of Non-small Cell Lung Cancer].

Science.gov (United States)

Liu, Guohui; Wang, Chunbo; E, Mingyan

2017-12-20

Non-small cell lung cancer is one of the most commom malignant tumor being harmful to people's life and health. Most of the patients have developed to the last stage which not suitable for surgical indications, so radiation and chemotherapy is the main treatment strategy. In recent years, with the theory of anti-angiogenesis therapy for malignant tumors, apatinib as a promising novel medicine to treat malignant tumors, represents synergistic antitumor effects in combination with radiotherapy. The underlying mechanisms may include make blood vessel normalization, alleviating inner hypoxia, and angiogenic factors regulation. Apatinib in combination with radiotherapy may become a new and effective treatment strategy of non-small cell lung cancer.

Radio(chemotherapy in locally advanced nonsmall cell lung cancer

Directory of Open Access Journals (Sweden)

Markus Glatzer

2016-03-01

Full Text Available Definitive radiochemotherapy is the standard treatment for many patients with locally advanced nonsmall cell lung cancer (NSCLC. Treatment outcomes have improved over the last decades. Several treatment regimens have been shown effective and safe. This review summarises the results of significant studies between 1996 and 2015 on concomitant and sequential radiochemotherapy regimens and radiation dose per fraction. Beside therapy regimens, optimised radiotherapy planning is indispensable to improve outcome and minimise radiation-induced toxicity. An insight into the rationale of radiotherapy planning for stage III NSCLC is also provided.

Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro.

Science.gov (United States)

Li, Yali; Yang, Fangfang; Zheng, Weidong; Hu, Mingxing; Wang, Juanxiu; Ma, Sisi; Deng, Yuanle; Luo, Yi; Ye, Tinghong; Yin, Wenya

2016-05-01

Most conventional treatments on non-small cell lung carcinoma always accompany with awful side effects, and the incidence and mortality rates of this cancer are increasing rapidly worldwide. The objective of this study was to examine the anticancer effects of extract of Punica granatum (pomegranate) leaves extract (PLE) on the non-small cell lung carcinoma cell line A549, H1299 and mouse Lewis lung carcinoma cell line LL/2 in vitro, and explore its mechanisms of action. Our results have shown that PLE inhibited cell proliferation in non-small cell lung carcinoma cell line in a concentration- and time-dependent manner. Flow cytometry (FCM) assay showed that PLE affected H1299 cell survival by arresting cell cycle progression in G2/M phase in a dose-dependent manner and inducing apoptosis. Moreover, PLE could also decrease the reactive oxygen species (ROS) and the mitochondrial membrane potential (ΔYm), indicating that PLE may induce apoptosis via mitochondria-mediated apoptotic pathway. Furthermore, PLE blocked H1299 cell migration and invasion, and the reduction of matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed in vitro. These results suggested that PLE could be an effective and safe chemotherapeutic agent in non-small cell lung carcinoma treatment by inhibiting proliferation, inducing apoptosis, cell cycle arrest and impairing cell migration and invasion. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The Impact of Smoking Status on the Efficacy of Erlotinib in Patients with Advanced Non-small Cell Lung Cancer

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Yilong WU

2009-12-01

Full Text Available Background and objective Erlotinib is a targeted treatment for advanced non-small cell lung cancer. Smoking status may be one of influencing factors of the efficacy of erlotinib. The aim of this study is to explore the impact of smoking status on the efficacy of erlotinib in patients with advanced non-small cell lung cancer. Methods Patients with nonsmall cell lung cancer who had been previously treated with at least one course of platinum based chemotherapy received 150 mg oral doses of erlotinib once daily until disease progression. Response rate, progression-free survival, overall survival were analyzed in the different smoking status groups. Kaplan-Meier method was used to analyze the survival rate. Results Fortyeight patients were enrolled into the study from December 2005 to September 2006. We followed up these patients until 28th December, 2008. Median follow up time was 30 months. The compliance rate was 100%. The response rate was 32.1% in the smoking group and 35% in the never smoking group (P=0.836; The median progression-free survival was 3 months and 9 months, respectively (P=0.033. The median overall survival was 5 months and 17 months, respectively (P=0.162. Conclusion Erlotinib is an effective drug for advanced non-small cell lung cancer patients with different smoking status. Progressionfree survival is better in the never smoking patients than the smoking patients.

Clinical potential of necitumumab in non-small cell lung carcinoma

Directory of Open Access Journals (Sweden)

Genova C

2016-08-01

Full Text Available Carlo Genova,1–3 Fred R Hirsch1 1Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO, USA; 2Lung Cancer Unit, IRCCS AOU San Martino IST, 3Department of Internal Medicine, School of Medicine, University of Genoa, Genoa, Italy Abstract: Despite significant progress, new therapeutic approaches for advanced non-small cell lung cancer (NSCLC are highly needed, particularly for the treatment of patients with squamous cell carcinoma. The epidermal growth factor receptor (EGFR is often overexpressed in NSCLC and represents a relevant target for specific treatments. Although EGFR mutations are more frequent in non-squamous histology, the receptor itself is more often overexpressed in squamous NSCLC. Necitumumab is a human monoclonal antibody that is able to inhibit the EGFR pathway and cause antibody-dependent cell cytotoxicity. This drug has been studied in combination with first-line chemotherapy for advanced NSCLC in two Phase III trials, and a significant survival benefit was reported in squamous NSCLC (SQUIRE trial; by contrast, necitumumab did not prove itself beneficial in non-squamous histotype (INSPIRE trial. On the basis of the SQUIRE results, necitumumab was approved in combination with cisplatin and gemcitabine as a first-line treatment for advanced squamous NSCLC, both in the US and Europe, where its availability is limited to patients with EGFR-expressing tumors. The aim of this review is to describe the tolerability and the efficacy of necitumumab by searching the available published data and define its potential role in the current landscape of NSCLC treatment. Keywords: necitumumab, EGFR, non-small cell lung cancer, monoclonal antibody, H-score

TP53 Mutations in Nonsmall Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Akira Mogi

2011-01-01

Full Text Available The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC and nonsmall cell lung cancer (NSCLC. The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

Epigenetic Modulation with HDAC Inhibitor CG200745 Induces Anti-Proliferation in Non-Small Cell Lung Cancer Cells

OpenAIRE

Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin

2015-01-01

Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of his...

Comparison between local ablative therapy and chemotherapy for non-resectable colorectal liver metastases: a prospective study

NARCIS (Netherlands)

Ruers, Theo J. M.; Joosten, Joris J.; Wiering, Bastiaan; Langenhoff, Barbara S.; Dekker, Heleen M.; Wobbes, Theo; Oyen, Wim J. G.; Krabbe, Paul F. M.; Punt, Cornelis J. A.

2007-01-01

There is a growing interest for the use of local ablative techniques in patients with non-resectable colorectal liver metastases. Evidence on the efficacy over systemic chemotherapy is, however, extremely weak. In this prospective study we aim to assess the additional benefits of local tumour

Comparison between local ablative therapy and chemotherapy for non-resectable colorectal liver metastases: a prospective study.

NARCIS (Netherlands)

Ruers, T.J.M.; Joosten, J.J.; Wiering, B.; Langenhoff, B.S.; Dekker, H.M.; Wobbes, Th.; Oyen, W.J.G.; Krabbe, P.F.M.; Punt, C.J.A.

2007-01-01

BACKGROUND: There is a growing interest for the use of local ablative techniques in patients with non-resectable colorectal liver metastases. Evidence on the efficacy over systemic chemotherapy is, however, extremely weak. In this prospective study we aim to assess the additional benefits of local

Clinical impact of ki-67 labeling index in non-small cell lung cancer

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Sørensen, Jens Benn

2013-01-01

The ki-67 index is a marker of proliferation in malignant tumors. Studies from the period 2000 to 2012 on the prognostic and predictive value of ki-67 labeling index (LI) in non-small cell cancer (NSCLC) are reviewed. Twenty-eight studies reported on the prognostic value of ki-67 index with various...

The 'grey area' between small cell and non-small cell lung carcinomas. Light and electron microscopy versus clinical data in 14 cases

NARCIS (Netherlands)

Mooi, W. J.; van Zandwijk, N.; Dingemans, K. P.; Koolen, M. G.; Wagenvoort, C. A.

1986-01-01

We studied 14 lung tumours which on light microscopy had posed difficulties on classification as either small cell or non-small cell carcinomas. The light and electron microscopical features were compared with patient follow-up data. Electron microscopy showed neuroendocrine granules in 12 cases,

[Construction of 2-dimensional tumor microvascular architecture phenotype in non-small cell lung cancer].

Science.gov (United States)

Liu, Jin-kang; Wang, Xiao-yi; Xiong, Zeng; Zhou, Hui; Zhou, Jian-hua; Fu, Chun-yan; Li, Bo

2008-08-01

To construct a technological platform of 2-dimensional tumor microvascular architecture phenotype (2D-TAMP) expression. Thirty samples of non-small cell lung cancer (NSCLC) were collected after surgery. The corresponding sections of tumor tissue specimens to the slice of CT perfusion imaging were selected. Immunohistochemical staining,Gomori methenamine silver stain, and electron microscope observation were performed to build a technological platform of 2D-TMAP expression by detecting the morphology and the integrity of basement membrane of microvasculature, microvascular density, various microvascular subtype, the degree of the maturity and lumenization of microvasculature, and the characteristics of immunogenetics of microvasculature. The technological platform of 2D-TMAP expression was constructed successfully. There was heterogeneity in 2D-TMAP expression of non-small cell lung cancer. The microvascular of NSCLC had certain characteristics. 2D-TMAP is a key technology that can be used to observe the overall state of micro-environment in tumor growth.

Radiotherapy alone for elderly patients with stage III non-small cell lung cancer

International Nuclear Information System (INIS)

Nakano, Kikuo; Hiramoto, Takehiko; Kanehara, Masasi; Doi, Mihoko; Furonaka, Osamu; Miyazu, Yuka; Hada, Yosihiro

1999-01-01

We undertook a retrospective study of elderly patients with stage III non-small cell lung cancer who had been treated solely with radiotherapy during the period 1986 to 1995. Our study was designed to assess the influence of age on survival and malnutrition in patients aged 75 years or older (elderly group) and patients aged 74 years or younger (younger group). Radiotherapy alone resulted in a median survival period of 11.5 months in the younger group and 6.3 months in the elderly group (p=0.0043). With the Cox multivariate model, good performance status, age less than 75 years, and good response were significant favorable independent predictors. Furthermore, the elderly group patients more frequently died of respiratory infections and had lower prognostic nutritional indexes than the younger group patients before and after radiotherapy. These findings suggested elderly patients with stage III non-small cell lung cancer who had been treated with radiotherapy alone had a poor prognosis and that malnutrition caused by radiotherapy was a factor contributing to the risk of death from respiratory infection in such patients. (author)

[Construction of lentiviral mediated CyPA siRNA and its functions in non-small cell lung cancer].

Science.gov (United States)

FENG, Yan-ming; WU, Yi-ming; TU, Xin-ming; XU, Zheng-shun; WU, Wei-dong

2010-02-01

To construct a lentiviral-vector-mediated CyPA small interference RNA (siRNA) and study its function in non-small cell lung cancer. First, four target sequences were selected according to CyPA mRNA sequence, the complementary DNA contained both sense and antisense oligonucleotides were designed, synthesized and cloned into the pGCL-GFP vector, which contained U6 promoter and green fluorescent protein (GFP). The resulting lentiviral vector containing CyPA shRNA was named Lv-shCyPA, and it was confirmed by PCR and sequencing. Next, it was cotransfected by Lipofectamine 2000 along with pHelper1.0 and pHelper 2.0 into 293T cells to package lentivirus particles. At the same time, the packed virus infected non-small cell lung cancer cell (A549), the level of CyPA protein at 5 d after infection was detected by Western Blot to screen the target of CyPA. A549 were infected with Lv-shCyPA and grown as xenografts in severe combined immunodeficient mice. Cell cycle and apoptosis were measured by FCM. It was confirmed by PCR and DNA sequencing that lentiviral-vector-mediated CyPA siRNA (Lv-shCyPA) producing CyPA shRNA was constructed successfully. The titer of concentrated virus were 1 x 10(7) TU/ml. Flow cytometric analysis demonstrated G2-M phase (11.40% +/- 0.68%) was decreased relatively in A549/LvshCyPA compared with control groups (14.52% +/- 1.19%) (Ppathways may lead to new targeted therapies for non-small cell lung cancer.

Changes in epidermal growth factor receptor expression during chemotherapy in non-small cell lung cancer

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

2014-01-01

BACKGROUND: Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors, and small biopsies may thus...

Assesment of prognostic factors in radical radiotherapy for patients with non-small cell lung cancer

International Nuclear Information System (INIS)

Chmielewska, E.

2000-01-01

Lung cancer is still the most severe problem of oncology throughout the word. In Poland there are some 20 000 new cases per annum, among them non-small cell lung cancer accounts for about 16 000 cases. The basic method of therapy of non-small cell lung cancers is surgery; however, in Polish conditions only about 15% of patients qualify for it. Therefore, there remains a large group of patients who are potential candidates for radiotherapy. Evaluation of a group of patients qualified for radical radiotherapy according to uniform rules, treated with the same protocol and assesed by the same group of physicians. The obtained results of therapy allow to evaluate the usefulness of radical radiotherapy in patients with non-operable non-small cell lung cancer and serve as a basis of search for more effective radiotherapy protocols. The aim of the study is to attempt to define the prognostic, therapeutical, clinical-and population-related factors for survival and local control in patients with non-operable, non-small cell lung cancer. Between January 1, 1990, and December 31, 1995, there were 2330 patients with non-small cell lung in the Ambulatory of the Cancer Centre in Warsaw. Basing on the results of clinical examination and additional examination, 260 patients qualified for radical radiotherapy. In this group there were 31 women (12%) and 229 men (88%). In a majority of cases the stage of the disease was advanced: stage IIIA was found in 114 patients (44%), and stage IIIB in 73 patients (28%). Retrospective analysis of the results of treatment was carried out. The material covered 260 patients. The survival time and the time to local progression were the basis for the analysis. The survival probability was calculated whit the Kaplan-Meier method. Multidimensional analysis of the prognostic factors (age, clinical advancement of the disease, performance status, loss of weight, LDH and haemoglobin level, tumour size, pulmonary function, prior exploratory thoracotomy

MicroRNA-429 induces tumorigenesis of human non-small cell lung cancer cells and targets multiple tumor suppressor genes

Energy Technology Data Exchange (ETDEWEB)

Lang, Yaoguo; Xu, Shidong; Ma, Jianqun; Wu, Jun [Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Jin, Shi; Cao, Shoubo [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Yu, Yan, E-mail: yuyan@hrbmu.edu.cn [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China)

2014-07-18

Highlights: • MiR-429 expression is upregulated in non-small cell lung cancer (NSCLC). • MiR-429 inhibits PTEN, RASSF8 and TIMP2 expression. • MiR-429 promotes metastasis and proliferation. • We report important regulatory mechanisms involved in NSCLC progression. • MiR-429 is a potential therapeutic target and diagnostic marker. - Abstract: Lung cancer is the major cause of cancer death globally. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression. Aberrant expression of microRNA (miRNA) has been implicated in cancer initiation and progression. In this study, we demonstrated that the expression of miR-429 are often upregulated in non-small cell lung cancer (NSCLC) compared with normal lung tissues, and its expression level is also increased in NSCLC cell lines compared with normal lung cells. Overexpression of miR-429 in A549 NSCLC cells significantly promoted cell proliferation, migration and invasion, whereas inhibition of miR-429 inhibits these effects. Furthermore, we demonstrated that miR-429 down-regulates PTEN, RASSF8 and TIMP2 expression by directly targeting the 3′-untranslated region of these target genes. Taken together, our results suggest that miR-429 plays an important role in promoting the proliferation and metastasis of NSCLC cells and is a potential target for NSCLC therapy.

The CXCR4/SDF-1 chemokine receptor axis: a new target therapeutic for non-small cell lung cancer.

Science.gov (United States)

Otsuka, Shannon; Bebb, Gwyn

2008-12-01

Chemokines are proinflammatory chemoattractant cytokines that regulate cell trafficking and adhesion. The CXCR4 chemokine receptor and its ligand, stromal cell derived factor (SDF-1), constitute a chemokine/receptor axis that has attracted great interest because of an increasing understanding of its role in cancer, including lung cancer. The CXCR4/SDF-1 complex activates several pathways that mediate chemotaxis, migration and secretion of angiopoietic factors. Neutralization of SDF-1 by anti-SDF-1 or anti-CXCR4 monoclonal antibody in preclinical in vivo studies results in a significant decrease of non-small cell lung cancer metastases. Since anti-SDF-1/CXCR4 strategies have already been developed for use in combating human immunodeficiency virus infections, it is likely that these approaches will be used in clinical trials in non-small cell lung cancer in the very near future.

Synchronous Oligometastatic Non-Small Cell Lung Cancer and Isolated Renal Cell Carcinoma: A Case Report and Literature Review.

Science.gov (United States)

Nguyen, Timothy K; Louie, Alexander V

2015-10-27

A 58-year-old gentleman presenting with a progressive headache, visual disturbance, decreased appetite, and weight loss was found to have a localized clear cell carcinoma of the kidney and synchronous Stage IV non-small cell lung cancer with a solitary brain metastasis. This case illustrates the challenges in distinguishing between primary and metastatic disease in a patient with both renal cell carcinoma and lung cancer. We highlight the uncertainties in the diagnosis and management of this unique clinical scenario and the potential implications on prognosis.

Intratumor heterogeneity and chemotherapy-induced changes in EGFR status in non-small cell lung cancer

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Sørensen, Jens Benn

2012-01-01

Biomarker expression is increasingly being used to customize treatment in non-small cell lung cancer (NSCLC). The choice of systemic treatment usually depends on biomarker expression in the initial diagnostic biopsy taken before initiation of first-line treatment. Chemotherapy induces DNA damages...

PD-L1 expression in non-small cell lung cancer : Correlations with genetic alterations

NARCIS (Netherlands)

Scheel, Andreas H.; Ansen, Sascha; Schultheis, Anne M.; Scheffler, Matthias; Fischer, Rieke N.; Michels, Sebastian; Hellmich, Martin; George, Julie; Zander, Thomas; Brockmann, Michael; Stoelben, Erich; Groen, Harry; Timens, Wim; Perner, Sven; von Bergwelt-Baildon, Michael; Buettner, Reinhard; Wolf, Juergen

2016-01-01

Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and

Sampling versus systematic full lymphatic dissection in surgical treatment of non-small cell lung cancer.

Science.gov (United States)

Koulaxouzidis, Georgios; Karagkiouzis, Grigorios; Konstantinou, Marios; Gkiozos, Ioannis; Syrigos, Konstantinos

2013-04-22

The extent of mediastinal lymph node assessment during surgery for non-small cell cancer remains controversial. Different techniques are used, ranging from simple visual inspection of the unopened mediastinum to an extended bilateral lymph node dissection. Furthermore, different terms are used to define these techniques. Sampling is the removal of one or more lymph nodes under the guidance of pre-operative findings. Systematic (full) nodal dissection is the removal of all mediastinal tissue containing the lymph nodes systematically within anatomical landmarks. A Medline search was conducted to identify articles in the English language that addressed the role of mediastinal lymph node resection in the treatment of non-small cell lung cancer. Opinions as to the reasons for favoring full lymphatic dissection include complete resection, improved nodal staging and better local control due to resection of undetected micrometastasis. Arguments against routine full lymphatic dissection are increased morbidity, increase in operative time, and lack of evidence of improved survival. For complete resection of non-small cell lung cancer, many authors recommend a systematic nodal dissection as the standard approach during surgery, and suggest that this provides both adequate nodal staging and guarantees complete resection. Whether extending the lymph node dissection influences survival or recurrence rate is still not known. There are valid arguments in favor in terms not only of an improved local control but also of an improved long-term survival. However, the impact of lymph node dissection on long-term survival should be further assessed by large-scale multicenter randomized trials.

Treatment of non-resectable malignant iris tumours with custom designed plaque radiotherapy

International Nuclear Information System (INIS)

Shields, C.L.; Shields, J.A.; Potter, P. De; Singh, A.D.; Hernandez, C.; Brady, L.W.

1995-01-01

Background- Plaque radiotherapy is the most common method of managing posterior uveal melanoma but its use for iris melanoma and iris metastases has not yet been evaluated. Methods -Fourteen patients with non-resectable iris melanoma and four with iris metastasis were treated with plaque radiotherapy. The tumour response to treatment and the local side effects of the radioactive plaque were evaluated. Results -In the iris melanoma group over a mean follow up of 26 (range 6-75) months, the tumour regressed in 13 of the 14 patients (93%) and recurred as diffuse seeding in one patient (7%). Despite large doses of radiation given transcorneally, the cornea developed epitheliopathy, abraxion, and oedema in only one case each. The major radiation side effects were localised iris vasculopathy without glaucoma in two cases, posterior synechiae in five cases, and cataract in six cases. In the iris metastasis group, tumour regression was observed in all four patients (100%) and radiation side effects were not evident over the relatively short mean follow up period of 8 (range 4-9) months. All of the 14 patients with irradiated iris melanoma have remained systemically healthy without metastasis while three of the four patients with irradiated iris metastases have died of metastases from the primary neoplasm. Conclusion - Custom designed plaque radiotherapy appears to be an effective alternative method of controlling non-resectable diffuse iris melanoma and solitary iris metastasis and has relatively few side effects. (author)

[Role of PET/CT in primitive non-small cell bronchopulmonary cancer].

Science.gov (United States)

Soumia, Fdil; Leila, Achachi; Mohamed, Raoufi; Laila, Herrak; Mustapha, Elftouh

2017-01-01

Bronchopulmonary cancer is a real public health problem. Morphological imaging plays a central role in its diagnosis, staging as well as post-therapeutic assessment but it has some limitations. Metabolic imaging is a more recent technique which allows to significantly improve the overall imagery performance. We conducted a retrospective, descriptive and analytical study at the Ibn Sina Hospital and at the Military Hospital of instruction Mohammed V in Rabat over a period of 18 months, between September 2014 and February 2016, in order to evaluate the role of Fluorodeoxyglucose-PET/CT in the staging and restaging of non-small cell bronchopulmonary cancer. Initial staging showed a vast majority of locally advanced and metastatic stages: stage IV (40%), Stage IIIB (36%), Stage IIIA (16%), Stage II (8%). PET-CT allowed to detect new sites which were not initially seen on CT scan in 24 cases: 15 new ganglion sites, 8 new adrenal sites and 6 sites of bone lesions. PET/CT allowed to modify initial tumor stage in 60% of cases: upstaging in 23 patients (46%) and downstaging in 7 patients(14%). The initial stage remained unchanged in 40% of patients. Our study confirms the data from the literature concerning the superiority of PET-CT in comparison with CT scan, but only in the optimization of the non-small cell bronchopulmonary cancer management, in particular in locoregional and distant staging.

Oligometastatic disease at presentation or recurrence for nonsmall cell lung cancer.

Science.gov (United States)

Gomez, Daniel R; Niibe, Yuzuru; Chang, Joe Y

2012-01-01

Oligometastatic Non-Small Cell Lung Cancer (NSCLC) presents a unique opportunity for potential curative therapy. Improved cancer staging using PET/CT, MRI, and future cellular and molecular staging with circulating tumor cells and/or molecular markers will identify more patients with truly oligometastasis disease that will benefit from definitive local treatment. Recent development of noninvasive local ablative therapy such as stereotactic radiotherapy makes it possible to eradicate multiple local diseases with minimal side effect. Novel systemic therapy may also control systemic spread and therefore make it possible to improve survival by eliminating local diseases. More research, particularly prospective studies, is ideally randomized studies are needed to validate the concept of oligometastasis.

Dithiolethione modified valproate and diclofenac increase E-cadherin expression and decrease proliferation of non-small cell lung cancer cells

OpenAIRE

Moody, Terry W.; Switzer, Christopher; Santana-Flores, Wilmarie; Ridnour, Lisa A.; Berna, Marc; Thill, Michelle; Jensen, Robert T.; Sparatore, Anna; Del Soldato, Piero; Yeh, Grace C; Roberts, David D.; Giaccone, Giuseppe; Wink, David A.

2009-01-01

The effects of dithiolethione-modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 μg/ml concentrations significantly reduced prostaglandin (PG)E2 levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 μg/ml, respectively. Using the MTT assay, 10...

Long-Term Excess Mortality for Survivors of Non-small Cell Lung Cancer in the Netherlands

NARCIS (Netherlands)

Janssen-Heijnen, Maryska L.; van Steenbergen, Liza N.; Steyerberg, Ewout; Visser, Otto; De Ruysscher, Dirk K.; Groen, Harry J.

Introduction: Most patients diagnosed with non-small cell lung cancer (NSCLC) die within the first few years after diagnosis. However, only little is known about those who have survived these first years. We aimed to study conditional 5-year relative survival rates for NSCLC patients during

Postoperative Radiation Therapy in Resected N2 Stage Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Lee, Chang Geol

1993-01-01

A total of forty patients with resected N2 stage non-small cell lung cancer treated with postoperative adjuvant radiation therapy between Jan. 1975 and Dec. 1990 at the Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei Cancer Center were retrospectively analysed to evaluate whether postoperative radiation therapy improves survival. Patterns of failure and prognostic factors affecting survival were also analysed. The 5 year overall and disease free survival rate were 26.3%, 27.3% and median survival 23.5 months. The 5 year survival rates by T-stage were T1 66.7%, T2 25.6% and T3 12.5%. Loco-regional failure rate was 14.3% and distant metastasis rate was 42.9% and both 2.9%. Statistically significant factor affecting distant failure rate was number of positive lymph nodes(>= 4). This retrospective study suggests that postoperative radiation therapy in resected N2 stage non-small cell lung cancer can reduce loco-regional recurrence and may improve survival rate as compared with other studies which were treated by surgery alone. Further study of systemic control is also needed due to high rate of distant metastasis

EGFR targeted therapy in non-small cell lung cancer: potential role of cetuximab

Directory of Open Access Journals (Sweden)

Chad A Reade

2009-05-01

Full Text Available Chad A Reade1, Apar Kishor Ganti1,21Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 2Section of Oncology-Hematology, Department of internal Medicine, VA Medical Center, Omaha, NE, USAAbstract: Chemotherapy alone has limited ability to significantly improve survival in non-small lung cancer (NSCLC beyond what has already been achieved. The epidermal growth factor (EGF pathway plays a vital role in the pathogenesis and progression of NSCLC. Two classes of drugs inhibit the EGF receptor (EGFR pathway: small molecules that inhibit the intracellular tyrosine kinase activity of the receptor, and monoclonal antibodies that target the extracellular domain in the ligand-binding region. Cetuximab is a human – mouse chimeric immunoglobulin G1 class monoclonal antibody directed against EGFR. Preclinical studies with cetuximab suggested that there was inhibition of growth of human NSCLC cell lines. Cetuximab is currently the focus of intense investigation in various patient populations with NSCLC. This review focuses on clinical trials of cetuximab in NSCLC and identifies future directions with this agent.Keywords: non-small cell lung cancer, EGFR, cetuximab, monoclonal antibodies

Hyperfractionated Radiotherapy with Concomitant Boost Technique for Unresectable Non-Small Cell Carcinoma of the Lung

International Nuclear Information System (INIS)

Chun, Ha Chung; Lee, Myung Za

1991-01-01

Twenty five patients with unresectable non-small cell carcinoma of the lung have been treated with hyperfractionated radiotherapy with concomitant boost technique since September, 1989. Those patients with history of previous surgery or chemotherapy, pleural effusion or significant weight loss (greater than 10% of body weight) were excluded from the study. Initially, 27 Gy were delivered in 15 fractions in 3 weeks to the large field. Thereafter, large field received 1.8 Gy and cone down boost field received 1.4Gy with twice a day fractinations up to 49.4Gy. After 49.4Gy, only boost field was treated twice a day with 1.8 and 1.4 Gy. Total tumor doses were 62.2Gy for 12 patients and 65.4Gy for remaining 13 patients. Follow up period was ranged from 6 to 24 month. Actuarial survival rates at 6, 12, and 18 month were 88%, 62%, and 38%, respectively. Corresponding disease free survival rates were 88%, 41%, and 21%, respectively. Actuarial cumulative local failure rates at 9,12 and 15 month were 36%, 42%, and 59%, respectively. No significant increase of acute or late complications including radiation pneumonitis was noted with maximum follow up of 24 month. Although the longer follow up is needed, it is worthwhile to try the prospective randomized study to evaluate the efficacy of hyperfractionated radiotherapy with concomitant boost technique for unresectable non-small cell lung cancers in view of excellent tolerance of this treatment. In the future, further increase of total radiation dose might be necessary to improve local control for non-small cell lung cancer

Prognostic significance of tissue polypeptidespecific antigen (TPS) in patients with advanced non-small cell lung cancer

NARCIS (Netherlands)

A. van der Gaast (Ate); C.H.H. Schoenmakers (Christian); T.C. Kok (Tjebbe); B.G. Blijenberg (Bert); W.C.J. Hop (Wim); T.A.W. Splinter (Ted)

1994-01-01

textabstractIn this study, we evaluated the prognostic value of the tumour marker, tissue polypeptide-specific antigen (TPS), in 203 patients with non-small cell lung cancer (NSCLC), and related this to several other known prognostic factors. TPS was significantly correlated with lactate

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro.

Science.gov (United States)

Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

2018-04-01

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

Clinical study on bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Li-Ping Yang1

2017-06-01

Full Text Available Objective: To investigate the effect of bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer on tumor markers, angiogenesis molecules and invasive growth molecules. Methods: A total of 68 patients who were diagnosed with non-small cell lung cancer complicated by pleural effusion in the Affiliated T.C.M Hospital of Southwest Medical University between June 2013 and August 2016 were selected and randomly divided into two groups, the combined group received bevacizumab combined with carboplatin chemotherapy, and the carboplatin group received carboplatin chemotherapy. Before treatment as well as 3 cycles and 6 cycles after treatment, the contents of tumor markers, angiogenesis molecules and invasive growth molecules in pleural effusion were examined. Results: 3 cycles and 6 cycles after treatment, CEA, SCCAg, CYFRA21-1, sHLA-G, VEGF, VEGFR, PTN, MMP7 and MMP10 contents in pleural effusion of both groups of patients were significantly lower than those before treatment while TIMP1 and TIMP2 contents were significantly higher than those before treatment, and CEA, SCCAg, CYFRA21-1, sHLA-G, VEGF, VEGFR, PTN, MMP7 and MMP10 contents in pleural effusion of combined group were significantly lower than those of carboplatin group while TIMP1 and TIMP2 contents were significantly higher than those of carboplatin group. Conclusion: Bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer can effectively kill cancer cells, and inhibit angiogenesis and cell invasion.

Oligometastatic Disease at Presentation or Recurrence for Nonsmall Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Daniel R. Gomez

2012-01-01

Full Text Available Oligometastatic Non-Small Cell Lung Cancer (NSCLC presents a unique opportunity for potential curative therapy. Improved cancer staging using PET/CT, MRI, and future cellular and molecular staging with circulating tumor cells and/or molecular markers will identify more patients with truly oligometastasis disease that will benefit from definitive local treatment. Recent development of noninvasive local ablative therapy such as stereotactic radiotherapy makes it possible to eradicate multiple local diseases with minimal side effect. Novel systemic therapy may also control systemic spread and therefore make it possible to improve survival by eliminating local diseases. More research, particularly prospective studies, is ideally randomized studies are needed to validate the concept of oligometastasis.

Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop

DEFF Research Database (Denmark)

Pirker, Robert; Herth, Felix J F; Kerr, Keith M

2010-01-01

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyros...

High frequency of p 16 promoter methylation in non-small cell lung carcinomas from Chile

Directory of Open Access Journals (Sweden)

LEDA M GUZMAN

2007-01-01

Full Text Available The inactivation of tumour suppressor genes by aberrant methylation of promoter regions has been described as a frequent event in neoplasia development, including lung cancer. The p16 gene is a tumour suppressor gene involved in the regulation of cell cycle progression that has been reported to be inactivated by promoter methylation in lung carcinomas at variable frequencies around the world in a smoking habit dependent manner. The purpose of this study was to investigate the methylation status of the promoter region of the p16 gene in 74 non-small cell lung carcinomas from Chile. The frequency of p16 gene inactivation by promoter methylation was determined as 79.7% (59/74. When we considered histological type, we observed that p16 promoter methylation was significantly higher in squamous cell carcinomas (30/33, 91% compared with adenocarcinomas (21/30, 70% (p=0.029. In addition, no association between p16 promoter methylation and gender, age or smoking habit was found (p=0.202, 0.202 and 0.147 respectively. Our results suggest that p16 promoter hypermethylation is a very frequent event in non-small cell lung carcinomas from Chile and could be smoking habit-independent

Concurrent chemo-radiotherapy for stage III non-small cell lung cancer

Energy Technology Data Exchange (ETDEWEB)

Inoue, Ryuji; Takada, Yoshiki; Obayashi, Kayoko; Kado, Tetsuji; Yamamoto, Hiroyuki; Hirota, Saeko; Soejima, Toshinori; Suzuki, Yasushi; Mimura, Fumitoshi [Hyogo Medical Center for Adult Disease, Akashi (Japan)

1994-12-01

In patients with unresectable stage III non-small cell lung cancer, we performed chemotherapy and concurrent thoracic radiotherapy. Thirty-five registered patients were intravenously treated with cisplatin (80mg/m{sup 2}) on day 1 and vindesine (3mg/m{sup 2}) on days 1, 3 and were irradiated from days 1 to 10 with single doses of 2.5 Gy up to a total dosage of 20 Gy. Each course lasted 28 days. Patients received 3 courses, and a total dosage of 60 Gy was delivered. Response to this treatment was evaluable in terms of results in 35 patients. Twenty-two patients showed partial response (response rate 62.9%), 10 had no change, and 3 cases had progressive disease. In 7.5 to 37.8 months observation, three PR patients are alive for more than 24 months without recurrence, but eight PR patients died of local relapse, and the median survival time was 15.7 months. Throughout this treatment course, grade 4 leukopenia was noted in 66% and grade 3 thrombocytopenia was observed in 3%. However all were reversible condition and no treatment-related death was observed. However, two cases died due to complications of pulmonary abscess, which occurred in the area of radiation pulmonary fibrosis about one year later after treatment. Although this concurrent chemo-radiotherapy is a tolerable treatment for non-small cell lung cancer and obtained a good response rate, it did not improve the survival rate. (author).

Concurrent chemo-radiotherapy for stage III non-small cell lung cancer

International Nuclear Information System (INIS)

Inoue, Ryuji; Takada, Yoshiki; Obayashi, Kayoko; Kado, Tetsuji; Yamamoto, Hiroyuki; Hirota, Saeko; Soejima, Toshinori; Suzuki, Yasushi; Mimura, Fumitoshi

1994-01-01

In patients with unresectable stage III non-small cell lung cancer, we performed chemotherapy and concurrent thoracic radiotherapy. Thirty-five registered patients were intravenously treated with cisplatin (80mg/m 2 ) on day 1 and vindesine (3mg/m 2 ) on days 1, 3 and were irradiated from days 1 to 10 with single doses of 2.5 Gy up to a total dosage of 20 Gy. Each course lasted 28 days. Patients received 3 courses, and a total dosage of 60 Gy was delivered. Response to this treatment was evaluable in terms of results in 35 patients. Twenty-two patients showed partial response (response rate 62.9%), 10 had no change, and 3 cases had progressive disease. In 7.5 to 37.8 months observation, three PR patients are alive for more than 24 months without recurrence, but eight PR patients died of local relapse, and the median survival time was 15.7 months. Throughout this treatment course, grade 4 leukopenia was noted in 66% and grade 3 thrombocytopenia was observed in 3%. However all were reversible condition and no treatment-related death was observed. However, two cases died due to complications of pulmonary abscess, which occurred in the area of radiation pulmonary fibrosis about one year later after treatment. Although this concurrent chemo-radiotherapy is a tolerable treatment for non-small cell lung cancer and obtained a good response rate, it did not improve the survival rate. (author)

Intraoperative plus external beam irradiation in nonresectable lung cancer

International Nuclear Information System (INIS)

Arian-Schad, K.S.; Juettner, F.M.; Ratzenhofer, B.; Leitner, H.; Porsch, G.; Pinter, H.; Ebner, F.; Hackl, A.G.; Friehs, G.B.

1990-01-01

Since 1987, 24 patients with inoperable non-small-cell lung cancer (NSCLC), stage T 1-3 N 0-2 M 0 , have undergone lymph node dissection and intraoperative radiation therapy (IORT) to the primary with 10-20 Gy. Patient selection criteria were nonresectability based on severe cardiorespiratory impairment, no radiological evidence of distant metastases and a Karnofsky performance status of >80. In 18 patients the IORT procedure was followed by an external beam radiation series (EBR) including the tumor with 46 Gy and the regional lymph nodes with 45/56 Gy. The tumor response was assessed by CAT-scan volumetry before the institution of IORT, 4 weeks later, before the onset of EBR, 8 weeks after the combined treatment course and on a 3 months basis thereafter. Prospectively, MRI of the thorax with/without Gadolinium-DTPA was performed to examine contrast enhancement and signal behavior of the tumor, in an attempt to differentiate residual disease compared to therapy-related collateral damage. So far, 18 patients have completed the combined treatment course with a median follow-up of 11 months (range 4.5 to 25 months). The overall local response rate (CR and PR) was 88.2 per cent. In detail, 11 complete responses, 6 partial responses and one minimal response were observed. The overall and recurrent-free survival at 25 months was 49.6 per cent and 83.3 per cent, respectively. (author). 31 refs.; 2 figs.; 3 tabs

Management of non-small cell lung cancer with oligometastasis.

Science.gov (United States)

Villaruz, Liza C; Kubicek, Gregory J; Socinski, Mark A

2012-08-01

Patients with oligometastatic Non-Small Cell Lung Cancer (NSCLC) present a potential opportunity for curative therapy; however, the challenge remains the definitive treatment of their localized disease and ablation of their limited overt metastatic sites of disease. In selecting patients with oligometastatic NSCLC for definitive therapy, proper staging through radiographic studies, including PET and brain MRI, and the pathologic staging of the mediastinal lymph nodes and potential sites of metastatic disease, are critical. With that in mind, the available literature suggests that in highly selected patients with solitary metastases to the brain, adrenals and other organs, long term survival may be achieved with combined definitive therapy of both the primary lung tumor and the solitary metastatic site.

The In Vitro Anti-Tumor Activity of Phycocyanin against Non-Small Cell Lung Cancer Cells

Directory of Open Access Journals (Sweden)

Shuai Hao

2018-05-01

Full Text Available Phycocyanin, a type of functional food colorant, is shown to have a potent anti-cancer property. Non-small cell lung cancer (NSCLC is one of the most aggressive form of cancers with few effective therapeutic options. Previous studies have demonstrated that phycocyanin exerts a growth inhibitory effect on NSCLC A549 cells. However, its biological function and underlying regulatory mechanism on other cells still remain unknown. Here, we investigated the in vitro function of phycocyanin on three typical NSCLC cell lines, NCI-H1299, NCI-H460, and LTEP-A2, for the first time. The results showed that phycocyanin could significantly induce apoptosis, cell cycle arrest, as well as suppress cell migration, proliferation, and the colony formation ability of NSCLC cells through regulating multiple key genes. Strikingly, phycocyanin was discovered to affect the cell phenotype through regulating the NF-κB signaling of NSCLC cells. Our findings demonstrated the anti-neoplastic function of phycocyanin and provided valuable information for the regulation of phycocyanin in NSCLC cells.

Effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase VEGF, NK cells and immune function in patients with non-squamous non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Feng Wen

2017-07-01

Full Text Available Objective: To explore effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase (MMPs, vascular esandothelial growth factor (VEGF, NK cells and immune function in patients with non-squamous non-small cell lung cancer. Method: A total of 86 cases of non-squamous non-small cell lung cancer patients were divided into control group (n=44 and observation group (n=42, control group was given docetaxel combined cisplatinum chemotherapy, pemetrexed combined cis-platinum chemotherapy, was applied for observation group. Compared MMP-2, MMP-9, VEGF, NK cells and immune function level before and after treatment in both groups. Results: MMP-2, MMP-9, VEGF, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups before treatment was no significant difference. After treatment, MMP-2, MMP-9, VEGF, CD8+level in both groups was significant lower than before treatment intra-group, and observation was lower than control group, there was significant difference. After treatment, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups was increased dramatically than before treatment of intra-group, moreover, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+level in observation group after treatment was obvious higher than in control group after treatment, there was significant difference. Conclusion: Pemetrexed combined with cis-platinum chemotherapy for non-squamous non-small cell lung cancer could effectively decrease serum MMPs, VEGF level and increase NK cell level, regulate immune function, with definite clinical significance.

Paclitaxel and the dietary flavonoid fisetin: a synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells.

Science.gov (United States)

Klimaszewska-Wisniewska, Anna; Halas-Wisniewska, Marta; Tadrowski, Tadeusz; Gagat, Maciej; Grzanka, Dariusz; Grzanka, Alina

2016-01-01

The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for overcoming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). The aim of this study was to investigate whether a naturally occurring diet-based flavonoid, fisetin, at physiologically attainable concentrations, could act synergistically with clinically achievable doses of paclitaxel to produce growth inhibitory and/or pro-death effects on A549 non-small cell lung cancer cells, and if it does, what mechanisms might be involved. The drug-drug interactions were analyzed based on the combination index method of Chou and Talalay and the data from MTT assays. To provide some insights into the mechanism underlying the synergistic action of fisetin and paclitaxel, selected morphological, biochemical and molecular parameters were examined, including the morphology of cell nuclei and mitotic spindles, the pattern of LC3-II immunostaining, the formation of autophagic vacuoles at the electron and fluorescence microscopic level, the disruption of cell membrane asymmetry/integrity, cell cycle progression and the expression level of LC3-II, Bax, Bcl-2 and caspase-3 mRNA. Here, we reported the first experimental evidence for the existence of synergism between fisetin and paclitaxel in the in vitro model of non-small cell lung cancer. This synergism was, at least partially, ascribed to the induction of mitotic catastrophe. The switch from the cytoprotective autophagy to the autophagic cell death was also implicated in the mechanism of the synergistic action of fisetin and paclitaxel in the A549 cells. In addition, we revealed that the synergism between fisetin and paclitaxel was cell line-specific as well as that fisetin synergizes with arsenic trioxide, but not with mitoxantrone and methotrexate in the A549 cells. Our results provide rationale for

Selective tumor irradiation without normal tissue exposure in non-resectable pancreatic cancer

International Nuclear Information System (INIS)

Order, S.E.; Siegel, J.A.; Lustig, R.A.; Principato, L.S.; Zeiger, L.; Lang, P.; Wallner, P.E.

1996-01-01

Purpose: To determine the maximum dose of colloidal 32 P that may be interstitially infused in non-resectable pancreatic cancer prior to external radiation [60 Gy + 5FU]. Materials and Methods: Forty-seven patients with non-resectable pancreatic cancer with and without metastasis entered a dose escalation Phase I study beginning at a specific activity of 4 mCi. Under CT guidance the center of the pancreatic tumor was localized by computer the distance and angle from a grid on the abdomen to the center of the tumor mass determined. Three drugs were infused: 4 mg Decadron - 10 minute delay; 2.5 million particles of macroaggregated albumin [MAA]; and with final dose escalation two infusions of 30 mCi colloidal chromic phosphate 32 P [3.5 ml] followed by a needle cleansing dose of .25 ml of macroaggregated albumin. Bremsstrahlung scans on three separate days determined tumor localization and radiation dose. One week later infusional brachytherapy was repeated, that is Decadron, MAA, colloidal 32 P, followed by three additional bremsstrahlung scans. Two weeks later a course of 60 Gy external radiation was initiated with four doses of 5FU [500 mg] administered with every other radiation treatment day. Toxicity was recorded using RTOG cooperative group criteria. CA19-9 and CEA were used as biomarkers to evaluate tumor progression or remission in conjunction with CT scans and clinical course. Results: Completion of the Phase I study was limited, not by toxicity, but by the volume of colloidal 32 P that could be infused into the stroma of the tumor, i.e. 3.5 ml containing 30 mCi. No significant (grade 3-4) toxicity occurred in patients with pancreatic cancer only. Patients without metastasis had reduction and, in some cases, elimination of CA19-9, etc. The median survival in 28 patients within the Phase I non-resectable pancreas cancer study without metastasis was one year in 19 patients; with metastasis was 6.9 months. The two infusions of 30 mCi 32 P ordinarily yields a

Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

Science.gov (United States)

2013-01-09

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

Application of detecting cerebrospinal fluid circulating tumor cells in the diagnosis of meningeal metastasis of non-small cell lung cancer

OpenAIRE

Rong JIANG; Chun-hua MA; Zi-long ZHU; Jin-duo LI; Bin WANG; Li-wei SUN; Yuan LÜ

2014-01-01

Objective To observe a new technology for the detection and enumeration of cerebrospinal fluid (CSF) circulating tumor cells (CTCs) in the diagnosis of non-small cell lung cancer (NSCLC) with meningeal metastasis (MM).  Methods Five cases of NSCLC with MM that were diagnosed by CSF cytology were selected, and 20 ml CSF samples were obtained by lumbar puncture for every patient. The tumor marker immunostaining-fluorescence in situ hybridization (TM-iFISH) technology was adapted to detect...

Circulating Tumor DNA in Predicting Outcomes in Patients With Stage IV Head and Neck Cancer or Stage III-IV Non-small Cell Lung Cancer

Science.gov (United States)

2018-01-12

Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway

International Nuclear Information System (INIS)

Duan Weiming; Xu Yaxiang; Dong Yujin; Cao Lili; Tong Jian; Zhou Xinwen

2013-01-01

miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy. (author)

Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR

Directory of Open Access Journals (Sweden)

Richer AL

2015-02-01

Full Text Available Amanda L Richer,1 Jacqueline M Friel,1 Vashti M Carson,2 Landon J Inge,1 Timothy G Whitsett2 1Norton Thoracic Institute, St Joseph’s Hospital and Medical Center, 2Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: Lung cancer remains the leading cause of cancer-related mortality worldwide. The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of non-small cell lung cancer (NSCLC. A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR have been identified in NSCLC. While targeted therapeutic successes have been demonstrated in the therapeutic targeting of EGFR and ALK, the majority of NSCLC tumors do not harbor these genomic events. This review looks at the current treatment paradigms for lung adenocarcinomas and squamous cell carcinomas, examining genomic aberrations that dictate therapy selection, as well as novel therapeutic strategies for tumors harboring mutations in KRAS, TP53, and LKB1 which, to date, have been considered “undruggable”. A more thorough understanding of the molecular alterations that govern NSCLC tumorigenesis, aided by next-generation sequencing, will lead to targeted therapeutic options expected to dramatically reduce the high mortality rate observed in lung cancer. Keywords: non-small cell lung cancer, precision medicine, epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene homolog, serine/threonine kinase 11, tumor protein p53

Screening and staging for non-small cell lung cancer by serum laser Raman spectroscopy.

Science.gov (United States)

Wang, Hong; Zhang, Shaohong; Wan, Limei; Sun, Hong; Tan, Jie; Su, Qiucheng

2018-08-05

Lung cancer is the leading cause of cancer-related death worldwide. Current clinical screening methods to detect lung cancer are expensive and associated with many complications. Raman spectroscopy is a spectroscopic technique that offers a convenient method to gain molecular information about biological samples. In this study, we measured the serum Raman spectral intensity of healthy volunteers and patients with different stages of non-small cell lung cancer. The purpose of this study was to evaluate the application of serum laser Raman spectroscopy as a low cost alternative method in the screening and staging of non-small cell lung cancer (NSCLC). The Raman spectra of the sera of peripheral venous blood were measured with a LabRAM HR 800 confocal Micro Raman spectrometer for individuals from five groups including 14 healthy volunteers (control group), 23 patients with stage I NSCLC (stage I group), 24 patients with stage II NSCLC (stage II group), 19 patients with stage III NSCLC (stage III group), 11 patients with stage IV NSCLC (stage IV group). Each serum sample was measured 3 times at different spots and the average spectra represented the signal of Raman spectra in each case. The Raman spectrum signal data of the five groups were statistically analyzed by analysis of variance (ANOVA), principal component analysis (PCA), linear discriminant analysis (LDA), and cross-validation. Raman spectral intensity was sequentially reduced in serum samples from control group, stage I group, stage II group and stage III/IV group. The strongest peak intensity was observed in the control group, and the weakest one was found in the stage III/IV group at bands of 848 cm -1 , 999 cm -1 , 1152 cm -1 , 1446 cm -1 and 1658 cm -1 (P Raman spectroscopy can effectively identify patients with stage I, stage II or stage III/IV Non-Small Cell Lung cancer using patient serum samples. Copyright © 2018 Elsevier B.V. All rights reserved.

Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance.

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Lobb, Richard J; van Amerongen, Rosa; Wiegmans, Adrian; Ham, Sunyoung; Larsen, Jill E; Möller, Andreas

2017-08-01

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes. © 2017 UICC.

The safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel in the treatment of non-small cell lung cancer patients with interstitial lung disease.

Science.gov (United States)

Yasuda, Yuichiro; Hattori, Yoshihiro; Tohnai, Rie; Ito, Shoichi; Kawa, Yoshitaka; Kono, Yuko; Urata, Yoshiko; Nogami, Munenobu; Takenaka, Daisuke; Negoro, Shunichi; Satouchi, Miyako

2018-01-01

The optimal chemotherapy regimen for non-small cell lung cancer patients with interstitial lung disease is unclear. We therefore investigated the safety and efficacy of carboplatin plus nab-paclitaxel as a first-line regimen for non-small cell lung cancer in patients with interstitial lung disease. We retrospectively reviewed advanced non-small cell lung cancer patients with interstitial lung disease who received carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen at Hyogo Cancer Center between February 2013 and August 2016. interstitial lung disease was diagnosed according to the findings of pretreatment chest high-resolution computed tomography. Twelve patients were included (male, n = 11; female, n = 1). The overall response rate was 67% and the disease control rate was 100%. The median progression free survival was 5.1 months (95% CI: 2.9-8.3 months) and the median overall survival was 14.9 months (95% CI: 4.8-not reached). A chemotherapy-related acute exacerbation of interstitial lung disease was observed in one patient; the extent of this event was Grade 2. There were no treatment-related deaths. Carboplatin plus nab-paclitaxel, as a first-line chemotherapy regimen for non-small cell lung cancer, showed favorable efficacy and safety in patients with preexisting interstitial lung disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Living with a diagnosis of non-small cell lung cancer: patients' lived experiences.

LENUS (Irish Health Repository)

McCarthy, Ita

2012-01-31

The aim of this study was to explore patients\\' experience of living with non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC know that their treatment is not with curative intent and can expect distressing symptoms. In this phenomenological study, six adults with a diagnosis of NSCLC were interviewed. Data was analysed guided by van Manen\\'s six-step process. Four main themes were interpreted: \\'Maintaining my life\\'; \\'The enemy within\\'; \\'Staying on the train\\

Patterns of failure and overall survival in patients with completely resected T3 N0 M0 non-small cell lung cancer

International Nuclear Information System (INIS)

Gould, Perry M.; Bonner, James A.; Sawyer, Timothy E.; Deschamps, Claude; Lange, Carla M.; Li Hongzhe

1999-01-01

Background: Previous studies of patients with surgically resected non-small cell lung cancer and chest wall invasion have shown conflicting results with respect to prognosis. Whether high-risk subsets of the T3 N0 M0 population exist with respect to patterns of failure and overall survival has been difficult to ascertain, owing to small numbers of patients in most series. Methods and Materials: A retrospective review was performed to determine patterns of failure and overall survival for patients with completely resected T3 N0 M0 non-small cell lung cancer. From 1979 to 1993, 92 evaluable patients underwent complete resection for T3 N0 M0 non-small cell lung cancer. The following potential prognostic factors were recorded from the history: tumor size, location, grade, histology, patient age, use of adjuvant radiation therapy (18 of 92 patients), and type of surgical procedure (chest wall or extrapleural resection). Results: The actuarial 2- and 4-year overall survival rates for the entire cohort were 48% and 35%, respectively. The actuarial local control at 4 years was 94%. Neither the type of surgical procedure performed nor the addition of thoracic radiation therapy impacted local control or overall survival. Conclusion: Patients with completely resected T3 N0 M0 non-small cell lung cancer have similar local control and overall survival irrespective of primary location, type of surgery performed, or use of adjuvant radiation therapy. Additionally, the tumor recurrence rate and overall survival found in this study support the placement of this group of patients in Stage IIB of the 1997 AJCC lung staging classification

Outcome following radiotherapy for loco-regionally recurrent non-small cell lung cancer

International Nuclear Information System (INIS)

Foo, K.; Yeghiaian-Alvandi, R.; Foroudi, F.

2005-01-01

Local and regional recurrence of non-small cell lung cancer is reported to occur in 13-20% of treatment failures after resection. Reported post-recurrent median survival following radiotherapy ranges from 9 to 14 months. This study examines survival following radiotherapy alone for patients with loco-regionally recurring non-small cell lung cancer after initial surgery. Fifty-five patients, receiving radiotherapy at Westmead Hospital between 1979 and 1997, were eligible for study. Data were collected retrospectively by reviewing patient records. The end-point was overall survival. Symptom control was also recorded. Prognostic factors for analysis included age, sex, original presenting stage, disease-free interval (DFI), performance status, site of recurrence, treatment intent and dose. The median overall survival was 11.5 months (95% confidence interval: 8.1-13.0). Survival following treatment with radical intent was 26 months compared to 10.5 months for patients treated with palliative intent (P = 0.025). There was no significant difference in survival for short (<2 years) or long DFI, performance status, radiation dose, age, sex, site of recurrence or stage. Most patients (55%) had partial or complete resolution of symptoms. Radiotherapy results in overall post-recurrence median survival of nearly 1 year, consistent with previous published data. Radical treatment intent predicts better prognosis as a result of patient selection and higher dose. Radiotherapy is effective at palliating symptoms of this disease Copyright (2005) Blackwell Publishing Asia Pty Ltd

Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor

Science.gov (United States)

2018-03-07

EGFR Exon 19 Deletion Mutation; EGFR Exon 20 Insertion Mutation; EGFR NP_005219.2:p.G719X; EGFR NP_005219.2:p.L858R; EGFR NP_005219.2:p.L861Q; EGFR NP_005219.2:p.T790M; EGFR T790M Mutation Negative; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7

Curative radiotherapy in non-small cell carcinoma of the lung

International Nuclear Information System (INIS)

Talton, B.M.; Constable, W.C.; Kersh, C.R.

1990-01-01

Recent reports suggest radiotherapy administered to the 5000-6000 cGy level can result in significant long-term survival in non-small cell carcinoma of the lung. This is particularly true for many cases that are technically operable but for medical or other reasons thoracotomy cannot be performed. Such patients drawn from Southern Appalachia where the principal industry is coal mining are the subject of this report. In this region coal miners pneumoconiosis (black lung) is common as well as other chronic respiratory disorders resulting in poor tolerance for surgery. Three hundred and eleven cases of non-small cell carcinoma were irradiated during the 4 years of 1980 through 1983. This group consisted of 77 patients with clinical Stage T1, T2, T3 all N0, M0 tumors, the majority of which were technically operable but upon whom no thoracotomy was performed because of medical reasons or patient refusal. All are available for 5-year study. Each of these patients was uniformly irradiated to 6000 cGy target dose in 30 fractions over 6 weeks using standard techniques.Comparison with reported surgical series treated for cure show little difference in survival up to 2 years. Thereafter, the survival curves diverge with radiotherapy patients dying at a somewhat higher rate although by 4 years both survival curves slope similarly. A possible explanation for this difference is the advantage thoracotomy offers in early case selection allowing exclusion of advance cases from surgical reports whereas radiotherapy must include patients with occult local metastasis not identifiable on clinical grounds. This experience, among other reports include evidence that radiotherapy can result in long-term survival or cure with minimal morbidity in lung cancer patients in whom surgery carries excessive risk

The prognostic effect of subpleural lesions in early stage non-small cell lung cancer: preliminary report

International Nuclear Information System (INIS)

Lee, Ho Jun; Lee, Hyung Sik; Hur, Won Joo; Lee, Ki Nam; Choi, Pill Jo

1998-01-01

We retrospectively analyzed the impact of subpleural lesions of early stage non-small cell lung cancer on the patterns of failure to support selection of postoperative adjuvant therapy. The study included 91 patients who underwent surgery for early stage non-small cell lung cancer at Donga University hospital from Dec 1990 to Sep 1996. Twenty five patients were excluded due to postoperative mortality (four patients, 4.4%) and stage III (21 patients). Of 66 patients, 22 patients were subpleural lesions (15 patients in stage I, and seven patients in stage II). Postoperative adjuvant radiation therapy was given to seven patients with T2N1 disease. The median follow-up duration was 29.5 months (range; 8-84 months). The overall survival rate was 69.5% at 3 years. For all patients who presented with (22 patients) and without (44 patients) subpleural lesions, 3-year overall survival rates were 35.5% and 84.6%, respectively (p=0.0017). For stage I patients who presented with (15 patients) and without (29 patients) subpleural lesions, 3-year overall survival rates were 33.1% and 92.3%, respectively (p=0.001). For stage II patients who presented with (7 patients) and without (15 patients) subpleural lesions, 3-year overall survival rates were 53.3% and 45.7%, respectively (p=0.911). For patients with T2NO disease (34 patients) who presented with (11 patients) and without (23 patients) subpleural lesions, 3-year overall survival rates were 27.3% and 90.3%,respectively (p=0.009).These observations suggest that the subpleural lesion play an important role as a prognostic factor for early stage non-small cell lung cancer. Especially for T2NO disease, patients with subpleural lesions showed significantly lower survival rate than those without that

SSX2-4 expression in early-stage non-small cell lung cancer

DEFF Research Database (Denmark)

Greve, K B V; Pøhl, M; Olsen, K E

2014-01-01

The expression of cancer/testis antigens SSX2, SSX3, and SSX4 in non-small cell lung cancers (NSCLC) was examined, since they are considered promising targets for cancer immunotherapy due to their immunogenicity and testis-restricted normal tissue expression. We characterized three SSX antibodies...... was only detected in 5 of 143 early-stage NSCLCs, which is rare compared to other cancer/testis antigens (e.g. MAGE-A and GAGE). However, further studies are needed to determine whether SSX can be used as a prognostic or predictive biomarker in NSCLC....

Thymidylate synthase protein expression levels remain stable during paclitaxel and carboplatin treatment in non-small cell lung cancer

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

2014-01-01

BACKGROUND: Thymidylate synthase (TS) is a potential predictive marker for efficacy of treatment with pemetrexed. The current study aimed at investigating whether TS expression changes during non-pemetrexed chemotherapy of non-small cell lung cancer (NSCLC), thus making rebiopsy necessary for dec...

Proportion and clinical features of never-smokers with non-small cell lung cancer

OpenAIRE

Cho, Jaeyoung; Choi, Sun Mi; Lee, Jinwoo; Lee, Chang-Hoon; Lee, Sang-Min; Kim, Dong-Wan; Yim, Jae-Joon; Kim, Young Tae; Yoo, Chul-Gyu; Kim, Young Whan; Han, Sung Koo; Park, Young Sik

2017-01-01

Background The proportion of never-smokers with non-small cell lung cancer (NSCLC) is increasing, but that in Korea has not been well addressed in a large population. We aimed to evaluate the proportion and clinical features of never-smokers with NSCLC in a large single institution. Methods We analyzed clinical data of 1860 consecutive patients who were newly diagnosed with NSCLC between June 2011 and December 2014. Results Of the 1860 NSCLC patients, 707 (38.0%) were never-smokers. The propo...

Preoperative nodal staging of non-small cell lung cancer using 99mTc-sestamibi spect/ct imaging

Directory of Open Access Journals (Sweden)

Juliana Muniz Miziara

2011-01-01

Full Text Available OBJECTIVES: The proper nodal staging of non-small cell lung cancer is important for choosing the best treatment modality. Although computed tomography remains the first-line imaging test for the primary staging of lung cancer, its limitations for mediastinum nodal staging are well known. The aim of this study is to evaluate the accuracy of hybrid single-photon emission computed tomography and computed tomography using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and to identify potential candidates for surgical treatment. METHODS: Prospective data were collected for 41 patients from December 2006 to February 2009. The patients underwent chest computed tomography and single-photon emission computed tomography/computed tomography examinations with 99mTc-sestamibi within a 30-day time period before surgery. Single-photon emission computed tomography/computed tomography was considered positive when there was focal uptake of sestamibi in the mediastinum, and computed tomography scan when there was lymph nodes larger than 10 mm in short axis. The results of single-photon emission computed tomography and computed tomography were correlated with pathology findings after surgery. RESULTS: Single-photon emission computed tomography/computed tomography correctly identified six out of 19 cases involving hilar lymph nodes and one out of seven cases involving nodal metastases in the mediastinum. The sensitivity, specificity, positive predictive value, and negative predictive value for 99mTc-sestamibi single-photon emission computed tomography/computed tomography in the hilum assessment were 31.6%, 95.5%, 85.7%, and 61.8%, respectively. The same values for the mediastinum were 14.3%, 97.1%, 50%, and 84.6%, respectively. For the hilar and mediastinal lymph nodes, chest tomography showed sensitivity values of 47.4% and 57.1%, specificity values of 95.5% and 91.2%, positive predictive values of 90% and 57.1% and negative

Preoperative nodal staging of non-small cell lung cancer using 99mTc-sestamibi SPECT/CT imaging

International Nuclear Information System (INIS)

Miziara, Juliana Muniz; Rocha, Euclides Timoteo da; Miziara, Jose Elias Abrao; Garcia, Gustavo Fabene; Simoes, Maria Izilda Previato; Lopes, Marco Antonio; Kerr, Ligia Maria; Buchpiguel, Carlos Alberto

2011-01-01

Objectives: The proper nodal staging of non-small cell lung cancer is important for choosing the best treatment modality. Although computed tomography remains the first-line imaging test for the primary staging of lung cancer, its limitations for mediastinum nodal staging are well known. The aim of this study is to evaluate the accuracy of hybrid single-photon emission computed tomography and computed tomography using 99m Tc-sestamibi in the nodal staging of patients with non-small cell lung cancer and to identify potential candidates for surgical treatment. Methods: Prospective data were collected for 41 patients from December 2006 to February 2009. The patients underwent chest computed tomography and single-photon emission computed tomography/computed tomography examinations with 99m Tc-sestamibi within a 30-day time period before surgery. Single-photon emission computed tomography/computed tomography was considered positive when there was focal uptake of sestamibi in the mediastinum, and computed tomography scan when there was lymph nodes larger than 10 mm in short axis. The results of single-photon emission computed tomography and computed tomography were correlated with pathology findings after surgery. Results: Single-photon emission computed tomography/computed tomography correctly identified six out of 19 cases involving hilar lymph nodes and one out of seven cases involving nodal metastases in the mediastinum. The sensitivity, specificity, positive predictive value, and negative predictive value for 99m Tc-sestamibi single-photon emission computed tomography/computed tomography in the hilum assessment were 31.6%, 95.5%, 85.7%, and 61.8%, respectively. The same values for the mediastinum were 14.3%, 97.1%, 50%, and 84.6%, respectively. For the hilar and mediastinal lymph nodes, chest tomography showed sensitivity values of 47.4% and 57.1%, specificity values of 95.5% and 91.2%, positive predictive values of 90% and 57.1% and negative predictive values of 67

Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EGFR Mutants in Non-Small Cell Lung Cancer

OpenAIRE

Ying Swan Ho; Lian Yee Yip; Nurhidayah Basri; Vivian Su Hui Chong; Chin Chye Teo; Eddy Tan; Kah Ling Lim; Gek San Tan; Xulei Yang; Si Yong Yeo; Mariko Si Yue Koh; Anantham Devanand; Angela Takano; Eng Huat Tan; Daniel Shao Weng Tan

2016-01-01

Cytology and histology forms the cornerstone for the diagnosis of non-small cell lung cancer (NSCLC) but obtaining sufficient tumour cells or tissue biopsies for these tests remains a challenge. We investigate the lipidome of lung pleural effusion (PE) for unique metabolic signatures to discriminate benign versus malignant PE and EGFR versus non-EGFR malignant subgroups to identify novel diagnostic markers that is independent of tumour cell availability. Using liquid chromatography mass spect...

Activity of gemcitabine in patients with non-small cell lung cancer : A multicentre, extended phase II study

NARCIS (Netherlands)

Gatzemeier, U; Shepherd, FA; LeChevalier, T; Weynants, P; Cottier, B; Groen, HJM; Rosso, R; Mattson, K; CortesFunes, H; Tonato, M; Burkes, RL; Gottfried, M; Voi, M

Gemcitabine is a novel nucleoside analogue with activity in solid tumours. This study assessed the objective response rate to gemcitabine given weekly intravenously at a dose of 1250 mg/m(2) for 3 weeks followed by 1 week of rest (one cycle) in chemonaive patients with inoperable non-small cell lung

Consideration of myocardial FDG uptake in differentiation of mediastinal lymph node of non-small cell lung cancer

International Nuclear Information System (INIS)

Eo, Jae Seon; Lee, Won Woo; Chung, Jin Haeng; So, Young; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul; Kim, Sang Eun

2004-01-01

The whole body FDG PET suffers from poor diagnostic competency in differentiation of mediastinal lymph node (LN) in non-small cell lung cancer. In addition to LN FDG uptake. We considered myocardial FDG uptake in mediastinal lymph node staging. Thirty-nine non-small cell lung cancer patients (male: female = 32: 7, age = 63±11 years) who underwent preoperative whole body FDG PET were enrolled. There were 18 squamous cell cancer, 13 adenocarcinoma, and 8 others. Maximum standard uptake values (maxSUVs) of myocardium and LNs using lean body weight were measured and compared with pathological results. Among 187 LNs which were confirmed postoperatively, 31 were malignant, and 156 benign. Of 31 malignant LNs, only 11 were visible on FDG PET (sensitivity : 35.5% = 11/31) but majority of 20 nonvisible metastatic LNs had relevant cause of false negative (11 peribroncheal, 3 mucine producing adenocarcinoma, or 6 low amount of tumor cells). Of 156 benign LNs, 137 were nonvisible (specificity : 87.8% 137/156) and 19 visible. Under subgroup analysis of 30 visible LNs on whole body FDG PET (11 malignant, and 19 benign), maxSUV of myocardium (p = 0.020) as well as maxSUV of LN (p = 0.002) were significant predictor of malignant LN in multivariate analysis. Using the ROC curve, a cut-off value of LN maxSUV > 2.4 provided sensitivity of 81.8% and specificity of 63.2% (AUC 0.775, 95% confidence interval = 0.586 to 0.906). Meanwhile, the composite criterion of LN maxSUV plus square root of myocardial maxSUV > 4.65 provided slightly improved diagnostic competencies (sensitivity 90.9%, specificity 84.2%, AUC 0.876, 95% confidence interval 0.704 to 0.966) (p = 0.08). Taking into consideration myocardial FDG uptake may improve the diagnostic competency of whole body FDG PET in differentiation of mediastinal LNs of non-small cell lung cancer

[Clinical effects for patients with recurrent advanced non-small cell lung cancer treated with icotinib hydrochloride].

Science.gov (United States)

Nong, Jingying; Qin, Na; Wang, Jinghui; Yang, Xinjie; Zhang, Hui; Wu, Yuhua; Lv, Jialin; Zhang, Quan; Zhang, Shucai

2013-05-01

Icotinib hydrochloride is the third single target EGFR-TKI used in clinical treatment of advanced non-small cell lung cancer (NSCLC). Clinical research reports on its efficacy and survival in patients with Recurrent Advanced NSCLC are still little.The aim of this study is to evaluate the efficacy and survival of Icotinib hydrochloride for patients with advanced non-small cell lung cancer who failed to previous chemotherapy and explore the association of clinical features with the efficacy and survival. The clinical data of 60 NSCLC patients referred to the Beijing Chest Hospital, Capital Medical University from March 2009 to July 2012 were retrospectively analyzed. The overall response rate (ORR) was 45.0% and the disease control rate (DCR) was 80.0%. The median progression-free survival (PFS) time was 6.7 months. RR and PFS in female were superior to male (P=0.014, 0.013, respectively). RR, DCR in 2nd-line subgroup were superior to ≥3rd-line subgroup (P=0.020, 0.024, respectively). RR, DCR and PFS in EGFR mutation carriers were significantly superior to wild-type patients (P=0.006, Icotinib hydrochloride is effective especially in EGFR mutation carriers and well tolerated in patients with recurrent advanced non-small-cell lung cancer.

The miR-599 promotes non-small cell lung cancer cell invasion via SATB2

International Nuclear Information System (INIS)

Tian, Wenjun; Wang, Guanghai; Liu, Yiqing; Huang, Zhenglan; Zhang, Caiqing; Ning, Kang; Yu, Cuixiang; Shen, Yajuan; Wang, Minghui; Li, Yuantang; Wang, Yong; Zhang, Bingchang; Zhao, Yaoran

2017-01-01

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we identified that miR-599 is up-regulated in non-small cell lung cancer (NSCLC) patients. It promoted NSCLC cell proliferation by negatively regulating SATB2. In NSCLC cell lines, CCK-8 proliferation assay indicated that the cell proliferation is promoted by miR-599 mimics. Transwell assay showed that miR-599 mimics promoted the invasion and migration of NSCLC cells. Luciferase assays confirmed that miR-599 directly binds to the 3'untranslated region of SATB2, and western blotting showed that miR-599 suppresses the expression of SATB2 at the protein level. This study indicates that miR-599 promotes proliferation and invasion of NSCLC cell lines via SATB2. The miR-599 may represent a potential therapeutic target for NSCLC treatment. - Highlights: • miR-599 is up-regulated in NSCLC. • miR-599 promotes the proliferation and invasion of NSCLC cells. • miR-599 inhibitors inhibits the proliferation and invasion of NSCLC cells. • miR-599 targets 3′ UTR of SATB2 in NSCLC cells. • miR-599 inhibits SATB2 in NSCLC cells.

In vitro optimization of non-small cell lung cancer activity with troxacitabine, L-1,3-dioxolane-cytidine, prodrugs

NARCIS (Netherlands)

Radi, Marco; Adema, Auke D.; Daft, Jonathan R.; Cho, Jong H.; Hoebe, Eveline K.; Alexander, Lou-Ella M. M.; Peters, Godefridus J.; Chu, Chung K.

2007-01-01

l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N4-Substituted fatty acid

Advances of Drug Resistance Marker of Gemcitabine for Non-small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Baorui LIU

2011-05-01

Full Text Available With the development of pharmacogenomics and pharmacogenetics, personal therapy based on genes has become one of the most effective ways to enhance chemotherapeutic effect on non-small cell lung cancer (NSCLC patients. Much attention has been paid to validate the predictive biomarkers of chemotherapy in order to guide chemotherapy and enhance effect in general. Gemcitabine is one of the common agents treating NSCLC recently. This review is mainly about the recent reports on potential biomarkers of Gemcitabine in tailored therapy of NSCLC.

F-18 fluorodeoxyglucose positron emission tomography in the mediastinal nodal staging of non-small cell lung carcinoma

International Nuclear Information System (INIS)

Berlangieri, S.U.; Scott, A.M.; Knight, S.; Fitt, G.J.; Hess, E.M.; Pathmaraj, K.; Hennessy, O.F.; Tochon-Danguy, H.J.; Chan, J.G.; Egan, G.F.; Sinclair, R.A.; Clarke, C.P.; McKay, W.J.; St Vincents Hospital, Fitzroy, VIC

1998-01-01

Full text: Positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG), as a metabolic tumour marker, has been proposed for staging of oncological disease. To determine its role in the mediastinal staging of lung cancer, a prospective comparison of FDG PET with surgery was performed in patients with suspected non-small cell lung carcinoma. The analysis group consists of 70 patients, 49 men and 21 women, mean age 64 yrs (range 41-83 yrs). The PET study was acquired on a Siemens 951/31R scanner over 3 bed positions, 45 minutes following 400MBq FDG. The emission scan was attenuation corrected using measured transmission data. The FDG PET were interpreted by a nuclear physician blinded to the clinical data and the results of the patients' CT scan. On PET, nodes were graded qualitatively on a 5 point scale with scores 4 or greater, positive for tumour involvement. Surgical specimens were obtained in all patients by thoracotomy or mediastinoscopy. The PET metabolic studies and pathology were mapped according to the American Thoracic Society nodal classification resulting in a total of 277 nodal stations evaluated. The PET studies analysed N2 or N3 tumour involvement by nodal station in comparison to histology of pathological specimens or direct visual assessment of the nodal stations at surgery. All patients had proven non-small cell lung carcinoma, except two, in whom, a tissue confirmation of the suspected diagnosis was not attained. PET excluded tumour in 237 of 246 nodal stations (specificity 96%). PET correctly identified 23 of 31 nodal stations with disease (sensitivity 74%). PET correctly staged 260 of 277 nodal stations (accuracy 94%) for disease. FDG PET is an accurate non-invasive functional imaging modality for the mediastinal staging of non-small cell lung cancer and has an important clinical role in the preoperative staging of lung cancer patients

Clinical application of radiofrequency ablation combined with bronchial artery infusion of docetaxel in treating non-small cell lung cancer

International Nuclear Information System (INIS)

Lu Xiong; Chen Fang; Lin Yun; Tan Taikang; Wei Wei

2010-01-01

Objective: To discuss the clinical application of radiofrequency ablation combined with bronchial artery infusion of docetaxel in treating non-small cell lung cancer and to summarize the experience of using this therapy in clinical practice. Methods: Radiofrequency ablation was performed in twenty-one patients with lung cancer. The diagnosis was confirmed by CT-guided percutaneous needle biopsy or bronchoscopic biopsy in all patients. One week after radiofrequency ablation treatment, bronchial artery infusion of docetaxel was conducted. The therapeutic results were observed and evaluated. Results: After the treatment, the lesion's size was markedly reduced and the clinical symptoms were dramatically improved in all patients. Conclusion: Radiofrequency ablation combined with bronchial artery infusion of docetaxel is a safe, effective and simple technique with excellent therapeutic results for the treatment of non-small cell lung cancer. It is really worth popularizing this technique in clinical practice. (authors)

77 FR 24717 - Scientific Information Request on Local Therapies for the Treatment of Stage I Non-Small Cell...

Science.gov (United States)

2012-04-25

... (e.g., details of studies conducted) from medical device industry stakeholders through public...-guidesreviews-and-reports/?pageaction=displayproduct&productid=965 . This notice is a request for industry... (clinical or biopsy) stage I (T1NOMO, T2NOMO) Non-Small Cell Lung Cancer (NSCLC) in adult patients (age 18...

Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer

DEFF Research Database (Denmark)

Hansen, Line V.; Skov, Birgit G; Ploug, Michael

2007-01-01

expression. In the present study, we therefore explored the possible association between C4.4A expression and prognosis in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Tissue sections from 108 NSCLC patients were subjected to immunohistochemical staining using a polyclonal antibody...

Patterns of failure and overall survival in patients with completely resected T3N0M0 nonsmall cell lung cancer

International Nuclear Information System (INIS)

Gould, P.M.; Bonner, J.A.; Sawyer, T.E.; Deschamps, C.; Foote, R.L.; Trastek, V.F.; Allen, M.S.; Pairolero, P.C.; Lange, C.; Li, H.

1997-01-01

Purpose/Objective: Previous studies of patients with surgically resected nonsmall cell lung cancer and chest wall invasion have shown conflicting results with respect to prognosis. Whether high risk subsets of the T3N0M0 population exist with respect to local, regional, and distant control as well as overall survival has been difficult to ascertain due to small numbers of patients in most reported series. Therefore, a review of patients with completely resected T3N0M0 nonsmall cell lung cancer was undertaken to analyze patient and tumor characteristics as well as surgical interventions that might influence patterns of failure and overall survival. Materials and Methods: A retrospective review was performed for all patients (91) with T3N0M0 nonsmall cell lung cancer who had undergone a complete resection between the years 1979 to 1993. The following potential prognostic factors were recorded from each patients history: tumor size, tumor location (bronchus vs. pleura vs. chestwall), tumor grade, histology, patient age, the use of adjuvant radiation therapy ((17(91)) patients received adjuvant therapy), and the type of surgical procedure performed (chestwall resection vs. extrapleural resection). The actuarial rates of freedom from local recurrence (FFLR), freedom from regional nodal recurrence (FFRR), freedom from distant recurrence (FFDR), and overall survival were calculated from the date of diagnosis by the method of Kaplan-Meier. Results: The following table illustrates two and five year outcomes: None of the patients, tumor, or treatment characteristics that were analyzed were associated with a significant influence on the four parameters outlined in the above table. Conclusion: Patients with completely resected T3N0M0 nonsmall cell lung cancer have a similar local control and overall survival irrespective of primary location, type of surgery performed, or use of adjuvant radiation therapy. Additionally, the tumor recurrence rate and overall survival found in

Subtyping of nonsmall cell lung cancer on cytology specimens: Reproducibility of cytopathologic diagnoses on sparse material

DEFF Research Database (Denmark)

Haukali, O. S.; Henrik, H.; Olsen, Karen Ege

2014-01-01

Cytologic examination of fine-needle aspiration (material is increasingly used in diagnosing lung cancer. High interobserver agreement in distinguishing small-cell lung cancer from nonsmall-cell lung cancer (NSCLC) on cytologic material has been demonstrated. Because of new treatment......, cytoscrape (CS) can convert cytologic material into tissue fragments useful for IHC. The purpose of this study was to test the reproducibility of pulmonary malignant diagnoses, in particular distinction between subgroups of NSCLC, based on smeared material and IHC on CS. A consecutive series of May...

SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer

International Nuclear Information System (INIS)

Cao, Rubo; Ding, Qian; Li, Pindong; Xue, Jun; Zou, Zhenwei; Huang, Jing; Peng, Gang

2013-01-01

Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance

Preoperative nodal staging of non-small cell lung cancer using {sup 99m}Tc-sestamibi SPECT/CT imaging

Energy Technology Data Exchange (ETDEWEB)

Miziara, Juliana Muniz; Rocha, Euclides Timoteo da; Miziara, Jose Elias Abrao; Garcia, Gustavo Fabene; Simoes, Maria Izilda Previato; Lopes, Marco Antonio; Kerr, Ligia Maria [Hospital de Cancer de Barretos, Barretos, SP (Brazil); Buchpiguel, Carlos Alberto, E-mail: julimiziara@ig.com.br [Faculdade de Medicina da Universidade da Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, SP (Brazil)

2011-07-01

Objectives: The proper nodal staging of non-small cell lung cancer is important for choosing the best treatment modality. Although computed tomography remains the first-line imaging test for the primary staging of lung cancer, its limitations for mediastinum nodal staging are well known. The aim of this study is to evaluate the accuracy of hybrid single-photon emission computed tomography and computed tomography using {sup 99m}Tc-sestamibi in the nodal staging of patients with non-small cell lung cancer and to identify potential candidates for surgical treatment. Methods: Prospective data were collected for 41 patients from December 2006 to February 2009. The patients underwent chest computed tomography and single-photon emission computed tomography/computed tomography examinations with {sup 99m}Tc-sestamibi within a 30-day time period before surgery. Single-photon emission computed tomography/computed tomography was considered positive when there was focal uptake of sestamibi in the mediastinum, and computed tomography scan when there was lymph nodes larger than 10 mm in short axis. The results of single-photon emission computed tomography and computed tomography were correlated with pathology findings after surgery. Results: Single-photon emission computed tomography/computed tomography correctly identified six out of 19 cases involving hilar lymph nodes and one out of seven cases involving nodal metastases in the mediastinum. The sensitivity, specificity, positive predictive value, and negative predictive value for {sup 99m}Tc-sestamibi single-photon emission computed tomography/computed tomography in the hilum assessment were 31.6%, 95.5%, 85.7%, and 61.8%, respectively. The same values for the mediastinum were 14.3%, 97.1%, 50%, and 84.6%, respectively. For the hilar and mediastinal lymph nodes, chest tomography showed sensitivity values of 47.4% and 57.1%, specificity values of 95.5% and 91.2%, positive predictive values of 90% and 57.1% and negative

A patient perspective on shared decision making in stage I non-small cell lung cancer: a mixed methods study

NARCIS (Netherlands)

Hopmans, W.; Damman, O.C.; Senan, S.; Hartemink, K.J.; Smit, E.F.; Timmermans, D.R.M.

2015-01-01

Background: Surgery and stereotactic ablative radiotherapy (SABR) are both curative treatment options for patients with a stage I non-small cell lung cancer (NSCLC). Consequently, there is growing interest in studying the role of patients in treatment decision making. We studied how patients with

Concurrent versus Sequential Chemoradiotherapy with Cisplatin and Vinorelbine in Locally Advanced Non-Small Cell Lung Cancer: A Randomized Study

Czech Academy of Sciences Publication Activity Database

Zatloukal, P.; Petruželka, L.; Zemanová, M.; Havel, L.; Janků, F.; Judas, L.; Kubík, A.; Křepela, E.; Fiala, P.; Pecen, Ladislav

2004-01-01

Roč. 46, - (2004), s. 87-98 ISSN 0169-5002 Institutional research plan: CEZ:AV0Z1030915 Keywords : concurrent chemoradiotherapy * sequential chemoradiotherapy * locally advanced non-small cell lung cancer * cisplatin * vinorelbine Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.914, year: 2004

CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

Directory of Open Access Journals (Sweden)

Diana Rosa Fernández Ruiz

2017-02-01

Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.

Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer

NARCIS (Netherlands)

Schuster-Uitterhoeve, A. L.; van de Vaart, P. J.; Schaake-Koning, C. C.; Benraadt, J.; Koolen, M. G.; González González, D.; Bartelink, H.

1996-01-01

The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before

Curcumin inhibits interferon-α induced NF-κB and COX-2 in human A549 non-small cell lung cancer cells

International Nuclear Information System (INIS)

Lee, Jeeyun; Im, Young-Hyuck; Jung, Hae Hyun; Kim, Joo Hyun; Park, Joon Oh; Kim, Kihyun; Kim, Won Seog; Ahn, Jin Seok; Jung, Chul Won; Park, Young Suk; Kang, Won Ki; Park, Keunchil

2005-01-01

The A549 cells, non-small cell lung cancer cell line from human, were resistant to interferon (IFN)-α treatment. The IFN-α-treated A549 cells showed increase in protein expression levels of NF-κB and COX-2. IFN-α induced NF-κB binding activity within 30 min and this increased binding activity was markedly suppressed with inclusion of curcumin. Curcumin also inhibited IFN-α-induced COX-2 expression in A549 cells. Within 10 min, IFN-α rapidly induced the binding activity of a γ- 32 P-labeled consensus GAS oligonucleotide probe, which was profoundly reversed by curcumin. Taken together, IFN-α-induced activations of NF-κB and COX-2 were inhibited by the addition of curcumin in A549 cells

Management of isolated nonresectable liver metastases in colorectal cancer patients: a case-control study of isolated hepatic perfusion with melphalan versus systemic chemotherapy

NARCIS (Netherlands)

van Iersel, L. B. J.; Koopman, M.; van de Velde, C. J. H.; Mol, L.; van Persijn van Meerten, E. L.; Hartgrink, H. H.; Kuppen, P. J. K.; Vahrmeijer, A. L.; Nortier, J. W. R.; Tollenaar, R. A. E. M.; Punt, C.; Gelderblom, H.

2010-01-01

To compare the median overall survival of patients with isolated nonresectable liver metastases in comparable groups of patients treated with either isolated hepatic perfusion (IHP) with melphalan or systemic chemotherapy. Colorectal cancer patients with isolated liver metastases, who underwent IHP,

Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

Directory of Open Access Journals (Sweden)

Zhong SHI

2015-02-01

Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

The treatment Results of Radiotherapy for nonsmall Cell Lung Cancer

International Nuclear Information System (INIS)

Yoon, Jong Chul; Sohn, Seung Chang; Suh, Hyun Suk; Jaun, Woo Ki; Kim, Dong Soon; Sohn, Kwang Hyun

1986-01-01

From Nov. 1983 through Jan. 1986, 43 patients with nonsmall cell lung cancer were treated by radiation therapy at Inje Medical College Paik Hospital. 38 patients were available for the analysis of this study. 33 patients received definite irradiation with curative intent, while 5 patients received postoperative irradiation. Chemotherapy was added in 12 patients before, during and after radio-therapy. 28 patients were squamous cell carcinoma and 10 patients were adenocarcinoma. There were 29 men and 9 women (median age, 58 years; range 34 to 74 years). Stage I was 1 patient, Stage 11, 7 patient, and Stage 111, 30 patients. Among 33 patients who received radiotherapy with curative intent, follow up radiological study revealed complete response in 12 patients (36%), partial response, in 9 patients (27%), and minimal response, in 5 patients (15%), while 7 patients (21%) were nonresponders. Median survival for all patients was 6.9 months; squamous cell carcinoma, 7.3 months, adenocarcinoma, 5.9 months. Responders survived median 7 months, while nonresponders survived median 1.9 months. Improved complete response rate and survival were shown in high radiation dose group. As prognostic factors, age, initial performance status, sex, histology and tumor location were evaluated

Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

Directory of Open Access Journals (Sweden)

Sung-Min Chun

Full Text Available Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

Science.gov (United States)

Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin

2015-01-01

Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

Bmi-1 expression modulates non-small cell lung cancer progression

Science.gov (United States)

Xiong, Dan; Ye, Yunlin; Fu, Yujie; Wang, Jinglong; Kuang, Bohua; Wang, Hongbo; Wang, Xiumin; Zu, Lidong; Xiao, Gang; Hao, Mingang; Wang, Jianhua

2015-01-01

Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression. PMID:25880371

Effects of Monoclonal Antibody Cetuximab on Proliferation of Non-small Cell Lung Cancer Cell lines

Directory of Open Access Journals (Sweden)

Zhen CHEN

2010-08-01

Full Text Available Background and objective The epidermal growth factor receptor (EGFR monoclonal antibody cetuximab has been used widely in non-small cell lung cancer patients. The aim of this study is to explore the effect of lung cancer cells (A549, H460, H1299, SPC-A-1 which were treated by cetuximab in vitro. Methods We studied the effects of increasing concentrations of cetuximab (1 nmol/L-625 nmol/L in four human lung cancer cell lines (A549, SPC-A-1, H460, H1229. CCK8 measured the inhibition of cell proliferation in each group. A549, SPC-A-1 were marked by PI and the statuses of apoptosis were observed. Western blot were used to detect the proliferation-related signaling protein and apoptosis-related protein in A549. Results The treatment with cetuximab resulted in the effect on cell proliferation and apoptosis in a time- and dosedependent manner. The expression of activated key enzymes (p-AKT, p-EGFR, p-MAPK in EGFR signaling transduction pathway were down-regulated more obviously. Conclusion Cetuximab is an effective targeted drug in the treatment of lung cancer cell lines, tissues, most likely to contribute to the inhibition of key enzymes in EGFR signaling transduction pathway.

MicroRNA-944 Affects Cell Growth by Targeting EPHA7 in Non-Small Cell Lung Cancer

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Minxia Liu

2016-09-01

Full Text Available MicroRNAs (miRNAs have critical roles in lung tumorigenesis and development. To determine aberrantly expressed miRNAs involved in non-small cell lung cancer (NSCLC and investigate pathophysiological functions and mechanisms, we firstly carried out small RNA deep sequencing in NSCLC cell lines (EPLC-32M1, A549 and 801D and a human immortalized cell line 16HBE, we then studied miRNA function by cell proliferation and apoptosis. cDNA microarray, luciferase reporter assay and miRNA transfection were used to investigate interaction between the miRNA and target gene. miR-944 was significantly down-regulated in NSCLC and had many putative targets. Moreover, the forced expression of miR-944 significantly inhibited the proliferation of NSCLC cells in vitro. By integrating mRNA expression data and miR-944-target prediction, we disclosed that EPHA7 was a potential target of miR-944, which was further verified by luciferase reporter assay and microRNA transfection. Our data indicated that miR-944 targets EPHA7 in NSCLC and regulates NSCLC cell proliferation, which may offer a new mechanism underlying the development and progression of NSCLC.

MicroRNA-944 Affects Cell Growth by Targeting EPHA7 in Non-Small Cell Lung Cancer.

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Liu, Minxia; Zhou, Kecheng; Cao, Yi

2016-09-26

MicroRNAs (miRNAs) have critical roles in lung tumorigenesis and development. To determine aberrantly expressed miRNAs involved in non-small cell lung cancer (NSCLC) and investigate pathophysiological functions and mechanisms, we firstly carried out small RNA deep sequencing in NSCLC cell lines (EPLC-32M1, A549 and 801D) and a human immortalized cell line 16HBE, we then studied miRNA function by cell proliferation and apoptosis. cDNA microarray, luciferase reporter assay and miRNA transfection were used to investigate interaction between the miRNA and target gene. miR-944 was significantly down-regulated in NSCLC and had many putative targets. Moreover, the forced expression of miR-944 significantly inhibited the proliferation of NSCLC cells in vitro. By integrating mRNA expression data and miR-944-target prediction, we disclosed that EPHA7 was a potential target of miR-944, which was further verified by luciferase reporter assay and microRNA transfection. Our data indicated that miR-944 targets EPHA7 in NSCLC and regulates NSCLC cell proliferation, which may offer a new mechanism underlying the development and progression of NSCLC.

Learning From Trials on Radiation Dose in Non-Small Cell Lung Cancer

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Bradley, Jeffrey, E-mail: jbradley@wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Hu, Chen [Division of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

2016-11-15

In this issue of the International Journal of Radiation Oncology • Biology • Physics, Taylor et al present a meta-analysis of published data supporting 2 findings: (1) radiation dose escalation seems to benefit patients who receive radiation alone for non-small cell lung cancer; and (2) radiation dose escalation has a detrimental effect on overall survival in the setting of concurrent chemotherapy. The latter finding is supported by data but has perplexed the oncology community. Perhaps these findings are not perplexing at all. Perhaps it is simply another lesson in the major principle in radiation oncology, to minimize radiation dose to normal tissues.

Flipped script for gefitinib: A reapproved tyrosine kinase inhibitor for first-line treatment of epidermal growth factor receptor mutation positive metastatic nonsmall cell lung cancer.

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Bogdanowicz, Brian S; Hoch, Matthew A; Hartranft, Megan E

2017-04-01

Purpose The approval history, pharmacology, pharmacokinetics, clinical trials, efficacy, dosing recommendations, drug interactions, safety, place in therapy, and economic considerations of gefitinib are reviewed. Summary Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death. Platinum-based chemotherapy and tyrosine kinase inhibitors, such as erlotinib and afatinib, are recommended therapies for nonsmall cell lung cancer. The European Medicines Association based their approval of gefitinib on the randomized, multicenter Iressa Pan-Asia Study (IPASS, NCT00322452) and a single-arm study showing effectiveness in Caucasians (IFUM, NCT01203917). Both studies were recently referenced by the United States Food & Drug Administration to reapprove gefitinib for the first-line treatment of advanced nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 substitution. Diarrhea, acneiform rash, and interstitial lung disease are known side effects of gefitinib. Conclusion Use of gefitinib for the first-line therapy of metastatic nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions (residues 747-750) or exon 21 substitution mutation (L858R) is well-documented and supported.

Feasibility of Pencil Beam Scanned Intensity Modulated Proton Therapy in Breath-hold for Locally Advanced Non-Small Cell Lung Cancer

DEFF Research Database (Denmark)

Gorgisyan, Jenny; Munck Af Rosenschold, Per; Perrin, Rosalind

2017-01-01

PURPOSE: We evaluated the feasibility of treating patients with locally advanced non-small cell lung cancer (NSCLC) with pencil beam scanned intensity modulated proton therapy (IMPT) in breath-hold. METHODS AND MATERIALS: Fifteen NSCLC patients who had previously received 66 Gy in 33 fractions wi...

Rsf-1 is overexpressed in non-small cell lung cancers and regulates cyclinD1 expression and ERK activity

International Nuclear Information System (INIS)

Li, Qingchang; Dong, Qianze; Wang, Enhua

2012-01-01

Highlights: ► Rsf-1 expression is elevated in non-small cell lung cancers. ► Rsf-1 depletion inhibits proliferation and increased apoptosis in lung cancer cells. ► Rsf-1 depletion decreases the level of cyclinD1 and phosphor-ERK expression. -- Abstract: Rsf-1 (HBXAP) was recently reported to be overexpressed in various cancers and associated with the malignant behavior of cancer cells. However, the expression of Rsf-1 in primary lung cancer and its biological roles in non-small cell lung cancer (NSCLC) have not been reported. The molecular mechanism of Rsf-1 in cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression pattern of Rsf-1 in NSCLC tissues and found that Rsf-1 was overexpressed at both the mRNA and protein levels. There was a significant association between Rsf-1 overexpression and TNM stage (p = 0.0220) and poor differentiation (p = 0.0013). Furthermore, knockdown of Rsf-1 expression in H1299 and H460 cells with high endogenous Rsf-1 expression resulted in a decrease of colony formation ability and inhibition of cell cycle progression. Rsf-1 knockdown also induced apoptosis in these cell lines. Further analysis showed that Rsf-1 knockdown decreased cyclin D1 expression and phospho-ERK levels. In conclusion, Rsf-1 is overexpressed in NSCLC and contributes to malignant cell growth by cyclin D1 and ERK modulation, which makes Rsf-1 a candidate therapeutic target in lung cancer.

A novel imidazopyridine PI3K inhibitor with anticancer activity in non-small cell lung cancer cells.

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Lee, Hyunseung; Kim, Soo Jung; Jung, Kyung Hee; Son, Mi Kwon; Yan, Hong Hua; Hong, Sungwoo; Hong, Soon-Sun

2013-08-01

Lung cancer is the leading cause of cancer-related mortality in the world, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases. Since more than 60% of NSCLC cases express the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors are used to treat NSCLC. However, due to the acquired resistance associated with EGFR-targeted therapy, other strategies for the treatment of NSCLC are urgently needed. Therefore, we investigated the anticancer effects of a novel phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, HS-173, in human NSCLC cell lines. HS-173 demonstrated anti-proliferative effects in NSCLC cells and effectively inhibited the PI3K signaling pathway in a dose‑dependent manner. In addition, it induced cell cycle arrest at G2/M phase as well as apoptosis. Taken together, our results demonstrate that HS-173 exhibits anticancer activities, including the induction of apoptosis, by blocking the PI3K/Akt/mTOR pathway in human NSCLC cell lines. We, therefore, suggest that this novel drug could potentially be used for targeted NSCLC therapy.

Stereotactic Body Radiotherapy for Centrally Located Non-small Cell Lung Cancer

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Yuming WAN

2018-05-01

Full Text Available A few study has proven that about 90% of local control rates might be benefit from stereotactic body radiotherapy (SBRT for patients with medically inoperable stage I non-small cell lung cancer (NSCLC, it is reported SBRT associated overall survival and tumor specific survival is comparable with those treated with surgery. SBRT has been accepted as the first line treatment for inoperable patients with peripheral located stage I NSCLC. However, the role of SBRT in centrally located lesions is controversial for potential toxic effects from the adjacent anatomical structure. This paper will review the definition, indication, dose regimens, dose-volume constraints for organs at risk, radiation technology, treatment side effect of centrally located NSCLC treated with SBRT and stereotactic body proton therapy.

FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

International Nuclear Information System (INIS)

Yan, Jun-Hai; Zhao, Chun-Liu; Ding, Lan-Bao; Zhou, Xi

2015-01-01

The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

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Yan, Jun-Hai; Zhao, Chun-Liu [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China); Ding, Lan-Bao [Department of Nuclear Medicine, Shanghai 10th People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Zhou, Xi, E-mail: modelmap@139.com [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China)

2015-10-09

The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

Efficacy and influence factors of icotinib hydrochloride in treating advanced non-small cell lung cancer.

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Ma, X-H; Tian, T-D; Liu, H-M; Li, Q-J; Gao, Q-L; Li, L; Shi, B

2017-01-01

To evaluate the efficacy and safety of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and discuss the influence factors on efficacy. 120 treatment-experienced patients confirmed by pathology or cytology with stage III B-IV non-small cell lung cancer took icotinib hydrochloride and erlotinib orally until the occurrence of disease progression or serious adverse reactions. Then, the efficacy of icotinib hydrochloride and the related influence factors were analyzed. In icotinib hydrochloride group, the response rate and the disease control rate were 30.00% and 65.00%, and the median progression-free survival time was 179 days (95% CI: 103.21-254.78); in erlotinib group, the response rate and the disease control rate were 25.00% and 56.70%, and the median progression-free survival time was 121 days (95% CI: 95.05-146.94). Moreover, the objective response rate and the disease control rate of second-line therapy were both superior to the third-line and above therapy. The objective response rate of patients with complete response/partial response/stable disease after the first-line therapy was higher than that of patients without response after the first-line therapy (picotinib hydrochloride is effective and safe in treating the treatment-experienced patients with advanced NSCLC, especially for patients with sensitive mutations.

Quality of life assessment as a predictor of survival in non-small cell lung cancer

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Staren Edgar D

2011-08-01

Full Text Available Abstract Background There are conflicting and inconsistent results in the literature on the prognostic role of quality of life (QoL in cancer. We investigated whether QoL at admission could predict survival in lung cancer patients. Methods The study population consisted of 1194 non-small cell lung cancer patients treated at our institution between Jan 2001 and Dec 2008. QoL was evaluated using EORTC-QLQ-C30 prior to initiation of treatment. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression evaluated the prognostic significance of QoL. Results Mean age at presentation was 58.3 years. There were 605 newly diagnosed and 589 previously treated patients; 601 males and 593 females. Stage of disease at diagnosis was I, 100; II, 63; III, 348; IV, 656; and 27 indeterminate. Upon multivariate analyses, global QoL as well as physical function predicted patient survival in the entire study population. Every 10-point increase in physical function was associated with a 10% increase in survival (95% CI = 6% to 14%, p Conclusions Baseline global QoL and physical function provide useful prognostic information in non-small cell lung cancer patients.

Placenta-specific protein 1 promotes cell proliferation and invasion in non-small cell lung cancer

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Yang, Li; Zha, Tian-Qi; He, Xiang; Chen, Liang; Zhu, Quan; Wu, Wei-Bing; Nie, Feng-Qi; Wang, Qian; Zang, Chong-Shuang; Zhang, Mei-Ling; He, Jing; Li, Wei; Jiang, Wen; Lu, Kai-Hua

2018-01-01

Pulmonary carcinoma-associated proteins have emerged as crucial players in governing fundamental biological processes such as cell proliferation, apoptosis and metastasis in human cancers. Placenta-specific protein 1 (PLAC1) is a cancer-related protein, which is activated and upregulated in a variety of malignant tissues, including prostate cancer, gastric adenocarcinoma, colorectal, epithelial ovarian and breast cancer. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression are still unknown. In the present study, we found that PLAC1 was significantly upregulated in NSCLC tissues, and its expression level was associated with advanced pathological stage and it was also correlated with shorter progression-free survival of lung cancer patients. Furthermore, knockdown of PLAC1 expression by siRNA inhibited cell proliferation, induced apoptosis and impaired invasive ability in NSCLC cells partly via regulation of epithelial-mesenchymal transition (EMT)-related protein expression. Our findings present that increased PLAC1 could be identified as a negative prognostic biomarker in NSCLC and regulate cell proliferation and invasion. Thus, we conclusively demonstrated that PLAC1 plays a key role in NSCLC development and progression, which may provide novel insights on the function of tumor-related gene-driven tumorigenesis. PMID:29138842

Cetuximab in combination with chemoradiotherapy in Chinese patients with non-resectable, locally advanced esophageal squamous cell carcinoma: A prospective, multicenter phase II trail

International Nuclear Information System (INIS)

Meng, Xue; Wang, Jianhua; Sun, Xindong; Wang, Lvhua; Ye, Ming; Feng, Pingbo; Zhu, Guangying; Lu, You; Han, Chun; Zhu, Shuchai; Liao, Zhongxing; Yu, Jinming

2013-01-01

Background and purpose: This multicenter phase II trial investigated cetuximab combined with chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC). Material and methods: Eligible patients with non-resectable, locally-advanced ESCC received cetuximab 400 mg/m 2 loading dose on day 1; and on day 1 of the 2nd–7th weeks: cetuximab 250 mg/m 2 , paclitaxel 45 mg/m 2 , and cisplatin 20 mg/m 2 , concurrent with 59.4 Gy/33 fractions of radiation therapy. Primary endpoint was clinical response rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and KRAS status. Results: Of 55 patients enrolled, 45 completed therapy. Forty-four patients had a clinical response: 29 complete response and 15 partial response. One-year PFS and OS of 45 evaluable patients were 84.23% and 93.33%, respectively, and 2-year PFS and OS were 74.87% and 80.00%, respectively. Non-hematologic adverse events were generally grade 1 or 2; primarily rash (92.7%), mucositis (45.5%), fatigue (41.8%), and nausea (38.2%). Grade 3 hematologic adverse events included neutropenia (32.7%) and anemia (1.8%). No KRAS mutations were identified in 50 evaluated samples. Conclusions: Cetuximab can be safely administered with chemoradiotherapy to patients with locally-advanced ESCC and may improve clinical response rate

Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var.

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Jiang, Y Q; Xu, X P; Guo, Q M; Xu, X C; Liu, Q Y; An, S H; Xu, J L; Su, F; Tai, J B

2016-09-02

Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P var. and cisplatin was also significantly inhibited (P var. (P var.-treated stem cells showed significant downregulation of the ABCC1, ABCB1, and LRP mRNA and MRP1, MDR1, and LRP (P var.-mediated downregulation of MRP1, MDR1, and LRP might contribute to the reversal of drug resistance in non-small cell lung cancer stem cells.

Single nucleotide polymorphisms as susceptibility, prognostic, and therapeutic markers of nonsmall cell lung cancer

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Zienolddiny S

2011-12-01

Full Text Available Shanbeh Zienolddiny, Vidar SkaugSection for Toxicology and Biological Work Environment, National Institute of Occupational Health, Oslo, NorwayAbstract: Lung cancer is a major public health problem throughout the world. Among the most frequent cancer types (prostate, breast, colorectal, stomach, lung, lung cancer is the leading cause of cancer-related deaths worldwide. Among the two major subtypes of small cell lung cancer and nonsmall cell lung cancer (NSCLC, 85% of tumors belong to the NSCLC histological types. Small cell lung cancer is associated with the shortest survival time. Although tobacco smoking has been recognized as the major risk factor for lung cancer, there is a great interindividual and interethnic difference in risk of developing lung cancer given exposure to similar environmental and lifestyle factors. This may indicate that in addition to chemical and environmental factors, genetic variations in the genome may contribute to risk modification. A common type of genetic variation in the genome, known as single nucleotide polymorphism, has been found to be associated with susceptibility to lung cancer. Interestingly, many of these polymorphisms are found in the genes that regulate major pathways of carcinogen metabolism (cytochrome P450 genes, detoxification (glutathione S-transferases, adduct removal (DNA repair genes, cell growth/apoptosis (TP53/MDM2, the immune system (cytokines/chemokines, and membrane receptors (nicotinic acetylcholine and dopaminergic receptors. Some of these polymorphisms have been shown to alter the level of mRNA, and protein structure and function. In addition to being susceptibility markers, several of these polymorphisms are emerging to be important for response to chemotherapy/radiotherapy and survival of patients. Therefore, it is hypothesized that single nucleotide polymorphisms will be valuable genetic markers in individual-based prognosis and therapy in future. Here we will review some of the most

Long-term Survival of Personalized Surgical Treatment of Locally Advanced Non-small Cell Lung Cancer Based on Molecular Staging

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Qinghua ZHOU

2011-02-01

Full Text Available Background and objective Approximately 35%-40% of patients with newly diagnosed non-small cell Lung cancer have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy. The aim of this study is to explore and summarize the probability of detection of micrometastasis in peripheral blood for molecular staging, and for selection of indication of surgical treatment, and beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in locally advanced lung cancer; to summarize the long-time survival result of personalized surgical treatment of 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. Methods CK19 mRNA expression of peripheral blood samples was detected in 516 lung cancer patients by RT-PCR before operation for molecular diagnosis of micrometastasis, personalized molecular staging, and for selection of indication of surgical treatment and the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in patients with locally advanced nonsmall cell lung cancer invaded heart, great vessels or both. The long-term survival result of personalized surgical treatment was retrospectively analyzed in 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. Results There were 322 patients with squamous cell carcinoma and 194 cases with adenocarcinoma in the series of 516 patients with locally advanced lung cancer involved heart, great vessels or both. There were 112 patients with IIIA disease and 404 cases with IIIB disease according to P-TNM staging. There were 97 patients with M-IIIA disease, 278 cases with M-IIIB disease and 141 cases with III disease according to our personalized molecular staging. Of the 516 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 256 cases; lobectomy combined with resection and reconstruction of partial left

Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis

NARCIS (Netherlands)

Janssen-Heijnen, M. L. G.; van Erning, F. N.; De Ruysscher, D. K.; Coebergh, J. W. W.; Groen, H. J. M.

Background: Many patients with non-small cell lung cancer (NSCLC) die within the first few years of diagnosis, and considerable excess mortality remains even after 5 years. We investigated the death rate and the distribution of causes of death for NSCLC patients by age and stage at diagnosis during

Predicting the prognosis of non-small cell lung cancer patient treated with conservative therapy using contrast-enhanced MR imaging

International Nuclear Information System (INIS)

Ohno, Y.; Adachi, S.; Motoyama, A.; Sugimura, K.; Kono, M.; Kusumoto, M.

2000-01-01

The aim of this study was to evaluate the therapeutic effect more accurately and predict the prognosis of treated non-small cell lung cancer by using contrast-enhanced magnetic resonance imaging (CE-MRI). Contrast-enhanced computed tomography (CE-CT) and CE-MRI were examined 90 non-small cell lung cancer patients treated with conservative therapies. Enhancement patterns of CE-MRI were classified into three types: peripheral; mottled; and homogeneous. Reduction ratio of tumor size (RRT) based on the World Health Organization response criteria and a new response rate; reduction ratio of viable tumor size (RRVT) which evaluates not only the reduction of tumor size but also changes in necrosis and/or cavity size, were evaluated. Changes of enhancement pattern were compared and correlated with pathological diagnosis. The RRTs, RRVTs, and interobserver agreements evaluated by all modalities were compared. The RRTs and RRVTs in each subgroup were correlated and compared with prognoses. Change of enhancement pattern depended on therapy had no tendency (p = 0.06). Enhancement pattern had significant correlation with pathological diagnosis (p < 0.0001). Partial response (PR) case of RRVT had significant difference between imaging techniques (p = 0.04). The RRVT of other cases and RRT had no significant difference. Interobserver agreements of RRT and RRVT were almost perfect (κ≥ 0.93). Prognosis had better correlation with RRVT than with RRT. Differences of relapse-free survival and survival between patients considered as having no change (NC) by RRT and PR by RRVT (NC-PR) and patients considered as having NC by RRT and RRVT were significant (p = 0.03, p = 0.01). There were no significant differences of relapse-free survival and survival between NC-PR patients and patients considered as having PR by RRT and RRVT. The CE-MRI technique could accurately evaluate the therapeutic effect and predict the prognosis of treated non-small cell lung cancer. (orig.)

The role of prophylactic cranial irradiation in regionally advanced non-small cell lung cancer. A Southwest Oncology Group Study

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Rusch, V.W.; Griffin, B.R.; Livingston, R.B. (Univ. of Washington, Seattle (USA))

1989-10-01

Lung cancer is the most common malignant disease in the United States. Only the few tumors detected very early are curable, but there has been some progress in the management of more advanced non-small cell lung cancer, particularly in regionally inoperable disease. Prevention of central nervous system relapse is an important issue in this group of patients because brain metastases ultimately develop in 20% to 25% of them. Seventy-three patients with regionally advanced non-small cell lung cancer were entered into a Phase II trial of neutron chest radiotherapy sandwiched between four cycles of chemotherapy including cisplatin, vinblastine, and mitomycin C. Prophylactic cranial irradiation was administered concurrently with chest radiotherapy (3000 cGy in 10 fractions in 15 patients; 3600 cGy in 18 fractions in the remaining 50 patients). Patients underwent computed tomographic scan of the brain before treatment and every 3 months after treatment. The initial overall response rate was 79%, but 65 of the 73 patients have subsequently died of recurrent disease. Median follow-up is 9 months for all 73 patients and 26 months for eight long-term survivors. No patient who completed the prophylactic cranial irradiation program had clinical or radiologic brain metastases. Toxic reactions to prophylactic cranial irradiation included reversible alopecia in all patients, progressive dementia in one patient, and possible optic neuritis in one patient. Both of these patients received 300 cGy per fraction of irradiation. The use of prophylactic cranial irradiation has been controversial, but its safety and efficacy in this trial supports its application in a group of patients at high risk for central nervous system relapse. Further evaluation of prophylactic cranial irradiation in clinical trials for regionally advanced non-small cell lung cancer is warranted.

PKC 412 sensitizes U1810 non-small cell lung cancer cells to DNA damage

International Nuclear Information System (INIS)

Hemstroem, Therese H.; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris

2005-01-01

Non-small cell lung carcinoma (NSCLC) is characterized by resistance to drug-induced apoptosis, which might explain the survival of lung cancer cells following treatment. Recently we have shown that the broad-range kinase inhibitor staurosporine (STS) reactivates the apoptotic machinery in U1810 NSCLC cells [Joseph et al., Oncogene 21 (2002) 65]. Lately, several STS analogs that are more specific in kinase inhibition have been suggested for tumor treatment. In this study the apoptosis-inducing ability of the STS analogs PKC 412 and Ro 31-8220 used alone or in combination with DNA-damaging agents in U1810 cells was investigated. In these cells Ro 31-8220 neither induced apoptosis when used alone, nor sensitized cells to etoposide treatment. PKC 412 as a single agent induced death of a small number of U1810 cells, whereas it efficiently triggered a dose- and time-dependent apoptosis in U1285 small cell lung carcinoma cells. In both cell types PKC 412 triggered release of mitochondrial proteins followed by caspase activation. However, concomitant activation of a caspase-independent pathway was essential to kill NSCLC cells. Importantly, PKC 412 was able to sensitize etoposide- and radiation-induced death of U1810 cells. The best sensitization was achieved when PKC 412 was administered 24 h after treatments. In U1810 cells, Ro 31-8220 decreased PMA-induced ERK phosphorylation as efficiently as PKC 412, indicating that the failure of Ro 31-8220 to induce apoptosis was not due to weaker inhibition of conventional and novel PKC isoforms. However, Ro 31-8220 increased the basal level of ERK and Akt phosphorylation in both cell lines, whereas Akt phosphorylation was suppressed in the U1810 cells, which might influence apoptosis. These results suggest that PKC 412 could be a useful tool in increasing the efficiency of therapy of NSCLC

Immune checkpoint inhibitors for nonsmall cell lung cancer treatment

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Yuh-Min Chen

2017-01-01

Full Text Available Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4 and the programmed cell death protein 1 (PD-1 pathway [PD-1/programmed death-ligand 1 (PD-L1] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.

Concurrent chemoradiation therapy in stage III non-small cell lung cancer

International Nuclear Information System (INIS)

Kim, I. A.; Choi, I. B.; Kang, K. M.; Jang, J. Y.; Song, J. S.; Lee, S. H.; Kuak, M. S.; Shinn, K. S.

1997-01-01

This study was tried to evaluate the potential benefits of concurrent chemoradiation therapy. Between April 1992 and March 1994, 32 patients who had stage III non-small cell lung cancer were treated with concurrent chemoradiation therapy. Historical control group consisted of 32 patients who had stage III non-small cell lung cancer were received conventionally fractionated radiation therapy alone. Total radiation dose ranged from 5580 cGy to 7000 cGy with median of 5940 cGy. Complete response rate was higher in chemoradiation therapy (CRT) group than radiation therapy (RT) group. In subgroup analyses for patients with good performance status, CRT group showed significantly higher overall survival rate compared with RT group. The prognostic factors affecting survival rate were performance status and pathologic subtype in CRT group. In RT alone group, performance status and stage (IIIa vs IIIb) were identified as a prognostic factors. The incidence of RTOG/EORTC grade 3-4 pulmonary toxicity ahd no significant differences in between CRT group and RT group (16% vs. 6%). The incidence of WHO grade 3-4 pulmonary fibrosis also had no significant differences in both group (38% vs. 25%). In analyses for relationship of field size and pulmonary toxicity, the patients who treated with field size beyond 200 cm 2 had significantly higher rates of pulmonary toxicities. The CRT group showed significantly higher local control rate than RT group. There were no significant differences of survival rate in status showed higher overall survival rate in CRT group than RT group. In spite of higher incidence of acute toxicities with concurrent chemoradiation therapy, the survival gain in subgroup of patients with good performance status were encouraging. CRT group showed higher rate of early death within 1 year, higher 2 year survival rate compared with RT group. Therefore, to evaluate the accurate effect on survival of concurrent chemoradiation therapy, systematic follow-up for long term

Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.

Science.gov (United States)

Banerjee, Jheelam; Papu John, Arokya M S; Schuller, Hildegard M

2015-12-15

Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients. © 2015 UICC.

Monitoring Response to Antiangiogenic Therapy in Non-Small Cell Lung Cancer Using Imaging Markers Derived from PET and Dynamic Contrast-Enhanced MRI

NARCIS (Netherlands)

de Langen, Adrianus J.; van den Boogaart, Vivian; Lubberink, Mark; Backes, Walter H.; Marcus, Johannes T.; van Tinteren, Harm; Pruim, Jan; Brans, Boudewijn; Leffers, Pieter; Dingemans, Anne-Marie C.; Smit, Egbert F.; Groen, Harry J. M.; Hoekstra, Otto S.

2011-01-01

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell

Induction chemotherapy followed by concurrent radiotherapy and chemotherapy in stage III non-small cell lung cancer

International Nuclear Information System (INIS)

Bouillet, T.; MOrere, J.F.; Piperno-Neuman, S.; Boaziz, C.; Breau, J.L.; Mazeron, J.J.; Haddad, E.

1997-01-01

The purpose was to determine the efficacy and safety of induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of stage III non-small cell lung cancer and whether the response to induction chemotherapy can predict the response to subsequent chemoradiotherapy and survival. In conclusion, there is a statistically significant relationship not only between the response to ICT and the response to CCrt, but also between the response to ICT and the local outcome and survival. (authors)

Novel agents in development for advanced non-small cell lung cancer.

Science.gov (United States)

Stinchcombe, Thomas E

2014-09-01

The identification of EGFR mutations and ALK rearrangements in nonsmall cell lung cancer (NSCLC) has led to the rapid development of targeted therapies and significant changes in the treatment paradigm. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and crizotinib are now standard therapies for patients with the appropriate molecular alteration. Current investigations are determining the mechanisms of resistance to targeted therapies and developing novel agents to combat resistance. For patients with KRAS mutant NSCLC, a phase III trial of the MEK inhibitor, selumetinib, has been initiated. For patients without a defined mutation or a mutation without a known targeted therapy, immunotherapy, ganetespib, nintedanib and MET inhibitors in combination with EGFR TKIs are in development. Preliminary results of phase III trials raise doubts about the future development of dacomitinib as a second-line agent.

Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411.

Directory of Open Access Journals (Sweden)

Sif Holmboe

Full Text Available Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.

Immunohistochemistry for predictive biomarkers in non-small cell lung cancer.

Science.gov (United States)

Mino-Kenudson, Mari

2017-10-01

In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC.

Increasing the accuracy of 18F-FDG PET/CT interpretation of "mildly positive" mediastinal nodes in the staging of non-small cell lung cancer.

LENUS (Irish Health Repository)

Moloney, F

2014-05-01

The aim of this study was to identify radiological factors that may reduce false-positive results and increase diagnostic accuracy when staging the mediastinum of patients with non-small cell lung carcinoma (NSCLC).

Presence of urokinase plasminogen activator, its inhibitor and receptor in small cell lung cancer and non-small cell lung cancer

DEFF Research Database (Denmark)

Pappot, H.; Pfeiffer, P.; Grøndahl Hansen, J.

1997-01-01

Spreading of cancer cells is dependent on the combined action of several proteolytic enzymes, such as serine proteases, comprising the urokinase pathway of plasminogen activation. Previous studies of lung cancer indicate that expression, localization and prognostic impact of the components...... of the plasminogen activation system differ in the different non-small cell lung cancer (NSCLC) types, whereas the expression of the components in small cell lung cancer (SCLC) has only sparingly been investigated. In the present study we investigate the presence of the components of the plasminogen activation...... that the plasminogen activation system could play a role in this type of cancer during invasion. In addition a difference in the levels of the components of the plasminogen activation system in NSCLC and SCLC is found, which could contribute to the differences in biology....

Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Dan PU

2013-11-01

Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments.

Science.gov (United States)

Alifrangis, Costi; Carter, Philip; Cereser, Biancastella; Chandrasinghe, Pramodh; Belluz, Lisa Del Bel; Lim, Eric; Moderau, Nina; Poyia, Fotini; Tabassum, Neha; Zhang, Hua; Krell, Jonathan; Stebbing, Justin

2018-02-27

In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not ( P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group ( P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival.

Reliable and valid assessment of competence in endoscopic ultrasonography and fine-needle aspiration for mediastinal staging of non-small cell lung cancer

NARCIS (Netherlands)

Konge, L.; Vilmann, P.; Clementsen, P.; Annema, J. T.; Ringsted, C.

2012-01-01

Background and study aims: Fine-needle aspiration (FNA) guided by endoscopic ultrasonography (EUS) is important in mediastinal staging of non-small cell lung cancer (NSCLC). Training standards and implementation strategies of this technique are currently under discussion. The aim of this study was

Pre-operative concurrent chemoradiotherapy for stage IIIA (N2) Non-Small cell lung cancer

International Nuclear Information System (INIS)

Lee, Kyu Chan; Ahn, Yong Chan; Park, Keun Chil

1999-01-01

This is to evaluate the acute complication, resection rate, and tumor down-staging after pre-operative concurrent chemoradiotherapy for stage IIIA (N2) non-small cell lung cancer. Fifteen patients with non-small cell lung cancer were enrolled in this study from May 1997 to June 1998 in Samsung Medical Center. The median age of the patients was 61 (range, 45-67) years and male to female ratio was 12:3. Pathologic types were squamous cell carcinoma (11) and adenocarcinoma (4). Pre-operative clinical tumor stages were cT1 in 2 patients, cT2 in 12, and cT3 in 1 and all were N2. Ten patients were proved to be N2 with mediastinoscopic biopsy and five had clinically evident mediastinal lymph node metastases on the chest CT scans. Pre-operative radiation therapy field included the primary tumor, the ipsilateral hilum, and the mediastinum. Total radiation dose was 45 Gy over 5 weeks with daily dose of 1.8 Gy. Pre-operative concurrent chemotherapy consisted of two cycles of intraventous cis-Platin (100 mg/m 2 ) on day 1 and oral Etoposide (50 mg/m 2 /day) on days 1 through 14 with 4 weeks' interval. Surgery was followed after the pre-operative re-evaluation including chest CT scan in 3 weeks of the completion of the concurrent chemoradiotherapy if there was no evidence of disease progression. Full dose radiation therapy was administered to all the 15 patients. Planned two cycles of chemotherapy was completed in 11 patients and one cycle was given to four. One treatment related death of acute respiratory distress syndrome occurred in 15 days of surgery. Hospital admission was required in three patients including one with radiation pneumonitis and two with neutropenic fever. Hematologic complications and other acute complications including esophagitis were tolerable. Resection rate was 92.3% (12/13) in 13 patients excluding two patients who refused surgery. Pleural seeding was found in one patient after thoracotomy and tumor resection was not feasible. Post-operative tumor

Pre-operative concurrent chemoradiotherapy for stage IIIA (N2) Non-Small cell lung cancer

Energy Technology Data Exchange (ETDEWEB)

Lee, Kyu Chan; Ahn, Yong Chan; Park, Keun Chil [College of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)] [and others

1999-06-01

This is to evaluate the acute complication, resection rate, and tumor down-staging after pre-operative concurrent chemoradiotherapy for stage IIIA (N2) non-small cell lung cancer. Fifteen patients with non-small cell lung cancer were enrolled in this study from May 1997 to June 1998 in Samsung Medical Center. The median age of the patients was 61 (range, 45-67) years and male to female ratio was 12:3. Pathologic types were squamous cell carcinoma (11) and adenocarcinoma (4). Pre-operative clinical tumor stages were cT1 in 2 patients, cT2 in 12, and cT3 in 1 and all were N2. Ten patients were proved to be N2 with mediastinoscopic biopsy and five had clinically evident mediastinal lymph node metastases on the chest CT scans. Pre-operative radiation therapy field included the primary tumor, the ipsilateral hilum, and the mediastinum. Total radiation dose was 45 Gy over 5 weeks with daily dose of 1.8 Gy. Pre-operative concurrent chemotherapy consisted of two cycles of intraventous cis-Platin (100 mg/m{sup 2}) on day 1 and oral Etoposide (50 mg/m{sup 2}/day) on days 1 through 14 with 4 weeks' interval. Surgery was followed after the pre-operative re-evaluation including chest CT scan in 3 weeks of the completion of the concurrent chemoradiotherapy if there was no evidence of disease progression. Full dose radiation therapy was administered to all the 15 patients. Planned two cycles of chemotherapy was completed in 11 patients and one cycle was given to four. One treatment related death of acute respiratory distress syndrome occurred in 15 days of surgery. Hospital admission was required in three patients including one with radiation pneumonitis and two with neutropenic fever. Hematologic complications and other acute complications including esophagitis were tolerable. Resection rate was 92.3% (12/13) in 13 patients excluding two patients who refused surgery. Pleural seeding was found in one patient after thoracotomy and tumor resection was not feasible. Post

Stereotactic radiotherapy for non-small cell lung cancer: From concept to clinical reality. 2011 update

International Nuclear Information System (INIS)

Girard, N.; Mornex, F.

2011-01-01

Only 60% of patients with early-stage non-small cell lung cancer (NSCLC), a priori bearing a favorable prognosis, undergo radical resection because of the very frequent co-morbidities occurring in smokers, precluding surgery to be safely performed. Stereotactic radiotherapy consists of the use of multiple radiation micro-beams, allowing high doses of radiation to be delivered to the tumour (ranging from 7.5 to 20 Gy per fraction) in a small number of fractions (one to eight on average). Several studies with long-term follow-up are now available, showing the effectiveness of stereotactic radiotherapy to control stage I/II non-small cell lung cancer in medically inoperable patients. Local control rates are consistently reported to be above 95% with a median survival of 34 to 45 months. Because of these excellent results, stereotactic radiation therapy is now being evaluated in operable patients in several randomized trials with a surgical arm. Ultimately, the efficacy of stereotactic radiotherapy in early-stage tumours leads to hypothesize that it may represent an opportunity for locally-advanced tumors. The specific toxicities of stereotactic radiotherapy mostly correspond to radiation-induced chest wall side effects, especially for peripheral tumours. The use of adapted fractionation schemes has made feasible the use of stereotactic radiotherapy to treat proximal tumours. Overall, from a technical concept to the availability of specific treatment devices and the publication of clinical results, stereotactic radiotherapy represents a model of implementation in thoracic oncology. (authors)

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study

OpenAIRE

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Jianping Xu, Xiaoyan Liu, Sheng Yang, Xiangru Zhang, Yuankai Shi Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People’s Republic of China Background: Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who resp...

[A Paired Case Controlled Study Comparing the Short-term Outcomes of Da Vinci RATS and VATS Approach for Non-small Cell Lung Cancer].

Science.gov (United States)

Dai, Feng; Xu, Shiguang; Xu, Wei; Ding, Renquan; Liu, Bo; Meng, Hao; Kang, Yunteng; Meng, Xiangrui; Lin, Jie; Wang, Shumin

2018-03-20

Da Vinci Surgical System is one of the greatest inventions of the 20th century, which represents the development direction of the precise minimally invasive surgical techniques, the aim of this study was to comparing the short-term outcomes between da Vinci robot-assisted lobectomy and video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer. 45 pairs of non-small cell lung cancer patients underwent pulmonary lobectomy with da Vinci Robotic assisted thoracoscopic (RATS) and VATS approach during the same period from January 2014 to January 2017. The operative time, estimated blood loss (EBL), total number and total groups of dissected lymph nodes, postoperative duration of drainage, the first day volume of drainage, total volume of drainage were compared. No perioperative death and convertion to thoracotomy occured in both groups. There were significant difference between RATS group and VATS group in EBL [(50.30±32.33) mL vs (208.60±132.63) mL], the first day volume of drainage [(275.00±145.42) mL vs (347.60±125.80) mL], the dissected total number [(22.67±9.67) vs (15.51±5.41)] and total team [(6.31±1.43) vs (4.91±1.04)] of lymph node. There were no significant difference in other outcomes. RATS is safe and effective and took better short-outcomes than VATS in non-small cell lung cancer.

Biochip-Based Detection of KRAS Mutation in Non-Small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Barbara Ziegler

2011-11-01

Full Text Available This study is aimed at evaluating the potential of a biochip assay to sensitively detect KRAS mutation in DNA from non-small cell lung cancer (NSCLC tissue samples. The assay covers 10 mutations in codons 12 and 13 of the KRAS gene, and is based on mutant-enriched PCR followed by reverse-hybridization of biotinylated amplification products to an array of sequence-specific probes immobilized on the tip of a rectangular plastic stick (biochip. Biochip hybridization identified 17 (21% samples to carry a KRAS mutation of which 16 (33% were adenocarcinomas and 1 (3% was a squamous cell carcinoma. All mutations were confirmed by DNA sequencing. Using 10 ng of starting DNA, the biochip assay demonstrated a detection limit of 1% mutant sequence in a background of wild-type DNA. Our results suggest that the biochip assay is a sensitive alternative to protocols currently in use for KRAS mutation testing on limited quantity samples.

Postoperative radiotherapy in stage III non-small cell lung cancer: Is a reassessment necessary in modern times?

OpenAIRE

Billiet, Charlotte

2017-01-01

Background: The role of postoperative radiation therapy (PORT) in patients with completely resected non-small cell lung cancer (NSCLC) with pathologically involved mediastinal lymph nodes (N2) remains unclear. Despite a reduction of local recurrence (LR), its effect on overall survival (OS) remains unproven. Therefore we conducted a review of the current literature. Methods: To investigate the benefit and safety of modern PORT, we identified published phase III trials for PORT. We inves...

Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy

NARCIS (Netherlands)

Wink, Krista C. J.; Belderbos, José S. A.; Dieleman, Edith M. T.; Rossi, Maddalena; Rasch, Coen R. N.; Damhuis, Ronald A. M.; Houben, Ruud M. A.; Troost, Esther G. C.

2016-01-01

The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients).

Gene Expression of the EGF System-a Prognostic Model in Non-Small Cell Lung Cancer Patients Without Activating EGFR Mutations

DEFF Research Database (Denmark)

Sandfeld-Paulsen, Birgitte; Folkersen, Birgitte Holst; Rasmussen, Torben Riis

2016-01-01

OBJECTIVES: Contradicting results have been demonstrated for the expression of the epidermal growth factor receptor (EGFR) as a prognostic marker in non-small cell lung cancer (NSCLC). The complexity of the EGF system with four interacting receptors and more than a dozen activating ligands is a l.......17-6.47], P model that takes the complexity of the EGF system into account and shows that this model is a strong prognostic marker in NSCLC patients.......OBJECTIVES: Contradicting results have been demonstrated for the expression of the epidermal growth factor receptor (EGFR) as a prognostic marker in non-small cell lung cancer (NSCLC). The complexity of the EGF system with four interacting receptors and more than a dozen activating ligands...... is a likely explanation. The aim of this study is to demonstrate that the combined network of receptors and ligands from the EGF system is a prognostic marker. MATERIAL AND METHODS: Gene expression of the receptors EGFR, HER2, HER3, HER4, and the ligands AREG, HB-EGF, EPI, TGF-α, and EGF was measured...

Non-cross resistant sequential single agent chemotherapy in first-line advanced non-small cell lung cancer patients: Results of a phase II study

NARCIS (Netherlands)

V. Surmont; J.G.J.V. Aerts (Joachim); K.Y. Tan; F.M.N.H. Schramel (Franz); R. Vernhout (Rene); H.C. Hoogsteden (Henk); R.J. van Klaveren (Rob)

2009-01-01

textabstractBackground. sequential chemotherapy can maintain dose intensity and preclude cumulative toxicity by increasing drug diversity. Purpose. to investigate the toxicity and efficacy of the sequential regimen of gemcitabine followed by paclitaxel in first line advanced stage non-small cell

Cisplatin-mediated radiosensitization of non-small cell lung cancer cells is stimulated by ATM inhibition

International Nuclear Information System (INIS)

Toulany, Mahmoud; Mihatsch, Julia; Holler, Marina; Chaachouay, Hassan; Rodemann, H. Peter

2014-01-01

Background and purpose: Cisplatin activates ataxia-telangiectasia-mutated (ATM), a protein with roles in DNA repair, cell cycle progression and autophagy. We investigated the radiosensitizing effect of cisplatin with respect to its effect on ATM pathway activation. Material and methods: Non-small cell lung cancer cells (NSCLC) cell lines (A549, H460) and human fibroblast (ATM-deficient AT5, ATM-proficient 1BR3) cells were used. The effects of cisplatin combined with irradiation on ATM pathway activity, clonogenicity, DNA double-strand break (DNA-DSB) repair and cell cycle progression were analyzed with Western blotting, colony formation and γ-H2AX foci assays as well as FACS analysis, respectively. Results: Cisplatin radiosensitized H460 cells, but not A549 cells. Radiosensitization of H460 cells was not due to impaired DNA-DSB repair, increased apoptosis or cell cycle dysregulation. The lack of radiosensitization demonstrated for A549 cells was associated with cisplatin-mediated stimulation of ATM (S1981) and AMPKα (T172) phosphorylation and autophagy. However, in both cell lines inhibition of ATM and autophagy by KU-55933 and chloroquine diphosphate (CQ) respectively resulted in a significant radiosensitization. Combined treatment with the AMPK inhibitor compound-C led to radiosensitization of A549 but not of H460 cells. As compared to the treatment with KU-55933 alone, radiosensitivity of A549 cells was markedly stimulated by the combination of KU-55933 and cisplatin. However, the combination of CQ and cisplatin did not modulate the pattern of radiation sensitivity of A549 or H460 cells. In accordance with the results that cisplatin via stimulation of ATM activity can abrogate its radiosensitizing effect, ATM deficient cells were significantly sensitized to ionizing radiation by cisplatin. Conclusion: The results obtained indicate that ATM targeting can potentiate cisplatin-induced radiosensitization

Quantitative proteomics identifies central players in erlotinib resistance of the non-small cell lung cancer cell line HCC827

DEFF Research Database (Denmark)

Jacobsen, Kirstine; Lund, Rikke Raaen; Beck, Hans Christian

Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression when treated. However, all patients relapse due to development of acquired resistance, which in 43-50% of cases are caused...... by a secondary mutation (T790M) in EGFR. Importantly, a majority of resistance cases are still unexplained. Our aim is to identify novel resistance mechanisms in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20...... or other EGFR or KRAS mutations, potentiating the identification of novel resistance mechanisms. We identified 2875 cytoplasmic proteins present in all 4 cell lines. Of these 87, 56 and 23 are upregulated >1.5 fold; and 117, 72 and 32 are downregulated >1.5 fold, respectively, in the 3 resistant clones...

Improving chemotherapy for patients with advanced non-small cell lung cancer

DEFF Research Database (Denmark)

von Plessen, Christian

2011-01-01

INTRODUCTION: Lung cancer is the third most common mortal disease in industrialised countries and the prognosis has been slow to improve. The largest subgroup has locally advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, these patients can usually not be cured and the main...... project. The description of the experiences can serve as an example for the improvement of microsystems in settings with similar problems. Finally, in the registry study of Norwegian patients with lung cancer, we found significant geographical and temporal variations of the utilisation of chemotherapy...... that were related to survival. Potential areas of improvement in the system of care for lung cancer are recruitment of patients in clinical studies, standardisation of the processes of care in outpatient clinics, definition of strategic aims of quality, development of balanced quality indicators, as well...

Quality of life of inoperable non-small cell lung carcinoma

International Nuclear Information System (INIS)

Minet, P.; Chevalier, P.; Gras, A.; Dejardin-Closon, M.T.; Bartsch, P.; Raets, D.; Lennes, G.

1987-01-01

Eighty one patients with inoperable non-small cell lung carcinoma (NSCLC) were entered in a randomized phase II trial comparing split-dose irradiation alone to combined treatment radiotherapy and polychemotherapy (C.A.P. + V.D.S.). The quality of life and the survival of the patients were studied. The authors have defined three classes of quality of life responses based on the time elapsed before the performance status index drops. A higher quality of life failure rate was observed in the combined treatment group (p non-significant) but the time elapsed before the Karnofsky index drops is longer in the combined treatment group for the quality of life 'no change' subgroup (p = 0.15). Survival and quality adjusted survival are similar in both treatment groups. The same conclusion holds for retrospective stratified treatment groups. The authors conclude that as far as the quality of life is concerned, polychemotherapy combined with the particular split-dose irradiation schedule used is an effective treatment of inoperable NSCLC. (Auth.)

Advances in surgical techniques in non-small cell lung cancer.

Science.gov (United States)

Kim, Anthony W; Detterbeck, Frank C

2013-12-01

Thoracic surgery is a dynamic field, and many scientific, technological, technical, and organizational changes are occurring. A prominent example is the use of less invasive approaches to major resection of non-small cell lung cancer (NSCLC), both thoracoscopic and robotic. Sophisticated technology corroborated by clinical data has led to these approaches becoming accepted additions to the armamentarium. Additionally, improvements in perioperative pain management have also contributed to dramatically changing the experience of patients who undergo modern thoracic surgery. Lung cancer is being detected more often at an early stage. At the same time, advances in techniques, patient care, clinical science, and multidisciplinary treatment support an increased role for aggressive resection in the face of larger locally advanced tumors or for those with limited metastatic disease. These advances, conducted in the setting of multidisciplinary decision making, have resulted in real and palpable advancements for patients with lung cancer. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The number and microlocalization of tumor-associated immune cells are associated with patient's survival time in non-small cell lung cancer

International Nuclear Information System (INIS)

Dai, Fuqiang; Liu, Lunxu; Che, Guowei; Yu, Nanbin; Pu, Qiang; Zhang, Shangfu; Ma, Junliang; Ma, Lin; You, Zongbing

2010-01-01

Tumor microenvironment is composed of tumor cells, fibroblasts, endothelial cells, and infiltrating immune cells. Tumor-associated immune cells may inhibit or promote tumor growth and progression. This study was conducted to determine whether the number and microlocalization of macrophages, mature dendritic cells and cytotoxic T cells in non-small cell lung cancer are associated with patient's survival time. Ninety-nine patients with non-small cell lung cancer (NSCLC) were included in this retrospective study. Paraffin-embedded NSCLC specimens and their clinicopathological data including up to 8-year follow-up information were used. Immunohistochemical staining for CD68 (marker for macrophages), CD83 (marker for mature dendritic cells), and CD8 (marker for cytotoxic T cells) was performed and evaluated in a blinded fashion. The numbers of immune cells in tumor islets and stroma, tumor islets, or tumor stroma were counted under a microscope. Correlation of the cell numbers and patient's survival time was analyzed using the Statistical Package for the Social Sciences (version 13.0). The numbers of macrophages, mature dendritic cells and cytotoxic T cells were significantly more in the tumor stroma than in the tumor islets. The number of macrophages in the tumor islets was positively associated with patient's survival time, whereas the number of macrophages in the tumor stroma was negatively associated with patient's survival time in both univariate and multivariate analyses. The number of mature dendritic cells in the tumor islets and stroma, tumor islets only, or tumor stroma only was positively associated with patient's survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets and stroma was positively associated with patient's survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets only or stroma

Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer.

Directory of Open Access Journals (Sweden)

Wang Zhang

Full Text Available This study aimed to understand the role of myeloid cell clusters in uninvolved regional lymph nodes from early stage non-small cell lung cancer patients.Uninvolved regional lymph node sections from 67 patients with stage I-III resected non-small cell lung cancer were immunostained to detect myeloid clusters, STAT3 activity and occult metastasis. Anthracosis intensity, myeloid cluster infiltration associated with anthracosis and pSTAT3 level were scored and correlated with patient survival. Multivariate Cox regression analysis was performed with prognostic variables. Human macrophages were used for in vitro nicotine treatment.CD68+ myeloid clusters associated with anthracosis and with an immunosuppressive and metastasis-promoting phenotype and elevated overall STAT3 activity were observed in uninvolved lymph nodes. In patients with a smoking history, myeloid cluster score significantly correlated with anthracosis intensity and pSTAT3 level (P<0.01. Nicotine activated STAT3 in macrophages in long-term culture. CD68+ myeloid clusters correlated and colocalized with occult metastasis. Myeloid cluster score was an independent prognostic factor (P = 0.049 and was associated with survival by Kaplan-Maier estimate in patients with a history of smoking (P = 0.055. The combination of myeloid cluster score with either lymph node stage or pSTAT3 level defined two populations with a significant difference in survival (P = 0.024 and P = 0.004, respectively.Myeloid clusters facilitate a pro-metastatic microenvironment in uninvolved regional lymph nodes and associate with occult metastasis in early stage non-small cell lung cancer. Myeloid cluster score is an independent prognostic factor for survival in patients with a history of smoking, and may present a novel method to inform therapy choices in the adjuvant setting. Further validation studies are warranted.

Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

Science.gov (United States)

Leung, Elaine Lai-Han; Fiscus, Ronald R.; Tung, James W.; Tin, Vicky Pui-Chi; Cheng, Lik Cheung; Sihoe, Alan Dart-Loon; Fink, Louis M.; Ma, Yupo; Wong, Maria Pik

2010-01-01

Background The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44− cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44− cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44− cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify

Gefitinib in advanced non-small cell lung cancer: does it deserve a second chance?

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Stinchcombe, Thomas E; Socinski, Mark A

2008-09-01

There has been intense investigation into the epidermal growth factor receptor (EGFR) as a therapeutic target in the treatment of non-small cell lung cancer (NSCLC). Currently there are two EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, approved for the treatment of advanced NSCLC. In a phase III trial (BR.21), treatment with erlotinib resulted in a statistically significant improvement in overall survival in patients who had experienced progression after one or two previous chemotherapy treatments in comparison with best supportive care (BSC). In contrast, in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, treatment with gefitinib did not result in a statistically significant improvement in overall survival time in comparison with BSC in patients who had received one or two previous chemotherapy treatments and were refractory to or intolerant of the previous chemotherapy. After the results of the ISEL trial, the U.S. Food and Drug Administration restricted the use of gefitinib, and gefitinib was effectively removed from routine clinical practice within the U.S. However, gefitinib was approved in other countries and clinical trials investigating gefitinib continued. Recently the Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) trial met the primary endpoint of demonstrating noninferiority in terms of overall survival for gefitinib (250 mg daily) in comparison with docetaxel (75 mg/m(2) every 3 weeks). Patients treated with gefitinib experienced a lower rate of treatment-related toxicity and higher rate of improvement in quality of life. Results of recent gefitinib trials have been provocative, and suggest a role for gefitinib in the treatment of advanced NSCLC.

Nontargeted Effect after Radiotherapy in a Patient with Non-Small Cell Lung Cancer and Bullous Pemphigoid

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Carsten Nieder

2015-01-01

Full Text Available Purpose. To describe tumor shrinkage of nonirradiated lung metastases in a patient with non-small cell lung cancer. Case Report. The patient had a concurrent autoimmune condition, bullous pemphigoid, which was clinically exacerbated during radiotherapy of mediastinal and axillary lymph node metastases. He also developed a series of infections during and after irradiation, and we hypothesize that the immunological events during this phase might have influenced the size of the nonirradiated metastases. Conclusion. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells’ activation of tumor-specific T cells. Even if the detailed mechanisms causing nontargeted immune modulatory effects in individual patients are poorly understood, clinical development of radioimmunotherapy is underway.

PET with 18F-fluorodeoxyglucose for staging of non-small cell lung cancer. Evidence-based recommendations and cost-effectiveness

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Weber, W.A.; Schwaiger, M.; Dietlein, M.; Schicha, H.; Hellwig, D.; Kirsch, C.M.

2003-01-01

Aims: To evaluate studies on the use of positron emission tomography with the glucose analog 18 F-fluorodeoxyglucose (FDG-PET) for the preoperative staging of patients with non-small cell lung cancer (NSCLC) according to the criteria of evidence based medicine and to discuss the cost-effectiveness of the technique. Methods: Clinical studies published between 1995 and 2002 on the preoperative staging of non-small cell lung cancer were used for this analysis. Studies that did not meet the criteria published by the European Agency for the Evaluation of Medicinal Products (EMEA) were excluded. The validity of the studies was evaluated by a standardized rating system developed by the Agency for Health Care Policy and Research (AHCPR). Results: For the detection of mediastinal lymph node metastases the mean sensitivity and specificity of FDG-PET on a patient basis is 85% and 87% (16 studies, 1355 patients). In studies that compared FDG-PET and computed tomography (CT) the mean sensitivity of CT was 66% at a specificity of 71%. In the detection of distant metastases FDG-PET correctly changed the tumor stage in 18% of the patients when compared to CT based staging (10 studies, 1073 patients). Five cost effectiveness analyses from the USA, Japan, and Germany concluded that FDG-PET improves the outcome of treatment at reduced or only slightly increased overall costs. Improvement of patient outcome was also demonstrated in a randomized trial, which found that the risk of a futile thoracotomy was reduced by 51% (p=0.003) when FDG-PET was added to the preoperative staging. Conclusion: According to the criteria of the AHCPR the use of FDG-PET for detection of mediastinal lymph node and distant metastases is documented at a level of evidence Ia and Ib, respectively. Since systematic analyses also indicate a favourable cost-effectiveness ratio FDG-PET has to be considered as 'strictly indicated' for the preoperative staging of a non-small cell lung cancer. (orig.) [de

Nrf2 mediates redox adaptation in NOX4-overexpressed non-small cell lung cancer cells

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Wu, Qipeng; Yao, Bei; Li, Ning; Ma, Lei; Deng, Yanchao; Yang, Yang; Zeng, Cheng; Yang, Zhicheng [Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Liu, Bing, E-mail: liubing520@gdpu.edu.cn [Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006 (China)

2017-03-15

The redox adaptation mechanisms in cancer cells are very complex and remain largely unclear. Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and confers apoptosis resistance on NSCLC cells. However, the comprehensive mechanisms for NOX4-mediated oxidative resistance of cancer cells remain still undentified. The present study found that NOX4-derived H{sub 2}O{sub 2} enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) stability via disruption of redox-dependent proteasomal degradation and stimulated its activity through activation of PI3K signaling. Specifically, the results showed that ectopic NOX4 expression did not induce apoptosis of A549 cells; however, inhibition of Nrf2 resulted in obvious apoptotic death of NOX4-overexpressed A549 cells, accompanied by a significant increase in H{sub 2}O{sub 2} level and decrease in GSH content. Besides, inhibition of Nrf2 could suppress cell growth and efficiently reverse the enhancement effect of NOX4 on cell growth. The in vivo data confirmed that inhibition of Nrf2 could interfere apoptosis resistance in NOX4-overexpressed A549 tumors and led to cell growth inhibition. In conclusion, these results reveal that Nrf2 is critically involved in redox adaptation regulation in NOX4-overexpressed NSCLC cells. Therefore, NOX4 and Nrf2 may be promising combination targets against malignant progression of NSCLC. - Highlights: • NOX4-derived H{sub 2}O{sub 2} upregulates Nrf2 expression and activity in NSCLC. • Nrf2 confers apoptosis resistance in NOX4-overexpressed NSCLC cells. • Inhibition of Nrf2 reverses the enhancement effect of NOX4 on cell growth.

TC-1 Overexpression Promotes Cell Proliferation in Human Non-Small Cell Lung Cancer that Can Be Inhibited by PD173074

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Zhang, Na; Bai, Guangzhen; Zhong, Daixing; Su, Kai; Liu, Boya; Li, Xiaofei; Wang, Yunjie; Wang, Xiaoping

2014-01-01

Thyroid cancer-1 (TC-1), a natively disordered protein, is widely expressed in vertebrates and overexpressed in many kinds of tumors. However, its exact role and regulation mechanism in human non-small cell lung cancer (NSCLC) are still unclear. In the present study, we found that TC-1 is highly expressed in NSCLC and that its aberrant expression is strongly associated with NSCLC cell proliferation. Exogenous TC-1 overexpression promotes cell proliferation, accelerates the cell G1-to-S-phase transition, and reduces apoptosis in NSCLC. The knockdown of TC-1, however, inhibits NSCLC cell proliferation, cycle transition, and apoptosis resistance. Furthermore, we also demonstrated that PD173074, which functions as an inhibitor of the TC-1 in NSCLC, decreases the expression of TC-1 and inhibits TC-1 overexpression mediated cell proliferation in vitro and in vivo. Nevertheless, the inhibition function of PD173074 on NSCLC cell proliferation was eliminated in cells with TC-1 knockdown. These results suggest that PD173074 plays a significant role in TC-1 overexpression mediated NSCLC cell proliferation and may be a potential intervention target for the prevention of cell proliferation in NSCLC. PMID:24941347

Cost and effectiveness studies in non-small cell lung cancer

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Pinar Yalcin-Balcik

2015-02-01

Full Text Available Lung cancer disease diagnosis and treatment is costly. As the numbers of inflicted rise so does the economic burden assumed for this cancer type. When the treatment expenditures are considered for all types of cancer, the lung cancer is thought to occupy a 20% share. The disease examined in two basic groups as small-cell lung cancer and non-small cell lung cancer (NSCLC is the most frequently encountered type of its kind nationally and in the World. This study considers the cost, effectiveness and cost effectiveness of platinum based chemotherapy medications with active ingredients pemetrexed and gemcitabine used for NSCLC. A review of studies relevant to the advanced stage NSCLC where majority of patients are positioned is foreseen to be useful to the decision makers since policy makers, regulating authorities and physicians require more information due to increased overall finance and costs, as well as treatment cost effectiveness. Furthermore, due to the entry attempt of pemetrexed active ingredient to the list of reimbursed medications for the first stage lung cancer treatment, it is assumed that a review of studies containing pemetrexed and gemcitabine will draw the attention of decision makers at the Social Security Instutition. [TAF Prev Med Bull 2015; 14(1.000: 55-64

Fusion positron emission/computed tomography underestimates the presence of hilar nodal metastases in patients with resected non-small cell lung cancer.

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Carrillo, Sergio A; Daniel, Vincent C; Hall, Nathan; Hitchcock, Charles L; Ross, Patrick; Kassis, Edmund S

2012-05-01

The 5-year survival for patients with resected stage II (N1) non-small cell lung cancer ranges from 40% to 55%. No data exist addressing the benefit of neoadjuvant therapy for patients with stage II disease. This is largely in part due to the lack of a reliable, minimally invasive method to assess hilar nodes. This study is aimed at determining the ability of fusion positron emission/computed tomography (PET/CT) to identify hilar metastases in patients with resected non-small cell lung cancer. A retrospective review of surgically resected patients with fusion PET/CT within 30 days of resection was performed. The sensitivity, specificity, positive predictive value, and negative predictive value for PET/CT in detecting hilar nodal metastases was calculated for a range of maximum standardized uptake values (SUVmax). Hilar nodes from patients with falsely positive PET/CT scans were analyzed for the presence of histoplasmosis. Additionally, the impact of hilar node size greater than 1 centimeter on the calculated values was assessed. There were 119 patients evaluated. The number of lymph nodes resected ranged from 1 to 12 (X=2.98). There was decreased sensitivity and increased specificity with higher SUVmax cutoff values. At the standard SUVmax value of 2.5, the sensitivity and specificity were only 48.5% and 80.2%. The addition of size of hilar node by CT led to a modest improvement in sensitivity at all SUVmax cutoff values. Fusion PET/CT lacks sensitivity and specificity in identifying hilar nodal metastasis in patients with resected non-small cell lung cancer. Further prospective studies assessing the utility of PET/CT versus alternative sampling techniques are warranted. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Safety and tolerability of combination therapy vs. standard treatment alone for patients with previously treated non-small cell lung cancer | Center for Cancer Research

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Dr. James Gulley is leading a team to test the safety and tolerability of the combination of nivolumab and CV301 to see if it can improve the survival for patientis with metastatic non-small cell lung cancer.  Learn more...

TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

International Nuclear Information System (INIS)

De Miguel, Diego; Gallego-Lleyda, Ana; Erviti-Ardanaz, Sandra; Anel, Alberto; Martinez-Lostao, Luis; Ayuso, José María; Fernández, Luis José; Ochoa, Ignacio; Pazo-Cid, Roberto; Del Agua, Celia

2016-01-01

Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment. (paper)

Human RNA polymerase II associated factor 1 complex promotes tumorigenesis by activating c-MYC transcription in non-small cell lung cancer

International Nuclear Information System (INIS)

Zhi, Xiuyi; Giroux-Leprieur, Etienne; Wislez, Marie; Hu, Mu; Zhang, Yi; Shi, Huaiyin; Du, Kaiqi; Wang, Lei

2015-01-01

Human RNA polymerase II (RNAPII)-associated factor 1 complex (hPAF1C) plays a crucial role in protein-coding gene transcription. Overexpression of hPAF1C has been implicated in the initiation and progression of various human cancers. However, the molecular pathways involved in tumorigenesis through hPAF1C remain to be elucidated. The current study suggested hPAF1C expression as a prognostic biomarker for early stage non-small cell lung cancer (NSCLC) and patients with low hPAF1C expression levels had significantly better overall survival. Furthermore, the expression of hPAF1C was found to be positively correlated with c-MYC expression in patient tumor samples and in cancer cell lines. Mechanistic studies indicated that hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription. These results demonstrated the prognostic value of hPAF1C in early-stage NSCLC and the role of hPAF1C in the transcriptional regulation of c-MYC oncogene during NSCLC tumorigenesis. - Highlights: • hPAF1C expression is a prognostic biomarker for early stage non-small cell lung cancer. • The expression of hPAF1C was positively correlated with c-MYC in tumor samples of patients and in several NSCLC cell lines. • hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription.

High glucose contributes to the proliferation and migration of non-small cell lung cancer cells via GAS5-TRIB3 axis.

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Ding, Cheng-Zhi; Guo, Xu-Feng; Wang, Guo-Lei; Wang, Hong-Tao; Xu, Guang-Hui; Liu, Yuan-Yuan; Wu, Zhen-Jiang; Chen, Yu-Hang; Wang, Jiao; Wang, Wen-Guang

2018-01-24

Despite the growing number of studies exhibited an association of diabetes mellitus (DM) and lung cancer progression, the concrete mechanism of DM aggravating lung cancer has not been elucidated. This study was to investigate whether and how high glucose (HG) contribute to the proliferation and migration of non-small cell lung cancer (NSCLC) cells in vitro. In the present study, we confirmed that HG promoted the proliferation and migration of NSCLC cells, and also induced an anti-apoptosis effect on NSCLC cells. Moreover, HG inhibited the expression of GAS5 in NSCLC cells but elevated the protein level of TRIB3. GAS5 overexpression promoted the degradation of TRIB3 protein by ubiquitination and inhibited the HG induced-proliferation, anti-apoptosis and migration of NSCLC cells. Importantly, TRIB3 overexpression reversed the effects of GAS5 on the HG-treated NSCLC cells. Taken together, down-regulated GAS5 by HG significantly enhanced the proliferation, anti-apoptosis and migration in NSCLC cells through TRIB3, thus promoting the carcinogenesis of NSCLC. ©2018 The Author(s).

Non-Small Cell Carcinoma Biomarker Testing: The Pathologist's Perspective.

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Elisa eBrega

2014-07-01

Full Text Available Biomarker testing has become standard of care for patients diagnosed with non-small cell lung cancer. Although it can be successfully performed in circulating tu-mor cells, at present, the vast majority of investigations are carried out using di-rect tumor sampling, either through aspiration methods, which render most often isolated cells, or tissue sampling, that could range from minute biopsies to large resections. Consequently, pathologists play a central role in this process. Recent evidence suggests that refining NSCLC diagnosis might be clinically signifi-cant, particularly in cases of lung adenocarcinomas (ADC, which in turn, has prompted a new proposal for the histologic classification of such pulmonary neo-plasms. These changes, in conjunction with the mandatory incorporation of biomarker testing in routine NSCLC tissue processing, have directly affected the pathologist’s role in lung cancer work-up. This new role pathologists must play is complex and demanding, and requires a close interaction with surgeons, oncologists, radiologists and molecular pathologists. Pathologists often find themselves as the central figure in the coordination of a process, that involves assuring that the tumor samples are properly fixed, but without disruption of the DNA structure, obtaining the proper diagnosis with a minimum of tissue waste, providing pre-analytical evaluation of tumor samples selected for biomarker testing, which includes assessment of the proportion of tumor to normal tissues, as well as cell viability, and assuring that this entire pro-cess happens in a timely fashion. Therefore, it is part of the pathologist’s respon-sibilities to assure that the samples received in their laboratories, be processed in a manner that allows for optimal biomarker testing. This article goal is to discuss the essential role pathologists must play NSCLC bi-omarker testing, as well as to provide a summarized review of the main NSCLC bi-omarkers of

Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

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Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

2018-03-30

Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

Coxsackie-adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer

International Nuclear Information System (INIS)

Zhang, Xiaochun; Fang, Bingliang; Mohan, Radhe; Chang, Joe Y.

2012-01-01

Background: Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie-adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC. Materials and methods: Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by Western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR-knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays. Results: CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial–mesenchymal transition. Conclusions: We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC.

Relationship between the depression status of patients with resectable non-small cell lung cancer and their family members in China.

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Wu, Xian-Ning; Su, Dan; Li, Hui-Ping; Wang, Wei-Li; Wu, Wei-Qin; Yang, Ya-Juan; Yu, Feng-Lei; Zhang, Jing-Ping

2013-10-01

Less work on depression status has been done with family members of patients with non-small cell lung cancer (NSCLC). This study investigated depression status of patients and their family members; and the relationship of the depression status between these two groups. This cross-sectional study enrolled 194 patients diagnosed with non-small cell lung cancer as well as their family members. In this study, a self-administered General Information Questionnaire was used to collect general information and the Self-rating Depression Scale (SDS) to assess depression status. Linear correlation analysis was used to probe the relationship of the depression status between patients and their family members. Of the 194 patients, 148 (76.3%) showed symptoms of depression. 148 (76.3%) family members had depression symptoms. The severity of depression in patients was positively correlated with that of family members (r = 0.577, p family members suffered depression, and the two were correlated. A prospective study might prove helpful in determining the real relationship existing between the two groups' mental status and whether early detection and intervention might ameliorate this current situation. Copyright © 2013 Elsevier Ltd. All rights reserved.

TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/β-catenin signaling.

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Peng, Yun; Cao, Jun; Yao, Xiao-Yi; Wang, Jian-Xin; Zhong, Mei-Zuo; Gan, Ping-Ping; Li, Jian-Huang

2017-08-08

We investigated the effects of tumor suppressor candidate 3 ( TUSC3 ) on autophagy in human non-small cell lung cancer (NSCLC) cells. A total of 118 NSCLC patients (88 males and 30 females) who underwent surgery at our institute were enrolled in the study. Immunohistochemical analysis revealed that TUSC3 protein expression was lower in NSCLC specimens than adjacent normal tissue. Correspondingly, there was greater methylation of TUSC3 in NSCLC than adjacent normal tissue. After transient transfection of A549 NSCLC cells with constructs designed to up-regulate or down-regulate TUSC3 expression, we analyzed the effects of inhibiting the Wnt pathway (XAV939) and autophagy (chloroquine, CQ) on the behavior of NSCLC cells. We also performed TOP/FOP-Flash reporter assays, MTT assays, Annexin V-FITC/propidium iodide staining, and acridine orange staining to evaluate Wnt/β-catenin signaling, cell proliferation, apoptosis, and autophagy, respectively. Expression of Wnt/β-catenin pathway components and autophagy-related proteins was analyzed using qRT-PCR and Western blotting. We found that TUSC3 inhibited cell proliferation and promoted both apoptosis and autophagy in A549 cells. In addition, TUSC3 increased expression of autophagy-related proteins. It also increased expression of Wnt/β-catenin signaling pathway components and promoted nuclear transfer of β-catenin, resulting in activation of Wnt/β-catenin signaling. TUSC3 thus induces autophagy in human NSCLC cells through activation of the Wnt/β-catenin signaling pathway.

Long-term results of a randomized controlled trial evaluating preoperative chemotherapy in resectable non-small cell lung cancer

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Chen, Zhiwei; Luo, Qingquan; Jian, Hong; Zhou, Zhen; Cheng, Baijun; Lu, Shun; Liao, Meilin

2013-01-01

Zhiwei Chen,* Qingquan Luo,* Hong Jian, Zhen Zhou, Baijun Cheng, Shun Lu, Meilin LiaoShanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equallyObjective: We aimed to evaluate whether preoperative chemotherapy provides benefits in the survival and prognosis of patients with non-small cell lung cancer (NSCLC) in resectable stages I to IIIA, except T1N0. Methods: In this ra...

Novel Anterior Brainstem Magnetic Resonance Imaging Findings in Non-Small Cell Lung Cancer with Leptomeningeal Carcinomatosis

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Chun-Yu Cheng

2017-10-01

Full Text Available Leptomeningeal carcinomatosis (LC is found in around 4% of patients with non-small cell lung cancer (NSCLC. The most common radiological finding of LC is diffuse leptomeningeal enhancement on contrast-enhanced brain magnetic resonance imaging (MRI. Herein, we report a novel brain MRI finding—non-enhanced, band-like, symmetric restricted diffusion along the anterior surface of the brainstem—of LC in four patients with NSCLC. We also identified three additional cases with similar MRI findings in a literature review. We hypothesized that the restricted diffusion along the anterior brainstem was caused by malignant cells concentrating in the cistern around the brainstem and infiltrating into the circumferential perforating arteries along the anterior brainstem surface, which then resulted in microinfarctions.

p53-Independent thermosensitization by mitomycin C in human non-small cell lung carcinoma cells

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Jin, Z.-H.; Matsumoto, H.; Hayashi, S.; Shioura, H.; Kitai, R.; Kano, E.; Hatashita, M.

2003-01-01

The combined treatment with hyperthermia and chemotherapeutic drugs such as cisplatin (CDDP), doxorubicin (DOX) and mitomycin C (MMC) has been widely adopted as a strategy of interdisciplinary cancer therapy to obtain greater therapeutic benefits. However, the involved mechanisms of the interactive cytotoxic effects of hyperthermia and MMC remain unclear. To elucidate the relationship between p53 functions and the interactive effects of the combined treatment with mild-hyperthermia and MMC, we examined the potentiation of cytotoxic effects, the induction of apoptosis, the changes in cell cycles and the accumulation of Hsp72 after the combined treatment with hyperthermia at 42 degree C and MMC using human non-small cell lung carcinoma H1299 transfectants with either null, wild-type (wt) or mutant (m) p53 gene. H1299/null, H1299/wtp53 and H1299/mp53 cells showed similar sensitivities to either hyperthermia at 42 degree C alone or MMC alone. The combined treatment resulted in a synergistically enhanced cytotoxicity in H1299 transfectants in a p53-independent manner. The mechanisms involved an enhancement of heat-induced apoptosis and a modulation of the cell cycle distribution by the combined treatment. The accumulation of Hsp72 was not suppressed by the combined treatment, as is not the case of the combined treatment with hyperthermia and either CDDP (1) or bleomycin (2). Our findings demonstrate a p53-independent mechanism for a synergistically cytotoxic enhancement by the combined treatment with mild-hyperthermia and MMC

Splenomegaly and tumor marker response following selective internal radiation therapy for non-resectable liver metastases from neuroendocrine tumor

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Shehata, M.; Yan, K.; Itoh, Seiji; King, J.; Glenn, D.; Quinn, R.; Morris, D.L.

2009-01-01

The aim of this study was to investigate changes in spleen size, the level of chromogranin A as a tumor marker, and the relationship between these two parameters before and 3 months after selective internal radiation therapy (SIRT) for non-resectable liver metastases from neuroendocrine tumor (NET). Our first serious adverse event with this relatively new treatment is also discussed. A retrospective review of a prospective database identified patients with non-resectable liver metastases from NET who underwent SIRT between 2003 and 2007. Patients who underwent CT scans before and 3 months after treatment were included. The patients were divided into two groups: those with and without a 20% or more increase in splenic volume on the CT scans. The percentages of patients showing a tumor marker response in the two groups were then compared. Fourteen patients were included in the present analysis. A tumor marker response was seen in 6 of 7 patients (85.7%) who showed an increase in splenic volume of >20%, and in 3 of 7 patients (42.9%) without an increase in splenic volume (p=0.266). There was one death as a result of oesophageal variceal bleeding due to portal hypertension at 9 months after treatment. Splenic enlargement after SIRT may be associated with tumor marker response, although this could not be confirmed statistically in this study due to the small number of patients. Long-term splenomegaly and portal hypertension may be important complications of SIRT. This issue needs to be investigated further using a larger number of patients and longer follow-up. (author)

ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer

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Zhao X

2014-02-01

Full Text Available Xiaoting Zhao, Yinan Guo, Wentao Yue, Lina Zhang, Meng Gu, Yue Wang Department of Cellular and Molecular Biology, Beijing TB and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China Background: Multidrug resistance protein 4 (MRP4, also known as ATP-cassette binding protein 4 (ABCC4, is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells. Methods: ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction. Results: ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. Conclusion: ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy. Keywords: ABCC4, cell proliferation, lung cancer, cell cycle

The Evolution of Therapies in Non-Small Cell Lung Cancer

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Boolell, Vishal, E-mail: vishal.boolell@monashhealth.org.au; Alamgeer, Muhammad [Department of Medical Oncology, Monash Medical Centre, 823-865 Centre Road, East Bentleigh VIC 3165 (Australia); Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton VIC 3168 (Australia); Watkins, David N. [Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton VIC 3168 (Australia); Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney NSW 2010 (Australia); UNSW Faculty of Medicine, St Vincent’s Clinical School, 390 Victoria Street, Darlinghurst, Sydney NSW 2010 (Australia); Department of Thoracic Medicine, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney NSW 2010 (Australia); Ganju, Vinod [Department of Medical Oncology, Monash Medical Centre, 823-865 Centre Road, East Bentleigh VIC 3165 (Australia); Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton VIC 3168 (Australia)

2015-09-09

The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.

Difficulties encountered and solutions found when implementing stereotactic radiotherapy of non-small cell lung cancer

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Assouline, A.; Halley, A.; Belghith, B.; Mazeron, J.J.; Feuvret, L.

2012-01-01

The aim of this paper is to describe the difficulties encountered when implementing stereotactic radiotherapy of non-small cell lung cancer (T1-T2, N0, M0) using a voluntary breath-hold technique. From 25/03/2010 to 22/02/2011, eight patients with a non-small cell lung cancer were selected for treatment. CT images were obtained with the patient maintaining breath-hold using a spirometer. Treatment was delivered when the patient maintains this level of breath-hold. Treatment was performed with a 4 MV and 10 MV photon beams from a linear accelerator Varian 2100CS, equipped with a 120 leaves collimator. 60 Gy or 48 Gy were delivered, in four sessions, to the 80% isodose. The planning target volume (PTV) was defined by adding a 5 mm margin to the internal target volume (ITV), the ITV corresponding to the gross tumour volume (GTV) plus a 3 mm margin. CTV is considered equal to GTV. The non-understanding of the gating technique, the great number of beams and the limited breath-hold times led to the failure of some treatments. It can be explained by some patients insufficient respiratory abilities and the low dose rate of one of the beams used for treatment, thus forcing some radiation fields to be delivered in two or three times. Implementing such a technique can be limited by the patients' physical abilities and the materials used. Some solutions were found: a training phase more intense with a coaching of the breath-hold technique more precise, or the use of an abdominal compression device. (authors)

Risk factors and management of oligometastatic non-small cell lung cancer.

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Patel, Akshar N; Simone, Charles B; Jabbour, Salma K

2016-08-01

Non-small cell lung cancer (NSCLC) is an aggressive malignancy with close to half of all patients presenting with metastatic disease. A proportion of these patients with limited metastatic disease, termed oligometastatic disease, have been shown to benefit from a definitive treatment approach. Synchronous and metachronous presentation of oligometastatic disease have prognostic significance, with current belief that metachronous disease is more favorable. Surgical excision of intracranial and extracranial oligometastatic disease has been shown to improve survival, especially in patients with lymph node-negative disease, adenocarcinoma histology and smaller thoracic tumors. Definitive radiation to sites of oligometastatic disease and initial thoracic disease has also been shown to have a similar impact on survival for both intracranial and extracranial disease. Recent studies have reported on the use of targeted agents combined with ablative doses of radiation in the oligometastatic setting with promising outcomes. In this review, we present the historical and current literature describing surgical and radiation treatment options for patients with oligometastatic NSCLC. © The Author(s), 2016.

Surgical treatment in non-small cell lung cancer with pulmonary oligometastasis.

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He, Jinyuan; Li, Yun; An, Jun; Hu, Liu; Zhang, Junhang

2017-02-02

Previous studies have demonstrated survival benefits for local treatment in solitary metastatic non-small cell lung cancer (NSCLC).This study aimed to investigate the effect of local surgery for NSCLC with pulmonary oligometastasis. This study included 21 patients of NSCLC with pulmonary oligometastasis between January 2003 and December 2013, which were divided into two groups, group A (11 cases) for local surgery and group B (10 cases) for systematic chemotherapy, compared the median survival time (MST) and 5-year survival rate between the two groups, and analyzed the impact of the pathological types, the TNM and pN stage of primary tumor, the site, and the mode and number of oligometastatic nodule on group A. The MST of group A and B were 37 and 11.6 months respectively, 5-year survival rates were 18.2 and 9.1% respectively (p  0.05). Local surgery significantly prolonged the overall survival time and 5-year survival rate of primary NSCLC with pulmonary oligometastasis.

Clinical Effects for Patients with Recurrent Advanced Non-small Cell Lung Cancer Treated with Icotinib Hydrochloride

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Jingying NONG

2013-05-01

Full Text Available Background and objective Icotinib hydrochloride is the third single target EGFR-TKI used in clinical treatment of advanced non-small cell lung cancer (NSCLC. Clinical research reports on its efficacy and survival in patients with Recurrent Advanced NSCLC are still little.The aim of this study is to evaluate the efficacy and survival of Icotinib hydrochloride for patients with advanced non-small cell lung cancer who failed to previous chemotherapy and explore the association of clinical features with the efficacy and survival. Methods The clinical data of 60 NSCLC patients referred to the Beijing Chest Hospital, Capital Medical University from March 2009 to July 2012 were retrospectively analyzed. Results The overall response rate (ORR was 45.0% and the disease control rate (DCR was 80.0%. The median progression-free survival (PFS time was 6.7 months. RR and PFS in female were superior to male (P=0.014, 0.013, respectively. RR, DCR in 2nd-line subgroup were superior to ≥3rd-line subgroup (P=0.020, 0.024, respectively. RR, DCR and PFS in EGFR mutation carriers were significantly superior to wild-type patients (P=0.006, <0.001, 0.002, respectively . There was no statistical difference in RR and PFS between those age <65 and ≥65 or PS<2 and PS≥2. There was no statistical difference in RR and DCR between exon 19 deletion and exon 21 mutations, while the former had much longer PFS (P=0.020. EGFR mutation and exon 19 deletion are the independent prognostic factors to significantly improve the PFS (P=0.009, 0.012, respectively. The side effects were generally mild and consisted of rash and diarrhea. Conclusion Icotinib hydrochloride is effective especially in EGFR mutation carriers and well tolerated in patients with recurrent advanced non-small-cell lung cancer.

Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells.

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Tang, Zheng-Hai; Cao, Wen-Xiang; Wang, Zhao-Yu; Lu, Jia-Hong; Liu, Bo; Chen, Xiuping; Lu, Jin-Jian

2017-08-01

Chelerythrine (CHE), a natural benzo[c]phenanthridine alkaloid, shows anti-cancer effect through a number of mechanisms. Herein, the effect and mechanism of the CHE-induced autophagy, a type II programmed cell death, in non-small cell lung cancer (NSCLC) cells were studied for the first time. CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a concentration-dependent manner in NSCLC A549 and NCI-H1299 cells. In addition, CHE triggered the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II). The CHE-induced expression of LC3-II was further increased in the combination treatment with chloroquine (CQ), an autophagy inhibitor, and large amounts of red-puncta were observed in the CHE-treated A549 cells with stable expression of mRFP-EGFP-LC3, indicating that CHE induces autophagy flux. Silence of beclin 1 reversed the CHE-induced expression of LC3-II. Inhibition of autophagy remarkably reversed the CHE-induced cell viability decrease and apoptosis in NCI-H1299 cells but not in A549 cells. Furthermore, CHE triggered reactive oxygen species (ROS) generation in both cell lines. A decreased level of ROS through pretreatment with N-acetyl-L-cysteine reversed the CHE-induced cell viability decrease, apoptosis, and autophagy. Taken together, CHE induced distinctive autophagy in A549 (accompanied autophagy) and NCI-H1299 (pro-death autophagy) cells and a decreased level of ROS reversed the effect of CHE in NSCLC cells in terms of cell viability, apoptosis, and autophagy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The role of positron emission tomography in mediastinal staging of patients with non-small cell lung cancer.

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d'Amico, Andrea; Turska-d'Amico, Maria; Jarzab, Barbara; Zielinski, Marcin

2015-01-01

To examine the diagnostic accuracy of positron emission tomography/computed tomography in evaluating the mediastinum of patients with non-small cell lung cancer compared to histopathology results. The prospective study was conducted at the Department of Thoracic Surgery of the Pulmonary Hospital in Zakopane, Poland, from September 2008 to August 2012 and comprised patients with radiologically-suspected lung cancer. All patients underwent histological verification by either mediastinoscopy alone or thoracotomy with mediastinal lymphanedectomy. Computed tomography and positron emission tomography/computed tomography data sets were compared with the results of the histopathology examinations. There were 80 patients in the study. In the diagnosis of mediastinal lymph nodes, computed tomography was able to detect 9(11.25%) true-positive, 17(21.25%) false-positive, 40(50%) true-negative and 14(17.5%) false-negative cases. The sensitivity, specificity and accuracy of the method were found to be 39%, 70% and 61% respectively, while the positive and negative predictive values were 35% and 74%. Positron emission tomography/computed tomography yielded 15(18.75%) true-positive, 12(15%) false-positive, 46(57.5%) true-negative and 7(8.75%) false-negative cases. Sensitivity was 68% while specificity was 79%. The accuracy was 96%, and the positive and negative predictive values were 55% and 87% respectively. Positron emission tomography/computed tomography had higher diagnostic accuracy than computed tomography in assessing mediastinal lymph nodes of patients with non-small cell lung cancer. However, a positive test requires histopathology confirmation.

Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells.

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Zhou, Fang; Du, Jin; Wang, Jianjun

2017-04-01

Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.

Resistance mechanisms to erlotinib in the non-small cell lung cancer cell line, HCC827 examined by RNA-seq

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Jacobsen, Kirstine; Alcaraz, Nicolas; Ditzel, Henrik

(Illumina) prior to sequencing on an Illumina HiSeq platform (100bp paired end). The resistant subclones were examined both in presence and absence of erlotinib. The data was analyzed by an in-house developed pipeline including quality control by Trim Galore v0.3.3, mapping of reads to HG19 by TopHat2 v.2......Background: Erlotinib, an EGFR selective reversible inhibitor, has dramatically changed the treatment of non-small cell lung cancer (NSCLC) as approximately 70% of patients show significant tumor regression upon treatment. However, all patients eventually relapse due to development of acquired...... - in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively), and prepared cDNA libraries of purified RNA from biological duplicates using TruSeq® Stranded Total RNA Ribo-Zero™ Gold...

Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer

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Jeppesen, Stefan Starup; Schytte, Tine; Jensen, Henrik R

2013-01-01

Abstract Introduction. Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is now an accepted and patient friendly treatment, but still controversy exists about its comparability to conventional radiation therapy (RT). The purpose of this single...... and SBRT predicted improved prognosis. However, staging procedure, confirmation procedure of recurrence and technical improvements of radiation treatment is likely to influence outcomes. However, SBRT seems to be as efficient as conventional RT and is a more convenient treatment for the patients....

Loss of Bad expression confers poor prognosis in non-small cell lung cancer.

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Huang, Yi; Liu, Dan; Chen, Bojiang; Zeng, Jing; Wang, Lei; Zhang, Shangfu; Mo, Xianming; Li, Weimin

2012-09-01

Proapoptotic BH-3-only protein Bad (Bcl-Xl/Bcl-2-associated death promoter homolog, Bad) initiates apoptosis in human cells, and contributes to tumorigenesis and chemotherapy resistant in malignancies. This study explored association between the Bad expression level and prognosis in patients with non-small cell lung cancer (NSCLC). In our study, a cohort of 88 resected primary NSCLC cases were collected and analyzed. Bad expression level was determined via immunohistochemical staining assay. The prognostic significances of Bad expression were evaluated with univariate and multivariate survival analysis. The results showed that compared with normal lung tissues, Bad expression level significantly decreased in NSCLC (P Bad expression was associated with adjuvant therapy status. Loss of Bad independently predicted poor prognosis in whole NSCLC cohort and early stage subjects (T1 + T2 and N0 + N1) (all P Bad negative phenotype in NSCLC patients with smoking history, especially lung squamous cell carcinoma (all P Bad is an independent and powerful predictor of adverse prognosis in NSCLC. Bad protein could be a new biomarker for selecting individual therapy strategies and predicting therapeutic response in subjects with NSCLC.

Assessment and prognostic analysis of EGFR mutations or/and HER2 overexpression in Uygur's Non-small Cell Lung Cancer.

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Shen, Hongli; Du, Guoli; Liu, Zhonghua; Bao, Jianling; Yu, Qin; Jia, Chunli; Liang, Xuelin; Shan, Li

2015-01-01

The epidermal growth factor receptor (EGFR) mutations and human epidermal growth factor receptor HER-2/neu (HER2) have been established roles in the signal transduction pathways leading to cell growth and differentiation. The present study focus on the significance of EGFR mutations combined with HER2 overexpression on survival outcomes in Non-small Cell Lung Cancer patients in Uygur population. A total of 111 consecutive Uygurods: A total of 111 consecutive Cell Lung Cancer under went lung Cell Lung biopsy or surgery at the Affiliated Tumor Hospital of Xin Jiang Medical University between March 2009 and January 2013 were included in this retrospective study. All the patients included had received gefitinib 250 mg once daily. The HER2 expression were evaluated by immunohistochemical staining with score of membranous staining being 0 = none, 1 = weak, 2 = 10-30% cells, 3≥30% cells stained, and Real-time PCR techniques were conducted to detect mutations of EGFR through 21 kinds of human EGFR gene mutation detection kits. A retrospective review of the medical records was analyzed to determine the correlation between the presence of EGFR mutations combined with HER2 overexpression and clinicopathological factors. The overall rate of EGFR mutation was 10.81% (n = 12), which mainly involved exons 19 (83.33%, n = 10), 21 (16.67%, n = 2). The overall rate of HER2 overexpression was 21.62% (n = 24). EGFR mutation combined with HER2 overexpression analysis was performed in 111 patients, with an overall rate of 5.41% (n = 6). Median progression-free survival and overall survival were significantly longer in the EGFR mutations group than in the wild type group (PFS: 10.0±1.5 versus 3.8±1.4 months, P = 0.000; OS: 27.3±2.9 versus 19.1±4.7 months, P = 0.000). The ORR in patients with HER2 overexpression was 29.17%, and 13.80% in those patients with HER2 negative, but no significant difference (P = 0.121). The median PFS and OS in HER2 positive group showed no significant

Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer

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Guo LG

2012-03-01

Full Text Available Liangran Guo1,2,4, Li Fan1,2, Jinfeng Ren1,2, Zhiqing Pang1,2, Yulong Ren1,2, Jingwei Li1,2, Ziyi Wen1,3, Yong Qian1,2, Lin Zhang1,2, Hang Ma4, Xinguo Jiang1,2 1School of Pharmacy, Fudan University, Zhangheng Road, Shanghai, 2Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Shanghai, 3School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; 4College of Pharmacy, University of Rhode Island, RI, USAAbstract: The intractability of non-small cell lung cancer (NSCLC to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4 or 5 (DR5. However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof

Identification of resistance mechanisms in erlotinib-resistant subclones of the non-small cell lung cancer cell line HCC827 by exome sequencing

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Jacobsen, Kirstine; Alcaraz, Nicolas; Lund, Rikke Raaen

the SeqCap EZ Human Exome Library v3.0 kit and whole-exome sequencing of these (100 bp paired-end) were performed on an Illumina HiSeq 2000 platform. Using a recently developed in-house analysis pipeline the sequencing data were analyzed. The analysis pipeline includes quality control using Trim......Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression upon treatment (Santarpia et. al., 2013). However, all patients relapse due to development of acquired resistance, which...... mutations in erlotinib-resistant subclones of the NSCLC cell line, HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively). DNA libraries of each subclone and the parental HCC827 cell line were prepared in biological duplicates using...

Comparison of different threshold 18FDG PET with computer tomography for defining gross tumor volume in non-small cell lung carcinoma

International Nuclear Information System (INIS)

Chen Shaoqing; Yu Jinming; Xing Ligang; Gong Heyi; Fu Zheng; Yang Guoren

2006-01-01

Objective: Under different standard uptake value(SUV), to assess gross tumor volume (GTV) definition for non-small cell lung cancer (NSCLC) with 18-fluoro-deoxy-glueose positron emission tomography( 18 FDG PET) both under definite threshold (42 percent threshold) and various relative threshold (threshold SUV/maximum SUV) derived from the linear regressive function, threshold SUV=0.307 x (mean target SUV) + 0.588, with computer tomography(CT). Methods: Of 20 patients with non-small cell lung cancer, the CT GTV (GTV CT ), PET GTV with 42 percents threshold (GTV 42% ) and PET GTV with relative threshold (GTV relate ) were obtained and compared. Results: The mean GTV 42% , mean GTV relate and mean GTV CT was (13 812.5±13 841.4), (24 325.3±22 454.7) and (28350.9± 26 079.8) mm 3 , respectively, with the difference in mean GTV among these three methods significant (F =. 10, P 42% was smaller than the GTV relate and the GTV CT (P relate and GTV CT (P = 0.125 ). Conclusion: The relative threshold is more suitable to define the gross tumor volume than the definite threshold. (authors)

Clinical significance of preoperative serum albumin level for prognosis in surgically resected patients with non-small cell lung cancer: Comparative study of normal lung, emphysema, and pulmonary fibrosis.

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Miura, Kentaro; Hamanaka, Kazutoshi; Koizumi, Tomonobu; Kitaguchi, Yoshiaki; Terada, Yukihiro; Nakamura, Daisuke; Kumeda, Hirotaka; Agatsuma, Hiroyuki; Hyogotani, Akira; Kawakami, Satoshi; Yoshizawa, Akihiko; Asaka, Shiho; Ito, Ken-Ichi

2017-09-01

This study was performed to clarify whether preoperative serum albumin level is related to the prognosis of non-small cell lung cancer patients undergoing surgical resection, and the relationships between serum albumin level and clinicopathological characteristics of lung cancer patients with emphysema or pulmonary fibrosis. We retrospectively evaluated 556 patients that underwent surgical resection for non-small cell lung cancer. The correlation between preoperative serum albumin level and survival was evaluated. Patients were divided into three groups according to the findings on chest high-resolution computed tomography (normal lung, emphysema, and pulmonary fibrosis), and the relationships between serum albumin level and clinicopathological characteristics, including prognosis, were evaluated. The cut-off value of serum albumin level was set at 4.2g/dL. Patients with low albumin levels (albumin emphysema group (n=48) and pulmonary fibrosis group (n=45) were significantly lower than that in the normal lung group (n=463) (p=0.009 and pulmonary fibrosis groups, but not in the emphysema group. Preoperative serum albumin level was an important prognostic factor for overall survival and recurrence-free survival in patients with resected non-small cell lung cancer. Divided into normal lung, emphysema, and pulmonary fibrosis groups, serum albumin level showed no influence only in patients in the emphysema group. Copyright © 2017 Elsevier B.V. All rights reserved.

BAD overexpression inhibits cell growth and induces apoptosis via mitochondrial-dependent pathway in non-small cell lung cancer.

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Jiang, Li; Luo, Man; Liu, Dan; Chen, Bojiang; Zhang, Wen; Mai, Lin; Zeng, Jing; Huang, Na; Huang, Yi; Mo, Xianming; Li, Weimin

2013-06-01

The pro-apoptotic Bcl-2 protein BAD initiated apoptosis in human cells and has been identified as a prognostic marker in non-small cell lung cancer (NSCLC). In this study, we aimed to explore the functions of BAD in NSCLC. Overexpression of BAD was performed by transfecting different NSCLC cell lines with wild-type BAD. Cell proliferation, cell cycle, apoptosis, and invasion were characterized in vitro. Tumorigenicity was analyzed in vivo. Western blot was performed to determine the effects of BAD overexpression on the Bcl-2 family proteins and apoptosis-related proteins. Overexpression of BAD significantly inhibited cell proliferation in H1299, H292, and SPC-A1 but not in SK-MES-1 and H460 cell lines in vitro. BAD overexpression also reduced the tumorigenicity of H1299/SPC-A1 cell in vivo. However, no appreciable effects on cell cycle distribution and invasion were observed in all these cell lines. BAD overexpression also induced apoptosis in all cell types, in which process expression of mitochondrial cytochrom c (cyto-c) and caspase 3 were increased, whereas Bcl-xl, Bcl-2, Bax and caspase 8 expressions did not changed. These findings indicated that a mitochondrial pathway, in which process cyto-c was released from mitochondrial to activate caspase 3, was involved in BAD overexpression-mediated apoptosis. Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions.

Characteristics of Metastatic Mediastinal Lymph Nodes of Non-Small Cell Lung Cancer on Preoperative F-18 FDG PET/CT

International Nuclear Information System (INIS)

Lee, Ah Young; Choi, Su Jung; Jung, Kyung Pyo; Park, Ji Sun; Lee, Seok Mo; Bae, Sang Kyun

2014-01-01

The aim of this study was to evaluate the characteristics of PET and CT features of mediastinal metastatic lymph nodes on F-18 FDG PET/CT and to determine the diagnostic criteria in nodal staging of non-small cell lung cancer. One hundred four non-small cell lung cancer patients who had preoperative F-18 FDG PET/CT were included. For quantitative analysis, the maximum SUV of the primary tumor, maximum SUV of the lymph nodes (SUVmax), size of the lymph nodes, and average Hounsfield units (aHUs) and maximum Hounsfield units (mHUs) of the lymph nodes were measured. The SUVmax, SUV ratio of the lymph node to blood pool (LN SUV/blood pool SUV), SUV ratio of the lymph node to primary tumor (LN SUV/primary tumor SUV), size, aHU, and mHU were compared between the benign and malignant lymph nodes. Among 372 dissected lymph node stations that were pathologically diagnosed after surgery, 49 node stations were malignant and 323 node stations benign. SUVmax, LN SUV/blood pool SUV, and size were significantly different between the malignant and benign lymph node stations (P <0.0001). However, there was no significant difference in LN SUV/primary tumor SUV (P =0.18), mHU (P =0.42), and aHU (P =0.98). Using receiver-operating characteristic curve analyses, there was no significant difference among these three variables (SUVmax, LN SUV/blood pool SUV, and size). The optimal cutoff values were 2.9 for SUVmax, 1.4 for LN SUV/blood pool SUV, and 5 mm for size. When the cutoff value of SUVmax≥2.9 and size≥5 mm were used in combination, the positive predictive value was 44.2%, and the negative predictive value was 90.9 %. When we evaluated the results based on the histology of the primary tumor, the negative predictive value was 92.3 % in adenocarcinoma (cutoff values of SUVmax≥2.3 and size≥5 mm) and 97.2 % in squamous cell carcinoma (cutoff values of SUVmax≥3.6 and size≥8 mm), separately. In the lymph node staging of non-small cell lung cancer, SUVmax, LN SUV/blood pool SUV

Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

International Nuclear Information System (INIS)

Li, Yuexia; Li, Xiaohui; Liu, Gang; Sun, Rongqing; Wang, Lirui; Wang, Jing; Wang, Hongmin

2015-01-01

Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression

Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

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Li, Yuexia [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Li, Xiaohui [Department of Cardiovascular Surgery, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003 (China); Liu, Gang; Sun, Rongqing; Wang, Lirui [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Jing, E-mail: jing_wang1980@163.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Hongmin, E-mail: hmwangzz@126.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China)

2015-01-30

Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression.

Improved radiotherapy for locally advanced Non-Small Cell Lung Carcinoma (NSCLC) patients

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Ottosson, Wiviann

to comply with the DIBH technique. For DIBH, the patients are guided to hold their breath almost at their maximum inspiration level during imaging and treatment. This leads to reduction of the breathing motion which decreases the movement of the tumor and OARs. It also expands the lung tissue which...... be reduced by the DIBH method for the lung cancer patients. The overall aim of the clinical part of this thesis was to clarify the potential benefit of offering DIBH gating, compared to free-breathing (FB), for lung cancer patients. Particularly, the benefits for locally advanced non-small cell lung cancer...... (NSCLC) patients were explored. For the dosimetric part of the thesis, the dosimetric aspects of correct dose calculations in heterogeneous patient-like geometries were studied. The clinical aspects of DIBH were evaluated in three different studies, where planning and setup verification images acquired...

Short-Term Results of Non-Small Cell Lung Cancer with Curative Radiotherapy

International Nuclear Information System (INIS)

Ahn, Sung Ja; Park, Seung Jin; Chung, Woong Ki; Nah, Byung Sik

1990-01-01

A retrospective analysis was performed on 102 patients with non-small cell lung cancer who received the curative radiotherapy from August 1985 to October 1988 at the Department of Therapeutic Radiology of Chonnam University Hospital. The follow-up period was ranged from 1 to 37 months and the median follow-up time was 15 months. The actuarial 1 and 2 year survival rate of all the patients was 28% and 5%, respectively. The median survival was 10 months for stage II, 6 months for stage III A, and 9 for III B and the actuarial 2 year survival tate was 12.5%, 12.1%, and 0% respectively. The treatment failure was identified in 32 patients and the locoregional failure was seem in 9 patients (28%) and the distant failure in 23 patients (72%). The initial performance status was related to the survival with statistical significance (p 0.05)

[Expression and clinical significance of Pokemon in non-small cell lung cancer].

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Zhao, Zhihong; Wang, Shengfa; Zhang, Tiewa

2007-12-20

Proto-oncogene Pokemon is the special transcription inhibitor of ARF,which can regulate cell growth and differentiation by ARF-P53 path.It may be the important monitoring target of tumor because of being upstream region of many tumor suppressor genes and proto-oncogenes.The aim of this study is to explore the clinical significance of Pokemon gene in non-small cell lung cancer(NSCLC). Immunohistochemistry was applied to detect the expression of Pokemon protein in 92 cases of NSCLC and 20 cases of paracancerous lung tissues.Correlation between abnormal expression of Pokemon with pathologic characteristics and prognosis of NSCLC was analyzed. Pokemon was not expressed in paracancerous lung tissues and was found in 66 of 92(71.7%) cases of lung cancer tissues.Expression of Pokemon was closely related to TNM stages(P=0.011).Survival rate of patients with negative Pokemon expression was significantly higher than that of those with positive Pokemon expression(P=0.0015).Pokemon expression was demonstrated as independent prognostic factor of NSCLC. Pokemon is expressed in NSCLC and it may be identified as a new diagnostic marker.High expression of Pokemon may indicate poor prognosis of patients with NSCLC.

Treatment of Early Stage Non-Small Cell Lung Cancer: Surgery or Stereotactic Ablative Radiotherapy?

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Esengül Koçak Uzel

2015-03-01

Full Text Available The management of early-stage Non-small Cell Lung Cancer (NSCLC has improved recently due to advances in surgical and radiation modalities. Minimally-invasive procedures like Video-assisted thoracoscopic surgery (VATS lobectomy decreases the morbidity of surgery, while the numerous methods of staging the mediastinum such as endobronchial and endoscopic ultrasound-guided biopsies are helping to achieve the objectives much more effectively. Stereotactic Ablative Radiotherapy (SABR has become the frontrunner as the standard of care in medically inoperable early stage NSCLC patients, and has also been branded as tolerable and highly effective. Ongoing researches using SABR are continuously validating the optimal dosing and fractionation schemes, while at the same time instituting its role for both inoperable and operable patients.

Transition from thoracotomy to uniportal video-assisted thoracic surgery in non-small cell lung cancer-the Oslo experience.

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Aamodt, Henrik

2016-01-01

Thoracoscopic surgery has been applied in medicine for more than 100 years. Still it is only within the last decade that it has gained momentum as a method in non-small cell lung cancer (NSCLC) surgery. Several approaches have been published, one of the more resent being uniportal video-assisted thoracic surgery (VATS). In this article we describe the transition from thoracotomy to uniportal VATS in our institution, the last step to uniportal VATS exemplified with two cases performed during our masterclass held in May 2016.

The Relevance of External Quality Assessment for Molecular Testing for ALK Positive Non-Small Cell Lung Cancer : Results from Two Pilot Rounds Show Room for Optimization

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Tembuyser, Lien; Tack, Veronique; Zwaenepoel, Karen; Pauwels, Patrick; Miller, Keith; Bubendorf, Lukas; Kerr, Keith; Schuuring, Ed; Thunnissen, Erik; Dequeker, Elisabeth M. C.

2014-01-01

Background and Purpose: Molecular profiling should be performed on all advanced non-small cell lung cancer with non-squamous histology to allow treatment selection. Currently, this should include EGFR mutation testing and testing for ALK rearrangements. ROS1 is another emerging target. ALK

Chemotherapy related toxicity in locally advanced non-small cell lung cancer

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Bahl Amit

2006-01-01

Full Text Available Background: For inoperable non-small cell lung cancer combined chemotherapy and radiotherapy plays an important role as a therapeutic modality. The aim of the present study was to analyze neoadjuvant chemotherapy related acute toxicity in locally advanced lung cancer (stage IIIA and IIIB in Indian patients using Cisplatin and Etoposide combination chemotherapy. Material and methods: Forty patients of locally advanced Non small cell lung cancer received three cycles neoadjuvant chemotherapy using Injection Cisplatin and Etoposide. The patients were taken for Radical radiotherapy to a dose of 60 Gray over 30 fractions in conventional fractionation after completing chemotherapy. Chemotherapy associated toxicity was assessed using common toxicity criteria (CTC v2.0 Results: Forty patients were available for final evaluation. Median age of presentation of patients was fifty-six years. Thirteen patients had Non small cell lung cancer stage IIIA while twenty-seven patients had Stage IIIB disease. Anemia was the most common hematological toxicity observed (seen in 81% of patients. Nausea and vomiting were the most common non -hematological toxicity seen. Sensory neuropathy was seen in 38%of patients. 88% patients developed alopecia. Seven patients developed febrile neutropenias. Conclusion: Neo-adjuvant chemotherapy using Cisplatin and Etoposide continues to be a basic regimen in the Indian set up despite availability of higher molecules, since it is cost effective, well tolerated and therapeutically effective. Blood transfusions, growth factors and supportive care can be used effectively to over come toxicity associated with this regimen.

Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-Based Virtual Screening

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Qianqian Wang

2018-03-01

Full Text Available Protein arginine methyltransferase 5 (PRMT5 is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors. In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied. MTT results showed that compound T1551 decreased cell viability of A549 and H460 non-small cell lung cancer cell lines. By inhibiting the methyltransferase activity of PRMT5, T1551 reduced the global level of H4R3 symmetric dimethylation (H4R3me2s. T1551 also downregulated the expression of oncogene FGFR3 and eIF4E, and disturbed the activation of related PI3K/AKT/mTOR and ERK signaling in A549 cell. Finally, we investigated the conformational spaces and identified collective motions important for description of T1551/PRMT5 complex by using molecular dynamics simulation and normal mode analysis methods. This study provides a novel non-SAM-competitive hit compound for developing small molecules targeting PRMT5 in non-small cell lung cancer.

An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients

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Hatim I. Alghamdi

2018-03-01

Full Text Available Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs and non-small cell lung cancers (NSCLCs in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs and Non-small cell lung cancers (NSCLCs registered in the Saudi Cancer Registry (SCR for the period 2009–2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC were included in the analysis, all Saudi nationals. A total of 213 (52.75% deaths occurred among lung cancer patients, 108 (54.82% among SCLCs and 105 (50.72% among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p = 0.04; but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p = 0.025 and a significant difference in stage of tumor (p = 0.006 and (p = 0.035 for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR = 5.87, 95% CI: 2.01 – 17.19 in SCLC and by 3-fold (OR = 3.29, 95% CI: 1.22 – 8.85 in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR = 0.36, 95% CI: 0.14 – 0.93. Age, sex, topography

An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients.

Science.gov (United States)

Alghamdi, Hatim I; Alshehri, Ali F; Farhat, Ghada N

2018-03-01

Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs) in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs) and Non-small cell lung cancers (NSCLCs) registered in the Saudi Cancer Registry (SCR) for the period 2009-2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC) were included in the analysis, all Saudi nationals. A total of 213 (52.75%) deaths occurred among lung cancer patients, 108 (54.82%) among SCLCs and 105 (50.72%) among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p=0.04); but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p=0.025) and a significant difference in stage of tumor (p=0.006) and (p=0.035) for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR=5.87, 95% CI: 2.01 - 17.19) in SCLC and by 3-fold (OR=3.29, 95% CI: 1.22 - 8.85) in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR=0.36, 95% CI: 0.14 - 0.93). Age, sex, topography and laterality were not associated with

Anti-tumor effect of bisphosphonate (YM529 on non-small cell lung cancer cell lines

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Date Hiroshi

2007-01-01

Full Text Available Abstract Background YM529 is a newly developed nitrogen-containing bisphosphonate (BP classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC. Methods Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157 were measured by MTS assay and calculated inhibition concentration 50 % (IC50 values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method. We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. Results We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 μM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819. Conclusion Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.

Expression of transcription factor Pokemon in non-small cell lung cancer and its clinical significance.

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Zhao, Zhi-hong; Wang, Sheng-fa; Yu, Liang; Wang, Ju; Chang, Hao; Yan, Wei-li; Fu, Kai; Zhang, Jian

2008-03-05

Transcription factor Pokemon, a central regulation gene of the important tumor suppressor ARF gene, exerted its activity by acting upstream of many tumor-suppressing genes and proto-oncogenes. Its expression in non-small cell lung cancer (NSCLC) and its clinical significance remains unclear. The aim of this study was to investigate the expression of Pokemon in NSCLC and to explore its correlation with the clinical pathological characteristics and its influence on patients' prognosis. Fifty-five cases of NSCLC were involved in this study. The expression of Pokemon in the tumor tissue, the corresponding tumor adjacent tissue and the surrounding tissue was detected via reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, with the aim of investigating the correlation between the expression of Pokemon in tumor tissue of NSCLC and its clinical pathological characteristics. Moreover, a prognostic analysis was carried out based upon the immunohistochemical (IHC) detection of the expression of Pokemon gene in archival tumor specimens (5 years ago) of 62 cases of NSCLC. Statistical significance of the expression of Pokemon mRNA and protein was determined in the tumor tissue, the tumor adjacent tissue and the surrounding tissue (PPokemon was determined not to be associated with the patients' sex, age, smoking condition, tumor differentiation degree, histology and lymph node metastasis condition. However, its relationship with TNM staging was established (PPokemon expression was significantly higher than that of those with positive Pokemon expression (P=0.004), therefore, the expression of Pokemon is believed to be an independent factor affecting prognosis (P=0.034). Pokemon was over-expressed in NSCLC tissue and the expression of Pokemon might be of clinical significance in non-small cell lung cancer prognostic evaluation.

Treatment results of radiotherapy for medically inoperable stage I/II non-small cell lung cancer

International Nuclear Information System (INIS)

Zhang Li; Wang Lvhua; Zhang Hongxing; Chen Dongfu; Xiao Zefen; Wang Mei; Feng Qinfu; Liang Jun; Zhou Zongmei; Ou Guangfei; Lv Jima; Yin Weibo

2008-01-01

Objective: To retrospectively analyze treatment results of radiotherapy for medically inoperable stage I/II non-small cell lung cancer. Methods: Between Jan. 2000 and Dec. 2005, fifty-eight such patients were enrolled into the database analysis, including 37 with clinical stage I and 21 with stage II disease. Fifty patients received radiotherapy alone and eight with radiotherapy and chemotherapy. Forty- three patients were treated with 3-D conformal radiotherapy (3D-CRT) and 15 with conventional radiotherapy. Results: The 1-, 2- and 3-year overall survival rates were 85%, 54% and 30%, and the median survival time was 26.2 months for the whole group. The corresponding figures were 88%, 60%, 36% and 30.8 months for cancer-specific survival; 84%, 64%, 31% and 30.8 months for Stage I disease; 81%, 47%, 28% and 18.8 months for Stage II disease; 95%, 57%, 33% and 30.8 months for 3D-CRT group and 53%, 44%, 24% and 15.3 months for conventional radiotherapy group. By logrank test, tumor volume, pneumonitis of Grade II or higher and weight loss more than 5% showed statistically significant impact on overall survival. Tumor volume was the only independent prognostic factor in Cox multivariable regression. Pneumonitis and esophagitis of Grade II or higher were 16% and 2%, respectively. Age and lung function before treatment had a significant relationship with pneumonitis. Failure included the local recurrence (33%) and distant metastasis (21%). There was no difference between the treatment modalities and failure sites. Conclusions: For medically inoperable early stage non-small cell lung cancer patients, tumor volume is the most important prognostic factor for overall survival. The conformal radiotherapy marginally improves the survival. The age and pulmonary function are related to the incidence of treatment induced pneumonitis. (authors)

Radiofrequency Ablation for Early-Stage Nonsmall Cell Lung Cancer

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Takao Hiraki

2014-01-01

Full Text Available This review examines studies of radiofrequency ablation (RFA of nonsmall cell lung cancer (NSCLC and discusses the role of RFA in treatment of early-stage NSCLC. RFA is usually performed under local anesthesia with computed tomography guidance. RFA-associated mortality, while being rare, can result from pulmonary events. RFA causes pneumothorax in up to 63% of cases, although pneumothorax requiring chest drainage occurs in less than 15% of procedures. Other severe complications are rare. After RFA of stage I NSCLC, 31–42% of patients show local progression. The 1-, 2-, 3-, and 5-year overall survival rates after RFA of stage I NSCLC were 78% to 100%, 53% to 86%, 36% to 88%, and 25% to 61%, respectively. The median survival time ranged from 29 to 67 months. The 1-, 2-, and 3-year cancer-specific survival rates after RFA of stage I NSCLC were 89% to 100%, 92% to 93%, and 59% to 88%, respectively. RFA has a higher local failure rate than sublobar resection and stereotactic body radiation therapy (SBRT. Therefore, RFA may currently be reserved for early-stage NSCLC patients who are unfit for sublobar resection or SBRT. Various technologies are being developed to improve clinical outcomes of RFA for early-stage NSCLC.

FPPS mediates TGF-β1-induced non-small cell lung cancer cell invasion and the EMT process via the RhoA/Rock1 pathway.

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Lin, Lin; Li, Ming; Lin, Lei; Xu, Xiaolin; Jiang, Gening; Wu, Liang

2018-02-05

Farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, was recently shown to play a role in cancer progression. However, its role in non-small cell lung cancer (NSCLC) metastasis and the underlying mechanism remain unclear. In this study, FPPS expression was significantly correlated with TNM stage, and metastasis. Inhibition or knockdown of FPPS blocked TGF-β1-induced cell invasion and epithelial-to-mesenchymal transition (EMT) process. FPPS expression of FPPS was induced by TGF-β1 and FPPS promoted cell invasion and EMT via the RhoA/Rock1 pathway. In conclusion, FPPS mediates TGF-β1-induced lung cancer cell invasion and EMT via the RhoA/Rock1 pathway. These findings suggest new treatment strategies to reduce mortality associated with metastasis in patients with NSCLC. Copyright © 2018 Elsevier Inc. All rights reserved.

Percentages of NKT cells in the tissues of patients with non-small cell lung cancer who underwent surgical treatment.

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Pyszniak, Maria; Rybojad, Paweł; Pogoda, Katarzyna; Jabłonka, Andrzej; Bojarska-Junak, Agnieszka; Tabarkiewicz, Jacek

2014-03-01

Natural killer T (NKT) cells are involved in the antitumor response by direct cytotoxicity and indirectly through activation of effector cells. Recent studies have shown a relationship between the number and function of NKT cells and clinical outcomes. NKT cells seem to represent a promising tool for immunotherapy of cancer. The aim of the study was to evaluate the distribution of NKT cells in peripheral blood, lymph nodes and tumor tissue of non-small cell lung cancer (NSCLC) patients, as well as development of the most efficient set of cytokines stimulating differentiation of NKT cells. We evaluated the percentage of iNKT+CD3+ cells in the tissues collected from patients with NSCLC. For the generation of NKT cells, we cultured cells isolated from the blood of 20 healthy donors and from the tissues of 4 NSCLC patients. Cells were stimulated with α-GalCer in combinations with cytokines. We noted significant differences in the percentages of NKT cells in the patients' tissues. The highest percentage of these cells was observed in the tumor tissue and the lowest in the lymph nodes. In vitro, in healthy donors all α-GalCer-cytokine combinations were effective in stimulation of NKT cells' proliferation. NKT cells' proliferation was the most efficiently stimulated by α-GalCer+IL-2+IL-7 and α-GalCer+IL-2+IFN-γ. Our results suggest that in the course of NSCLC, NKT cells migrate to the primary tumor and accumulate therein. All tested combinations of α-GalCer and cytokines were capable of generation of NKT cells in vitro.

KDM6B Elicits Cell Apoptosis by Promoting Nuclear Translocation of FOXO1 in Non-Small Cell Lung Cancer

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Jun Ma

2015-08-01

Full Text Available Background/Aims: Non-small cell lung carcinoma (NSCLC is the most common type of lung cancer and the cause of most cancer-related deaths. The molecular mechanisms that are involved in NSCLC development are currently not well understood. Accumulating evidence shows that histone demethylases play important roles in the regulation of pathological developmental processes in many diseases, including various types of cancers. Methods: Mitochondrial membrane potential assays, migration and invasion assays, caspase-3 and caspase-9 activity assays and western blot analysis were used in this research. Results: We found that overexpression of KDM6B, a demethylase that acts on histone H3 at lysine 27 (H3K27, inhibited cell growth by initiating mitochondria-dependent apoptosis and by attenuating the invasion-metastasis cascade in NSCLC cells. Moreover, our results showed that KDM6B directly interacted with FOXO1 and that overexpression of KDM6B promoted nuclear accumulation of FOXO1. The effects of KDM6B on cell apoptosis and metastasis were weakened by knockdown of FOXO1 expression. On the contrary, knocking down expression of KDM6B inhibited cell apoptosis and promoted cell growth by mitigating the nuclear translocation of FOXO1 in NSCLC cells. Conclusions: These findings suggest that KDM6B may act in a pro-apoptotic role in NSCLC by causing the nuclear translocation of FOXO1.

Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target.

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Mariëlle I Gallegos Ruiz

Full Text Available BACKGROUND: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC is essential to improve early diagnosis and treatment for this disease. METHODOLOGY AND PRINCIPAL FINDINGS: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%, which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008, survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04. Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. CONCLUSIONS: We suggest that targeting HSP90 will have clinical impact for NSCLC patients.

The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer

DEFF Research Database (Denmark)

Nygaard, Anneli Dowler; Garm Spindler, Karen-Lise; Pallisgaard, Niels

2013-01-01

BACKGROUND: Lung cancer is one of the most common malignant diseases worldwide and associated with considerable morbidity and mortality. New agents targeting the epidermal growth factor system are emerging, but only a subgroup of the patients will benefit from the therapy. Cell free DNA (cf......DNA) in the blood allows for tumour specific analyses, including KRAS-mutations, and the aim of the study was to investigate the possible prognostic value of plasma mutated KRAS (pmKRAS) in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with newly diagnosed, advanced NSCLC eligible....... RESULTS: The study included 246 patients receiving a minimum of 1 treatment cycle, and all but four were evaluable for response according to RECIST. Forty-three patients (17.5%) presented with a KRAS mutation. OS was 8.9 months and PFS by intention to treat 5.4 months. Patients with a detectable plasma...

Clinical outcome of fiducial-less CyberKnife radiosurgery for stage I non-small cell lung cancer

International Nuclear Information System (INIS)

Jung, In Hye; Song, Si Yeol; Cho, Byung Chul; Kwak, Jung Won; Jung, Nuri Hyun; Kim, Su Ssan; Choi, Eun Kyung; Jung, Jin Hong; Je, Hyoung Uk; Choi, Won Sik

2015-01-01

To evaluate the treatment results in early stage non-small cell lung cancer patients who have undergone fiducial-less CyberKnife radiosurgery (CKRS). From June 2011 to November 2013, 58 patients underwent CKRS at Asan Medical Center for stage I lung cancer. After excluding 14 patients, we retrospectively reviewed the records of the remaining 44 patients. All analyses were performed using SPSS ver. 21. The median age at diagnosis was 75 years. Most patients had inoperable primary lung cancer with a poor pulmonary function test with comorbidity or old age. The clinical stage was IA in 30 patients (68.2%), IB in 14 (31.8%). The mean tumor size was 2.6 cm (range, 1.2 to 4.8 cm), and the tumor was smaller than 2 cm in 12 patients (27.3%). The radiation dose given was 48-60 Gy in 3-4 fractions. In a median follow-up of 23.1 months, local recurrence occurred in three patients (2-year local recurrence-free survival rate, 90.4%) and distant metastasis occurred in 13 patients. All patients tolerated the radiosurgery well, only two patients developing grade 3 dyspnea. The most common complications were radiation-induced fibrosis and pneumonitis. Eight patients died due to cancer progression. The results showed that fiducial-less CKRS shows comparable local tumor control and survival rates to those of LINAC-based SABR or CKRS with a fiducial marker. Thus, fiducial-less CKRS using Xsight lung tracking system can be effectively and safely performed for patients with medically inoperable stage I non-small cell lung cancer without any risk of procedure-related complication

Clinical outcome of fiducial-less CyberKnife radiosurgery for stage I non-small cell lung cancer

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Jung, In Hye; Song, Si Yeol; Cho, Byung Chul; Kwak, Jung Won; Jung, Nuri Hyun; Kim, Su Ssan; Choi, Eun Kyung [Dept. of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Jin Hong [Dept. of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul (Korea, Republic of); Je, Hyoung Uk [Dept. of Radiation Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of); Choi, Won Sik [Dept. of Radiation Oncology, Gangneung Asan Hospital, Uiversity of Ulsan College of Medicine, Gangneung (Korea, Republic of)

2015-06-15

To evaluate the treatment results in early stage non-small cell lung cancer patients who have undergone fiducial-less CyberKnife radiosurgery (CKRS). From June 2011 to November 2013, 58 patients underwent CKRS at Asan Medical Center for stage I lung cancer. After excluding 14 patients, we retrospectively reviewed the records of the remaining 44 patients. All analyses were performed using SPSS ver. 21. The median age at diagnosis was 75 years. Most patients had inoperable primary lung cancer with a poor pulmonary function test with comorbidity or old age. The clinical stage was IA in 30 patients (68.2%), IB in 14 (31.8%). The mean tumor size was 2.6 cm (range, 1.2 to 4.8 cm), and the tumor was smaller than 2 cm in 12 patients (27.3%). The radiation dose given was 48-60 Gy in 3-4 fractions. In a median follow-up of 23.1 months, local recurrence occurred in three patients (2-year local recurrence-free survival rate, 90.4%) and distant metastasis occurred in 13 patients. All patients tolerated the radiosurgery well, only two patients developing grade 3 dyspnea. The most common complications were radiation-induced fibrosis and pneumonitis. Eight patients died due to cancer progression. The results showed that fiducial-less CKRS shows comparable local tumor control and survival rates to those of LINAC-based SABR or CKRS with a fiducial marker. Thus, fiducial-less CKRS using Xsight lung tracking system can be effectively and safely performed for patients with medically inoperable stage I non-small cell lung cancer without any risk of procedure-related complication.

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

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Gu, Aiqin; Shi, Chunlei; Xiong, Liwen; Chu, Tianqing; Pei, Jun; Han, Baohui

2013-02-01

To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (Picotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

Erlotinib plus parenteral nutrition: an opportunity to get through the hardest days of advanced non-small cell lung cancer with cancer anorexia-cachexia syndrome.

Science.gov (United States)

Zang, Yuan-Sheng; Fang, Zheng; Li, Bing

2013-03-01

This case study details the poor performance status of a patient with non-small cell lung cancer and cancer anorexia-cachexia syndrome got through the hardest days of high tumor burden and malnutrition, by using a combined therapy of lung cancer-targeted therapy drug and parenteral nutrition. The related literatures were reviewed.

Pain affecting procedures in non-resectable pancreatic carcinoma.

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Plachkov, I; Chernopolski, P; Bozhkov, V; Madjov, R

2013-01-01

Pancreatic cancer is third most common cancer of the gastrointestinal tract in Bulgaria, accouting for 11, 6% in 2008. The leading symptom in patients with pancreatic cancer is the pain. The pain can be related with neoplasms and their metastasis. We should use all kind of resourses for pain relief: conventional drugs (according to the three steps strategy of WHO), interventional or surgical procedures. To present the interventional and surgical techniques in our practice and to share our experience for pain control in patients with nonresectable pancreatic cancer to improve their quality of life. In a seven year period (2004-2011) we performed 59 thoracoscopic splanhnicectomies/30--bilateral/ 4 intraoperative resections of celiac ganglion, 25 CT--control celiac plexus neurolysis and 90 cases pain relief with epidural analgesia. Concerning the quality of life we applied a questionnaire of a spannish medical center " City of Hope" adapted for patients with cancer and the level of pain with visual analogue scale VAS. The long-term duration of the pain relief technique depends on applied technic, of cancer invasion and of the technic itself. The technique with the longest effect are the intraoperative celiac ganglion removal and the bilateral thoracoscopic splanhnicectomy. On the other hand the shortest effect we report the celiac plexus neurolysis, and the epudural analgesia. These data are in correlation with the reduction of the pain shown using VAS thus improving the quality of life. The surgical and interventional methods for control of cancer pain have their own collocation improving the quality of life of these patients. New strategies for the pain control are need in the future.

Cure in a patient with multiple osseus metastases in non-small cell lung cancer: a case report.

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Hawighorst, H; Gademann, G

1993-10-01

This case was reported to describe a case of cure in a 61-year old patient with squamous cell lung cancer and multiple extrathoracic metastasis. A left upper lobectomy of lung for a squamous cell carcinoma was performed on a 61-year old man with curative intent. Four months later two osseus metastases were irradiated with Cobalt 60 up to 40 Gy. The two irradiated lesions showed continuously shrinkage as well as signs of recalcification. Eleven years later the patient shows clinically absolute well being and on CT there are no signs of recurrent disease of the lung or bone anymore. To our knowledge has nobody so far reported of a case of as squamous cell lung cancer which was operated and irradiated on thus resulting in cure. Further on the authors discuss that it might well be worthwhile to define subgroups in stage 4 non-small cell lung cancer (presence of extrathoracic metastases) which might benefit from a more aggressive treatment approach than pure palliation.

Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

DEFF Research Database (Denmark)

Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

2014-01-01

INTRODUCTION: Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice...... NSCLC patients stage T1-4N0-1 was treated with surgery alone without preceding chemotherapy (OP-group). Paired repeated samples were compared in order to evaluate for changes in TUBB3 expression. RESULTS: No statistically significant change in TUBB3 expression was observed between initial diagnostic...... during chemotherapy. MATERIALS AND METHODS: TUBB3 expression was investigated by immunohistochemistry performed on diagnostic biopsies and on available subsequent resection specimens in 65 NSCLC patients stage T1-3N0-2 who received neoadjuvant carboplatin and paclitaxel (NAC-group). Another group of 53...

Induction of apoptosis in non-small cell lung carcinoma A549 cells by PGD₂ metabolite, 15d-PGJ₂.

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Wang, Jun-Jie; Mak, Oi-Tong

2011-11-01

PGD2 (prostaglandin D2) is a mediator in various pathophysiological processes, including inflammation and tumorigenesis. PGD2 can be converted into active metabolites and is known to activate two distinct receptors, DP (PGD2 receptor) and CRTH2/DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). In the past, PGD2 was thought to be involved principally in the process of inflammation. However, in recent years, several studies have shown that PGD2 has anti-proliferative ability against tumorigenesis and can induce cellular apoptosis via activation of the caspase-dependent pathway in human colorectal cancer cells, leukaemia cells and eosinophils. In the lung, where PGD2 is highly released when sensitized mast cells are challenged with allergen, the mechanism of PGD2-induced apoptosis is unclear. In the present study, A549 cells, a type of NSCLC (non-small cell lung carcinoma), were treated with PGD2 under various conditions, including while blocking DP and CRTH2/DP2 with the selective antagonists BWA868C and ramatroban respectively. We report here that PGD2 induces A549 cell death through the intrinsic apoptotic pathway, although the process does not appear to involve either DP or CRTH2/DP2. Similar results were also found with H2199 cells, another type of NSCLC. We found that PGD2 metabolites induce apoptosis effectively and that 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) is a likely candidate for the principal apoptotic inducer in PGD2-induced apoptosis in NSCLC A549 cells.

Randomize Trial of Cisplatin plus Gemcitabine with either Sorafenib or Placebo as First-line Therapy for Non-small Cell Lung Cancer

OpenAIRE

Yan WANG; Lin WANG; Yutao LIU; Shufei YU; Xiangru ZHANG; Yuankai SHI; Yan SUN

2011-01-01

Background and objective Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. Methods Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or ...

The Evolution of Therapies in Non-Small Cell Lung Cancer

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Vishal Boolell

2015-09-01

Full Text Available The landscape of advanced non-small lung cancer (NSCLC therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR mutations and anaplastic lymphoma kinase (ALK gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs. Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4 and programmed death-1 receptor (PD-1, which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.

Garcinol from Garcinia indica Downregulates Cancer Stem-like Cell Biomarker ALDH1A1 in Nonsmall Cell Lung Cancer A549 Cells through DDIT3 Activation.

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Wang, Jinhan; Wang, Liwen; Ho, Chi-Tang; Zhang, Kunsheng; Liu, Qiang; Zhao, Hui

2017-05-10

Nonsmall cell lung cancer (NSCLC) is the predominant type of lung cancer. Patients with NSCLC show high mortality rates because of failure to clean up cancer stem cells (CSCs). The anticancer activity of phytochemical garcinol has been identified in various cancer cell models. However, the effect of garcinol on NSCLC cell lines is still lacking. Of the NSCLC cell lines we tested, A549 cells were the most sensitive to garcinol. Interestingly, Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) was preferentially expressed in A549 cells and downregulated by the addition of garcinol. We also found that garcinol enriched DNA damage-inducible transcript 3 (DDIT3) and then altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in a decreased binding of C/EBPβ to the endogenous ALDH1A1 promoter. Furthermore, garcinol's inhibition of ALDH1A1 was identified in a xenograft mice model. Garcinol repressed ALDH1A1 transcription in A549 cells through alterations in the interaction between DDIT3 and C/EBPβ. Garcinol could be a potential dietary phytochemical candidate for NSCLCs patients whose tumors harbored high ALDH1A1 expression.

Maximizing Benefits from Maintenance Pemetrexed with Stereotactic Ablative Radiotherapy in Oligoprogressive Non-Squamous Non-Small Cell Lung Cancer

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Shao-Lun Lu

2016-08-01

Full Text Available Maintenance pemetrexed offers survival benefit with well-tolerated toxicities for advanced non-squamous non-small cell lung cancer (NSCLC. We present 3 consecutively enrolled patients with advanced non-squamous NSCLC, receiving stereotactic ablative radiotherapy (SABR for oligoprogressive disease during maintenance pemetrexed. All of them had sustained local control of thoracic oligoprogression after the SABR, while maintenance pemetrexed were kept for additionally long progression-free interval. SABR targeting oligoprogression with continued pemetrexed is an effective and safe approach to extend exposure of maintenance pemetrexed, thus maximizing the benefit from it.

Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

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Coffey Matthew C

2009-07-01

Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer

DEFF Research Database (Denmark)

Donnem, Tom; Hald, Sigurd M; Paulsen, Erna-Elise

2015-01-01

PURPOSE: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In non-small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunol....... CONCLUSIONS: Stromal CD8(+) TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore....... immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8(+) tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8(+) TIL density...... from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. RESULTS: Stromal CD8(+) TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P

Hesperidin suppresses the migration and invasion of non-small cell lung cancer cells by inhibiting the SDF-1/CXCR-4 pathway.

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Xia, Rongmu; Xu, Gang; Huang, Yue; Sheng, Xin; Xu, Xianlin; Lu, Hongling

2018-05-15

of CXCR-4. Subsequent RT-qPCR and western blot analyses also confirmed that hesperidin had a significant effect on the expression of EMT-related proteins, including MMP-9, CK-19 and Vimentin, in A549 cells. In summary, we demonstrated that hesperidin inhibited the migratory and invasive capabilities of A549 human non-small cell lung cancer cells by the mediation of the SDF-1/CXCR-4 signaling cascade, thus providing the foundation for the development of hesperidin as a safer and more effective anticancer drug for non-small cell lung cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Polymeric Nanoparticles Containing Taxanes Enhance Chemoradiotherapeutic Efficacy in Non-small Cell Lung Cancer

International Nuclear Information System (INIS)

Jung, Joohee; Park, Sung-Jin; Chung, Hye Kyung; Kang, Hye-Won; Lee, Sa-Won; Seo, Min Hyo; Park, Heon Joo; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

2012-01-01

Purpose: To reduce the side effects and improve the efficacy of chemoradiation therapy, taxanes were incorporated into polymeric nanoparticles (PNP), and their synergic effect on radiation therapy in non-small cell lung cancer was evaluated. Methods and Materials: The properties of PNP-taxanes were characterized by transmission electron microscopy and dynamic light scattering. The chemoradiotherapeutic efficacy of PNP-taxanes was determined by clonogenic assay, cellular morphology, and flow cytometry in A549 cells. In mice bearing A549-derived tumors, the tumor growth delay was examined after the treatment of PNP-taxanes and/or ionizing radiation (IR). Results: The PNP-taxanes were found to be approximately 45 nm in average diameter and to have high solubility in water. They showed the properties of active internalization into cells and preserved the anticancer effect of free taxanes. The survival fraction of A549 cells by clonogenic assay was significantly reduced in the group receiving combined treatment of PNP-taxanes and IR. In addition, in vivo radiotherapeutic efficacy was markedly enhanced by the intravenous injection of PNP-taxanes into the xenograft mice. Conclusions: We have demonstrated the feasibility of PNP-taxanes to enhance the efficacy of chemoradiation therapy. These results suggest PNP-taxanes can hold an invaluable and promising position in treating human cancers as a novel and effective chemoradiation therapy agent.

MEK inhibition in non-small cell lung cancer.

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Stinchcombe, Thomas E; Johnson, Gary L

2014-11-01

KRAS mutations are the most common mutations in non-small cell lung cancer (NSCLC) with adenocarcinoma histology. KRAS mutations result in the activation of the RAF-MEK-ERK pathway, and agents that target RAF-MEK-ERK pathways have been investigated in KRAS mutant NSCLC. The two agents furthest in development are selumetinib and trametinib. Trametinib has greater binding for the MEK1/2 allosteric site, and generally has superior pharmacokinetics. A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival, and a statistically significant improvement in progression-free survival and objective response rate. However, a concerning rate of hospital admission, grade 3 or 4 neutropenia, and febrile neutropenia was observed with the combination. Trials have investigated MEK inhibitors as single agents and in combination with erlotinib, and the data do not support the further development. The activity of MEK inhibitors appears to be similar in patients with KRAS mutant and wild-type NSCLC suggesting KRAS mutation status is not a reliable biomarker for efficacy. It is possible that mutations of genes in addition to KRAS mutations impact the activity of MEK inhibitors, or specific subsets of KRAS mutations may be resistant or susceptible to MEK inhibition. Other potential explanations are gene amplifications, alternative RNA splicing of genes resulting in activation of their protein products, and deregulation of noncoding RNAs and consequent altered protein expression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Wedge resection and segmentectomy in patients with stage I non-small cell lung carcinoma

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Konstantinos Reveliotis

2014-09-01

Full Text Available The use of sublobar resections as definitive management in stage I non-small cell lung carcinoma is a controversial topic in the medical community. We intend to report the latest developments and trends in relative indications for each of the above-mentioned surgical approaches for the treatment of stage I non-small cell lung carcinoma as well as the results of studies regarding local recurrence, disease-free survival and five-year survival rates. We reviewed 45 prospective and retrospective studies conducted over the last 25 years listed in the Pubmed and Scopus electronic databases. Trials were identified through bibliographies and a manual search in journals. Authors, citations, objectives and results were extracted. No meta-analysis was performed. Validation of results was discussed. Segmentectomies are superior to wedge resections in terms of local recurrences and cancer-related mortality rates. Sublobar resections are superior to lobectomy in preserving the pulmonary parenchyma. High-risk patients should undergo segmentectomy, whereas lobectomies are superior to segmentectomies only for tumors >2 cm (T2bN0M0 in terms of disease-free and overall 5-year survival. In most studies no significant differences were found in tumors <2 cm. Disease-free surgical margins are crucial to prevent local recurrences. Systematic lymphadenectomy is mandatory regardless of the type of resection used. In sublobar resections with less thorough nodal dissections, adjuvant radiotherapy can be used. This approach is preferable in case of prior resection. In pure bronchoalveolar carcinoma, segmentectomy is recommended. Sublobar resections are associated with a shorter hospital stay. The selection of the type of resection in T1aN0M0 tumors should depend on characteristic of the patient and the tumor. Patient age, cardiopulmonary reserve and tumor size are the most important factors to be considered. However further prospective randomized trials are needed to

Reliable and valid assessment of competence in endoscopic ultrasonography and fine-needle aspiration for mediastinal staging of non-small cell lung cancer

DEFF Research Database (Denmark)

Konge, Lars; Vilmann, P; Clementsen, P

2012-01-01

Fine-needle aspiration (FNA) guided by endoscopic ultrasonography (EUS) is important in mediastinal staging of non-small cell lung cancer (NSCLC). Training standards and implementation strategies of this technique are currently under discussion. The aim of this study was to explore the reliabilit...... and validity of a newly developed EUS Assessment Tool (EUSAT) designed to measure competence in EUS - FNA for mediastinal staging of NSCLC....

Cytoplasmic RAP1 mediates cisplatin resistance of non-small cell lung cancer.

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Xiao, Lu; Lan, Xiaoying; Shi, Xianping; Zhao, Kai; Wang, Dongrui; Wang, Xuejun; Li, Faqian; Huang, Hongbiao; Liu, Jinbao

2017-05-18

Cytotoxic chemotherapy agents (e.g., cisplatin) are the first-line drugs to treat non-small cell lung cancer (NSCLC) but NSCLC develops resistance to the agent, limiting therapeutic efficacy. Despite many approaches to identifying the underlying mechanism for cisplatin resistance, there remains a lack of effective targets in the population that resist cisplatin treatment. In this study, we sought to investigate the role of cytoplasmic RAP1, a previously identified positive regulator of NF-κB signaling, in the development of cisplatin resistance in NSCLC cells. We found that the expression of cytoplasmic RAP1 was significantly higher in high-grade NSCLC tissues than in low-grade NSCLC; compared with a normal pulmonary epithelial cell line, the A549 NSCLC cells exhibited more cytoplasmic RAP1 expression as well as increased NF-κB activity; cisplatin treatment resulted in a further increase of cytoplasmic RAP1 in A549 cells; overexpression of RAP1 desensitized the A549 cells to cisplatin, and conversely, RAP1 depletion in the NSCLC cells reduced their proliferation and increased their sensitivity to cisplatin, indicating that RAP1 is required for cell growth and has a key mediating role in the development of cisplatin resistance in NSCLC cells. The RAP1-mediated cisplatin resistance was associated with the activation of NF-κB signaling and the upregulation of the antiapoptosis factor BCL-2. Intriguingly, in the small portion of RAP1-depleted cells that survived cisplatin treatment, no induction of NF-κB activity and BCL-2 expression was observed. Furthermore, in established cisplatin-resistant A549 cells, RAP1 depletion caused BCL2 depletion, caspase activation and dramatic lethality to the cells. Hence, our results demonstrate that the cytoplasmic RAP1-NF-κB-BCL2 axis represents a key pathway to cisplatin resistance in NSCLC cells, identifying RAP1 as a marker and a potential therapeutic target for cisplatin resistance of NSCLC.

Limited Impact of Setup and Range Uncertainties, Breathing Motion, and Interplay Effects in Robustly Optimized Intensity Modulated Proton Therapy for Stage III Non-small Cell Lung Cancer

NARCIS (Netherlands)

Inoue, Tatsuya; Widder, Joachim; van Dijk, Lisanne V; Takegawa, Hideki; Koizumi, Masahiko; Takashina, Masaaki; Usui, Keisuke; Kurokawa, Chie; Sugimoto, Satoru; Saito, Anneyuko I; Sasai, Keisuke; Van't Veld, Aart A; Langendijk, Johannes A; Korevaar, Erik W

2016-01-01

Purpose: To investigate the impact of setup and range uncertainties, breathing motion, and interplay effects using scanning pencil beams in robustly optimized intensity modulated proton therapy (IMPT) for stage III non-small cell lung cancer (NSCLC). Methods and Materials: Three-field IMPT plans

Pilot study of alternating radiotherapy and three-drug combined chemotherapy consisting of ifosfamide, cisplatin and vindesine in localized inoperable non-small cell lung cancer

International Nuclear Information System (INIS)

Rikimaru, Toru; Tanaka, Yasuyuki; Ichikawa, Yoichiro; Oizumi, Kotaro; Fukurono, Kazuyoshi; Hayabuchi, Naofumi

1993-01-01

During the period from February 1991 through October 1992, we conducted a pilot phase II trial of an 'Alternating Radiotherapy and Chemotherapy' for 15 patients with localized inoperable non-small cell lung cancer. The combined regimen, consisting of ifosfamide 1.5 g/m 2 on days 1 through 3, cisplatin 80 mg/m 2 and vindesine 3 mg/m 2 on day 1, was given repeatedly every 4 weeks. Patients were treated in a split course fashion with combination chemotherapy sandwiched between radiation therapy (total dose 60 Gy). Of 15 evaluable patients, complete remission, partial remission and no change were obtained in 1, 13 and 1 patients, respectively, with an overall response rate of 93.3%. The median survival for all patients was 62 weeks. Hematologic toxicity was severe and was judged to be dose limiting. It was, however, clinically manageable with colony stimulating factor. These results indicate that this alternating radiotherapy and chemotherapy is feasible for localized non-small cell lung cancer and warrants further clinical trials. (author)

Jolkinolide B inhibits glycolysis by downregulating hexokinase 2 expression through inactivating the Akt/mTOR pathway in non-small cell lung cancer cells.

Science.gov (United States)

Gao, Xiang; Han, Han

2018-06-01

Jolkinolide B (JB), a bioactive compound isolated from herbal medicine, has been found to inhibit tumor growth by altering glycolysis. However, whether glycolysis is influenced by JB in non-small cell lung cancer (NSCLC) cells and the mechanism remain unknown. The aim of the present study was to evaluate the effect of JB on the glycolysis in NSCLC cells and the underlying molecular mechanism. The results showed that JB treatment inhibited cell viability of A549 and H1299 cells in a concentration-dependent manner. JB reduced the glucose consumption, lactate production, and HK2 expression. The expressions of p-Akt and p-mTOR were also decreased by JB treatment. Knockdown of HK2 reduced glucose consumption and lactate production. Inhibition of the Akt/mTOR pathway decreased HK2 expression and inhibited glycolysis. In conclusion, the results indicated that JB inhibits glycolysis by down-regulating HK2 expression through inactivating the Akt/mTOR pathway in NSCLC cells, suggesting that JB might be a potential therapeutic agent for the treatment of NSCLC. © 2018 Wiley Periodicals, Inc.

Risk factors for venous thromboembolism in non-small cell lung cancer%非小细胞肺癌合并静脉血栓栓塞症危险因素研究

Institute of Scientific and Technical Information of China (English)

毕乙瑶; 张莹; 艾力曼·马合木提; 王在义; 刘晖

2017-01-01

目的 探讨非小细胞肺癌(NSCLC)患者发生静脉血栓栓塞症(VTE)的危险因素.方法 回顾性分析2005年1月至2016年1月新疆医科大学第一附属医院收治的57例NSCLC合并VTE患者的资料,选取同期在我院确诊为NSCLC的患者105例,用二元logistic回归分析NSCLC患者并发VTE的可能危险因素.结果 二元logistic回归多因素分析显示,化疗(OR =5.91,95％CI:1.47～10.76)、白细胞＞11×109/L(OR=7.54,95％ CI:1.69～13.25)、白蛋白＜35 g/L(OR =5.25,95％ CI:1.89～12.42)、D-二聚体＞500 μg/L(OR=25.16,95％ CI:7.87～80.41)与NSCLC患者发生VTE存在显著的相关关系.结论 化疗、白细胞＞1i×109/L、白蛋白＜35 g/L、D-二聚体＞500 μg/L是NSCLC患者并发VTE的独立危险因素.%Objective To discuss risk factors of venous thromboembolism (VTE) in patients with non-small cell lung cancer.Methods We retrospectively analyzed the data of patients with non-small cell lung cancer combined with VTE (n =57) and patients with non-small cell lung cancer (n =105) in the First Affiliated Hospital of Xinjiang Medical University from January 2005 to January 2016.Using binary logistic regression model,we examined risk factors in non-small cell lung cancer associatied with VTE.Results Multivariable analysis in binary logistic regression model showed that chemotherapy (OR =5.91,95％ CI:1.47-10.76),white blood cell ＞ 11 × 109/L(OR =7.54,95％ CI:1.69-13.25),albumin ＜35 g/L(OR =5.25,95％ CI:1.89-12.42),D-dimer ＞500 μg/L (OR =25.16,95％ CI:7.87-80.41)were independently associated with VTE.Conclusions Chemotherapy,white blood cell ＞ 11 × 109/L,albumin ＜35 g/L,D-dimer ＞500 μg/L are independent risk factors for incident VTE in patients with non-small cell lung cancer.

Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

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Jia Shen

2017-07-01

Full Text Available Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

Prognostic value of pretreatment serum carcinoembryonic antigen and squamous cell carcinoma antigen levels for patients with stage I-III non-small cell lung cancer treated with radiation therapy alone

International Nuclear Information System (INIS)

Saito, Yoshihiro; Mitsuhashi, Norio; Hayakawa, Kazushige

1998-01-01

Serum carcinoembryonic antigen (CEA) and serum squamous cell carcinoma antigen (SCC Ag) levels have been reported to be useful as prognostic factors, indicators of clinical response, and predictors for recurrence in patients with lung cancer treated by surgery or chemotherapy. We investigated whether pretreatment serum CEA and SCC Ag levels were useful as independent prognostic factors in patients with stage I to III non-small cell lung cancer who were treated with radiation therapy alone. The serum CEA and SCC Ag levels were measured in 158 and 47 patients, respectively, before radiation therapy. Serum CEA and SCC Ag levels were measured by sandwich radioimmunoassay using the CEA-RIA (radioimmunoassay) kit and the SCC-RIA kit. Serum CEA and SCC Ag levels were above reference values in 19% and 30% of the patients, respectively. The 5-year survival rates were significantly better for patients with a negative SCC Ag result than for those with positive SCC Ag levels (p=0.0001), though no significant difference in survival rates was seen by CEA positivity (p=0.25). SCC Ag positivity (p=0.0006) and stage (p=0.04) were the important prognostic factors, as determined by multivariate analyses. Pretreatment serum SCC Ag level may be useful as an independent prognostic factor in patients with stage I to III non-small cell lung cancer who are treated with radiation therapy alone. (author)

Smoking habits of patients with newly diagnosed stage IIIA/IIIB non-small cell lung cancer

International Nuclear Information System (INIS)

Sloan, J.; Bonner, J.A.; McGinnis, W.L.; Stella, P.; Marks, R.

1997-01-01

Purpose: This study was performed to assess the smoking habits and changes in the cigarette smoking habits of patients prior to, at the time of and after the diagnosis of unresectable stage IIIA/IIIB non-small cell lung cancer. Methods: Patients with the diagnosis of unresectable stage IIIA/IIIB non-small cell lung cancer who had agreed to enter a phase III North Central Cancer Treatment Group Trial comparing twice daily thoracic radiation therapy (TRT) given with chemotherapy to once daily TRT given with chemotherapy were asked to fill out a questionnaire regarding their past and present cigarette smoking habits. This questionnaire included information regarding the number of years of smoking, number of packs of cigarettes smoked per day and the time frame of smoking history. Subsequently, patients were given questionnaires to assess changes in smoking history at the halfway point of treatment, and during follow-up visits. Results: Of the 140 patients who were entered on the above noted trial, 132 filled out baseline questionnaires and were the subject of this study. Of these 132 patients, 126 (95%) had either smoked cigarettes in the past or smoked at the time of study entry. The median pack years of smoking. (years of smoking x packs per day) was 43 with a range of 3-169 pack years. Of the 126 patients with a smoking history, 124 provided information regarding the status of their smoking at the time of entry on the study: 89 (72%) claimed to have quit smoking and, 35 (28%) reported that they continued to smoke an average of one pack per day. Of the 89 patients who had quit smoking, roughly one third had quit within the month before study entry and 45% had quit during the 8 month period prior to entry on the study. Of the 35 patients who continued to smoke at the time of entry on the study, 21 indicated that they stopped smoking during the period following randomization. Hence 10% of the original 140 patients entered on study continued to smoke an average of one

Recent advances in the treatment of non-small cell and small cell lung cancer.

Science.gov (United States)

Stinchcombe, Thomas E

2014-01-01

Recent presentations at the American Society of Clinical Oncology (ASCO) meeting from 30 May to 3 June, 2014, will impact routine clinical care and the development of clinical trials in non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (ES-SCLC). Patients with activating epidermal growth factor receptor (EGFR) mutations, defined as exon 19 and exon 21 L858R point mutations, experience a high objective response rate and prolonged progression-free survival with EGFR tyrosine kinase inhibitors. However, inevitably, patients experience disease progression and the most common mechanism of acquired resistance is an EGFR exon 20 T790M mutation. Several agents (AZD9291, CO-1686 and HM61713) have demonstrated impressive activity in patients with T790M resistance mutations. Additional data on the efficacy of first-line therapy with afatinib and the combination of erlotinib and bevacizumab for patients with EGFR mutant NSCLC were presented. The results of a phase III trial of crizotinib compared to platinum-pemetrexed in the first-line setting, and a phase I trial and expansion cohort of ceritinib, provided additional efficacy and toxicity data for patients with anaplastic lymphoma kinase rearranged NSCLC. A phase III trial of cisplatin and gemcitabine, with and without necitumumab, revealed an improvement in overall survival with the addition of necitumumab in patients with squamous NSCLC. In the second-line setting, a phase III trial of docetaxel with ramucirumab or placebo revealed an improvement in overall survival with the addition of ramucirumab. In extensive stage small cell lung cancer phase III trials of consolidative thoracic radiation therapy and prophylactic cranial radiation failed to reveal an improvement in overall survival.

Evaluation of pentavalent Tc-99m DMSA scintigraphy in small cell and nonsmall cell lung cancers

International Nuclear Information System (INIS)

Atasever, T.; Guendogdu, C.; Vural, G.; Kapucu, L.Oe.; Karalezli, A.; Uenlue, M.

1997-01-01

Aim: The purpose of this study was to evaluate the clinical usefulness of Tc-99m (V) DMSA in patients suspected of lung cancer and determine whether this agent may have value in differentiation between small cell (SCLC) and non-small cell (NSCLC) lung carcinoma. Methods: Thirty-six patients with clinical and radiological suspicion of primary lung carcinoma were injected 450-600 MBq of Tc-99m (V) DMSA intravenously. Whole body and planar anterior, posterior thorax images were obtained 4-5 h after injection of the radioactive complex. Results: Histopathological results confirmed 23 NSCLC, 10 SCLC and 1 metastatic lung carcinoma and 2 lung abscess. Nineteen of the 23 (82%) NSCLC and all of the 10 (100%) SCLC cases showed Tc-99m (V) DMSA uptake. Single metastatic lung cancer also accumulated radiotracer. Lung abscess did not show uptake. Lesion/Nonlesion (L/N) ratio of SCLC (1.59±0.32) and NSCLC (1.43±0.19) tumour types did not show statistical difference (p>0.05). Tc-99m (V) DMSA whole body imaging also showed bone metastases. Conclusion: Tc-99m (V) DMSA is a noninvasive and cheap imaging method to detect malignant lung cancers and their bone metastases but, differentiation of SCLC and NSCLC is not possible. (orig.) [de

Overexpression of EMMPRIN is associated with lymph node metastasis and advanced stage of non-small cell lung cancer: a retrospective study

OpenAIRE

Liu, Bing; Wan, Zhaohui; Sheng, Baowei; Lin, Yong; Fu, Tian; Zeng, Qingdi; Qi, Congcong

2017-01-01

Background Previous studies show that overexpression of EMMPRIN involved in the malignant biological behavior of tumors. This investigation was to disclose the expression status of EMMPRIN in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis of NSCLC. Methods The expression of EMMPRIN was examined using immunohistochemistry and enzyme-linked immunosorbent assay. The clinical value of EMMPRIN was evaluated by drawing a receiver operating characteristic (ROC) curve. Re...

Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965).

NARCIS (Netherlands)

Dziadziuszko, R; Ardizzoni, A.; Postmus, P.E.; Smit, E.F.; Price, A; Debruyne, C.; Legrand, C; Giaccone, G.

2003-01-01

This study was performed to evaluate the activity of single-agent temozolomide in two groups of chemotherapy-naive non-small cell lung cancer (NSCLC) patients, with (12 patients) and without (13 patients) brain metastases (BM). Patients in both groups were treated with temozolomide 200 mg/m(2)/day,

Clinical Application of 18F-FDG PET in Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Choi, Joon Young

2008-01-01

This review focuses on the clinical use of 18 F-FDG PET to evaluate solitary pulmonary nodule (SPN) and non-small cell lung cancer (NSCLC). When SPN or mass without calcification is found on chest X-ray or CT, 18 F-FDG PET is an effective modality to differentiate benign from malignant lesions. For initial staging of NSCLC, 18 F-FDG PET is useful, and proved to be cost-effective in several countries. 18 F-FDG PET is useful for detecting recurrence, restaging and evaluating residual tumor after curative therapy in NSCLC. For therapy response assessment, 18 F-FDG PET may be effective after chemotherapy or radiation therapy. 18 F-FDG PET is useful to predict pathological response after neoadjuvant therapy in NSCLC. For radiation therapy planning, 18 F-FDG PET may be helpful, but requires further investigations. PET/CT is better for evaluating NSCLC than conventional PET

Antibody guided targeting of non-small cell lung cancer using 111In-labeled HMFG1 F(ab')2 fragments

International Nuclear Information System (INIS)

Kalofonos, H.P.; Sivolapenko, G.B.; Courtenay-Luck, N.S.

1988-01-01

Immunoscintigraphy using F(ab')2 fragments of tumor-associated monoclonal antibody HMFG1 was performed in 14 patients with primary and metastatic non-small cell carcinoma of lung cancer. The antibody was conjugated with diethylenetriamine pentaacetic acid and labeled with 111 In. Quality control studies showed efficient incorporation of 111 In onto antibody (5 mCi/mg), no significant loss of immunoreactivity, and in vitro and in vivo stability. The optimal time for imaging was between 48 and 72 h. Following i.v. administration, serum activity fell rapidly (t1/2a = 2.5 +/- 1.3 (SD) h; t1/2b = 42 +/- 4.5 h). The majority of the radioactivity was associated with the plasma and not with the blood cells. All patients had a significant concentration of 111 In in the liver (approximately 20% of the injected dose, 48 h postadministration). No toxicity was encountered. No human antimurine-IgG antibody was detected in any of the patients within 4 months of follow-up, even in patients receiving two administrations of F(ab')2 fragments. Localization of all primary lesions and the majority (80%) of metastatic lesions was achieved. Seven of 14 patients were also studied using a 111 In-labeled nonspecific antibody (Fab')2 fragment (4C4). In three patients the specificity index was higher than the other four (P less than 0.05). We conclude that although successful targeting of 111 In-labeled (Fab')2 fragments of HMFG1 can be achieved in patients with non-small cell carcinoma of lung, observable tumor localization can also be achieved using a nonspecific antibody

Monocytopenia; Induction by Vinorelbine, Cisplatin and Doxorubicin in Breast, Non-Small Cell Lung and Cervix Cancer Patients

Science.gov (United States)

Nazir, Taha; Taha, Nida; Islam, Azahrul; Abraham, Suraj; Mahmood, Adeel; Mustafa, Mazhar

2016-01-01

Background The neoplasm is still a potential threat for breast, Non-Small Cell Lung (NSCL) and cervix cancer patients. Those gradually invade into other body organs, inducing complex pathological complications. Whereas, the anticancer drugs suppress the bone marrow, resulting serious hematological toxicities. Thus, the monocytic toxicity may the chance of infections, particularly in AID’s patients. Objective We aimed this retrospective study to investigate the monocytopenia induced by vinorelbine following chemotherapy in cancer patients. Patients and method A total 60 adult cancer patients were divided into two groups; Group-1 patients received the treatment of Vinorelbine alone while group 2 patients received Vinorelbine based combination chemotherapy. Result The overall comparison of mean monocyte count (×103 per μl) with time showed a significant statistical difference (p value <0.001) for G-I and no significant difference for G-II (p value <0.08). The independent comparison of mean values for two groups at every week confirms the non-significant statistical difference during all of the five weeks (p values 0.551, 0.112, 0.559, 0.372, 0.468 respectively). In addition of that, the comparison of mean values observed before therapy with that of week 4 (after therapy) showed significant difference in G-I (p value <0.001) and non-significant in G-II (p value 0.053). Conclusion Monocytopenia is induced in both of the chemotherapy protocols allows the clinical oncologists and consultant physicians to select either of the chemotherapy protocol. The therapeutic efficacy should constitute the intervening consideration to treat the breast, cervix and NSCL (Non-Small Cell Lung’s) cancers. PMID:27833519

Non-small cell lung cancer: the era of targeted therapy

Directory of Open Access Journals (Sweden)

Antonoff MB

2012-07-01

Full Text Available Mara B Antonoff, Jonathan D'CunhaDivision of Thoracic and Foregut Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN, USAAbstract: In this review, the authors aim to provide an overview of current molecular targeted therapies for NSCLC, to propose an algorithm for clinical application of presently available treatment strategies, and to identify future directions for this important area of research. Historically, choice of treatment algorithm for the management of non-small cell lung cancer (NSCLC has relied heavily upon histology and clinical staging information, typically assigning patients to surgery, chemotherapy, radiation, or a combination thereof. However, previous treatment strategies have been fraught with disappointing response rates and significant systemic toxicities. The concept of personalized therapy for NSCLC involves characterization of each individual patient's tumor, in terms of genetic aberrations and expected biologic behavior, and using this information to tailor subsequent clinical management. Several driver mutations have been identified to date in subsets of patients with NSCLC, and, by focusing on specific molecular targets, new agents have been developed with the intent of treating the cancer cells while causing minimal toxicity to benign, healthy cells. In particular, current strategies exist to identify patients with epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase rearrangements, with promising results upon clinical application of agents targeting these abnormalities. Moving forward, attempts are being made to determine comprehensive genetic and biologic characterization of individuals' NSCLC tumors and to incorporate these findings into everyday practice. The era of targeted therapy is upon us. As we seek to expand our knowledge of the specific molecular and cellular derangements leading to growth and proliferation of NSCLC tumors, our efforts bring us closer to

MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma.

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Lu-Kai Wang

Full Text Available Non-small cell lung cancers (NSCLCs cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R, TGF-beta receptor type-1 (TGFBR1, and epidermal growth factor receptor (EGFR, are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.

Dithiolethione modified valproate and diclofenac increase E-cadherin expression and decrease proliferation of non-small cell lung cancer cells.

Science.gov (United States)

Moody, Terry W; Switzer, Christopher; Santana-Flores, Wilmarie; Ridnour, Lisa A; Berna, Marc; Thill, Michelle; Jensen, Robert T; Sparatore, Anna; Del Soldato, Piero; Yeh, Grace C; Roberts, David D; Giaccone, Giuseppe; Wink, David A

2010-05-01

The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 microg/ml concentrations significantly reduced prostaglandin (PG)E(2) levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 microg/ml, respectively. Using the MTT assay, 10 microg/ml S-valproate, NO-aspirin and Cay10404, a selective COX-2 inhibitor, but not SC-560, a selective COX-1 inhibitor, inhibited the growth of A549 cells. In vivo, 18mg/kg i.p. of S-valproate and S-diclofenac, but not S-sulindac, significantly inhibited A549 or NCI-H1299 xenograft proliferation in nude mice, but had no effect on the nude mouse body weight. The mechanism by which S-valproate and S-diclofenac inhibited the growth of NSCLC cells was investigated. Nitric oxide-aspirin but not S-valproate caused apoptosis of NSCLC cells. By Western blot, S-valproate and S-diclofenac increased E-cadherin but reduced vimentin and ZEB1 (a transcriptional suppressor of E-cadherin) protein expression in NSCLC cells. Because S-valproate and S-diclofenac inhibit the growth of NSCLC cells and reduce PGE(2) levels, they may prove beneficial in the chemoprevention and/or therapy of NSCLC. Published by Elsevier Ireland Ltd.

Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.

LENUS (Irish Health Repository)

Burke, Louise

2012-02-03

PURPOSE: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. EXPERIMENTAL DESIGN: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. RESULTS: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). CONCLUSIONS: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

Directory of Open Access Journals (Sweden)

Navin Sarin

Full Text Available The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2, xeroderma pigmentosum complementation group C (XPC, stress inducible protein (SIP and p21 compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

Neuropsychological evaluation of patients with inoperable non-small cell lung cancer treated with combination chemotherapy or radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Kaasa, S; Olsnes, B T; Mastekaasa, A

1988-01-01

Neuropsychological tests were used to evaluate possible central nervous system dysfunction in patients treated with chemotherapy. Ninety-five patients with non-small cell lung cancer limited disease were randomized to either radiotherapy (2.8 Gyx15) or combination chemotherapy with cisplatin and etoposide. In order to evaluate cognitive functions three neuropsychological tests were applied: Trail Making, Benton Visual Retention Test and Verbal Learning. Changes in the patients' test scores before and after treatment were compared. The chemotherapy patients showed reduced performance on some of the neuropsychological tests compared to the radiotherapy group. This indicates a treatment related effect on the central nervous system, possibly caused by the combination chemotherapy.

Neuropsychological evaluation of patients with inoperable non-small cell lung cancer treated with combination chemotherapy or radiotherapy

International Nuclear Information System (INIS)

Kaasa, S.; Olsnes, B.T.; Mastekaasa, A.

1988-01-01

Neuropsychological tests were used to evaluate possible central nervous system dysfunction in patients treated with chemotherapy. Ninety-five patients with non-small cell lung cancer limited disease were randomized to either radiotherapy (2.8 Gyx15) or combination chemotherapy with cisplatin and etoposide. In order to evaluate cognitive functions three neuropsychological tests were applied: Trail Making, Benton Visual Retention Test and Verbal Learning. Changes in the patients' test scores before and after treatment were compared. The chemotherapy patients showed reduced performance on some of the neuropsychological tests compared to the radiotherapy group. This indicates a treatment related effect on the central nervous system, possibly caused by the combination chemotherapy. (orig.)

Phase II study of a trimodal preoperative treatment followed by radical surgery or radiotherapy in non-resectable cervical cancer ≥ Figo IIB

International Nuclear Information System (INIS)

Cho, C.; Gellermann, J.; Jungnickel, K.; Kuemmel, S.; Hildebrandt, B.; Wust, P

2005-01-01

Full text: Regional hyperthermia is combined with radiochemotherapy to achieve resectability in non-resectable cervical carcinoma. In a phase II study at the Charite Medical School approved by the institutionals ethical committee non-resectable cervical carcinoma of at least FIGO IIB were treated with radiochemotherapy combined with regional hyperthermia. The treatment concept comprises cisplatinum therapy of 40 mg/sqm body surface once weekly during regional hyperthermia supplementing radiation therapy of 5 x 1.8 Gy to a total dose of 45 - 50.4 Gy. A gynecological status and imaging is performed for evaluation of resectability of the tumor. If a tumor resection was not feasable radiation was completed to 59.4 - 63 Gy supplemented by 4 - 5 afterloading sessions. Regional hyperthermia was conducted with SIGMA 60 or SIGMA Eye applicator of the system BSD-2000, on average steady state temperatures between 40-41 o C were achieved over the therapeutic time. From 2000 to 2003 we recruited 30 patients. Acute toxicity was in the usual range (10-15 % grade ≥ 3). Two thirds were FIGO stage III/IV with tumor diameters > 6 cm. After treatment 20/30 (67 %) of the former inoperable cases were evaluated as resectable, 3 of these patients refused surgery. Of the remaining 17 cases 14 patients were R0-resected, 2 patients were R1-resected, and 1 patient had a positive paraaortal lymphnode. In 13/30 patients nonsurgical treatment was continued. Response was achieved in 23/30 patients (77 %), i.e. 14 resectable cases with downstaging and 9 partial remissions (PR) after hyperthermic radiochemotherapy with 45 - 50.4 Gy. Response correlated well with thermal parameters, in particular the mean temperature in the vaginal reference point. For the whole group a three year overall survival of 60 % was achieved together with a moderate late toxicity ≥ 3 in 4/30 patients (13 %). R0-resected patients have an excellent prognosis with a 3-year survival of 95 % and a late toxicity ≥ 3 below

Treatment, therapy results and survival for non-small cell lung cancer in a period of new therapeutic modalities and cytotoxic substances

International Nuclear Information System (INIS)

Treff, J.

2002-09-01

During the last years considerable changes have been made in the treatment of non-small cell lung cancer. This retrospective study analyzed besides the common characteristics the treatment, response rates and overall survival of patients with non-small cell lung cancer in a central internistical and oncological outpatient department. 328 patients treated at the haematology-oncology outpatient department were included in this study. Requirements have been patients with histologically or cytologically verified non-small cell lung cancer, diagnosis between 1989 and 2001 and comprehensible courses of disease and treatment. Results: Most of the patients were men (72 %) and only 28 % were women. Median age at diagnosis was 61 years; 8.8 % of the patients were aged under 45 years. Adenocarcinoma (46 %) and squamous cell carcinoma (36 %) were the most frequent histologic types. At time of diagnosis 68 % of the patients have been in an already advanced stage IIIB or IV. Surprisingly the diagnosis resulted for 25 % of the patients by chance, 75 % of the patients were diagnosed due to symptoms. Only 8 % of the patients did not receive a specific therapy (surgery, radiation therapy, chemotherapy) due to their advanced disease. 21 patients were treated in a neoadjuvant setting and for 10 (48 %) surgery with curative intention could be performed. The most frequently given chemotherapy in the first-line palliative therapy were Cis-, Carboplatin/VP 16 (40 %) and Cis-, Carboplatin/Navelbine (27 %). The response rate was poor - six complete responses (2.5 %) and 34 (14.3 %) partial responses. 107 patients received a second-line chemotherapy. The overall median survival of all patients was 13.5 months. The stage at time of diagnosis was the most important prognostic factor. Interestingly enough also a survival benefit for women could be demonstrated (15.5 months vs. 13 months). The common characteristics of the analyzed patients correspond to the typical collective of patients in a

Docosahexaenoic Acid Induces Cell Death in Human Non-Small Cell Lung Cancer Cells by Repressing mTOR via AMPK Activation and PI3K/Akt Inhibition

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Nayeong Kim

2015-01-01

Full Text Available The anticancer properties and mechanism of action of omega-3 polyunsaturated fatty acids (ω3-PUFAs have been demonstrated in several cancers; however, the mechanism in lung cancer remains unclear. Here, we show that docosahexaenoic acid (DHA, a ω3-PUFA, induced apoptosis and autophagy in non-small cell lung cancer (NSCLC cells. DHA-induced cell death was accompanied by AMP-activated protein kinase (AMPK activation and inactivated phosphatidylinositol 3-kinase (PI3K/Akt/mammalian target of rapamycin (mTOR signaling. Knocking down AMPK and overexpressing Akt increased mTOR activity and attenuated DHA-induced cell death, suggesting that DHA induces cell death via AMPK- and Akt-regulated mTOR inactivation. This was confirmed in Fat-1 transgenic mice, which produce ω3-PUFAs. Lewis lung cancer (LLC tumor cells implanted into Fat-1 mice showed slower growth, lower phospho-Akt levels, and higher levels of apoptosis and autophagy than cells implanted into wild-type mice. Taken together, these data suggest that DHA-induced apoptosis and autophagy in NSCLC cells are associated with AMPK activation and PI3K/Akt inhibition, which in turn lead to suppression of mTOR; thus ω3-PUFAs may be utilized as potential therapeutic agents for NSCLC treatment.

Bystander effects in radiotherapy of non-small cell lung cancer

International Nuclear Information System (INIS)

McKenzie, D.R.

2011-01-01

Full text: School of Physics, The University of Sydney, Australia Objectives The bystander effect causes a response in unirradiated cells that are in communication with cells that receive a radiation dose. In recent work we have shown that there are 3 types bystander effect and that the expression of these effects follows a Ii course. The aim of this work is to identify the conditions for the three types of bystander effects in radiotherapy of non-small cell II cancer. A human non small cell lung cancer cell line (NCI-H460) was irradiated with a 6 MV photon beam produced from a Varian I i near accelerator to doses of 2, 4, 6 and 8 Gy. These cells v termed donor cells. At selected time intervals after exposure (5,15 and 60 min), the medium was transferred to receiver cells of the cell line in separate flasks. The clonogenic survival fraction of the receiver cells was determined following 5 days of incubation comparing cells receiving transfer of medium from exposed cells to cell receiving transfer from sham exposed cells. The experimental design controlled for the density of cells in the donor flask, the e of irradiation on the medium alone and on the donor cell metabolites. The results show a strong time course for the bystander signal expression, which is dependent on the density of cells in the donor receiver flasks. Sub lethal doses of radiation resulted in a proliferative response at short time intervals after exposure [15 min] but a toxic response when medium transfer was carried out after 60 min. A higher cell density in the donor flasks produces an increased response in the receiver flasks for the same volume of medium transferred. The latter response corresponds to Bystander Effect type 1 in which a reduced survival is observed in cells receiving medium from cells that receive a high but not lethal dose. The proliferative response, corresponding to Bystander Effect type 3 is more general and is not strongly dependent on dose. Following a lethal dose of

Cure in a patient with multiple osseus metastases in non-small cell lung cancer: a case report

International Nuclear Information System (INIS)

Hawighorst, H.; Gademann, G.

1993-01-01

Purpose: This case was reported to describe a case of cure in a 61-year old patient with squamous cell lung cancer and multiple extrathoracic metastasis. Methods and materials: A left upper lobectomy of lung for a squamous cell carcinoma was performed on a 61-year old man with curative intent. Fourt months later two osseous metastases were irradiated with Cobalt 60 up to 40 Gy. Results: The two irradiated lesions showed continuously shrinkage as well as signs of recalcification. Eleven years later the patient shows clinically absolut well being and on CT there are no signs of recurrent disease of the lung or bone anymore. Discussion: To our knowledge has nobody so far reported of a case of a squamous cell lung cancer which was operated and irradiated on thus resulting in cure. Furtheron the authors discuss that it might well be worthwile to define subgroups in stage 4 non-small cell lung cancer (presence of extrathoracic metastases) which might benefit from a more aggressive treatment approach than pure palliation. (orig.) [de

Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-Small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Ning Li

2018-02-01

Full Text Available Erythropoietin-producing hepatocellular carcinoma A2 (EphA2 is overexpressed in more than 90% of non-small cell lung cancer (NSCLC but not significantly in normal lung tissue. It is therefore an important tumor antigen target for chimeric antigen receptors (CAR-T-based therapy in NSCLC. Here, we developed a specific CAR targeted to EphA2, and the anti-tumor effects of this CAR were investigated. A second generation CAR with co-stimulatory receptor 4-1BB targeted to EphA2 was developed. The functionality of EphA2-specific T cells in vitro was tested with flow cytometry and real-time cell electronic sensing system assays. The effect in vivo was evaluated in xenograft SCID Beige mouse model of EphA2 positive NSCLC. These EphA2-specifc T cells can cause tumor cell lysis by producing the cytokines IFN-γ when cocultured with EphA2-positive targets, and the cytotoxicity effects was specific in vitro. In vivo, the tumor signals of mice treated with EphA2-specifc T cells presented the tendency of decrease, and was much lower than the mice treated with non-transduced T cells. The anti-tumor effects of this CAR-T technology in vivo and vitro had been confirmed. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive NSCLC.

Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells

International Nuclear Information System (INIS)

Tang, Zheng-Hai; Cao, Wen-Xiang; Su, Min-Xia; Chen, Xiuping; Lu, Jin-Jian

2017-01-01

Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-L-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells. - Highlights: • Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells. • Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines. • ROS generation contributed to osimertinib-induced cytoplasmic

Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells

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Tang, Zheng-Hai; Cao, Wen-Xiang; Su, Min-Xia; Chen, Xiuping; Lu, Jin-Jian, E-mail: jinjianlu@umac.mo

2017-04-15

Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-L-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells. - Highlights: • Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells. • Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines. • ROS generation contributed to osimertinib-induced cytoplasmic

The expression of GST isoenzymes and p53 in non-small cell lung cancer.

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MĂźzeyyen Ozhavzali

2010-06-01

Full Text Available This study investigated the immunohistochemical staining characteristics of glutathione-S-transferase alpha, pi, mu, theta and p53 in non-small cell lung carcinoma and normal lung tissue from 50 patients. The relationships between expressions of the Glutathione-S-transferase isoenzymes and some clinicopathological features were also examined. Expression of glutathione-S-transferase pi, mu, alpha, theta and p53 was assessed by immunohistochemistry for primary lung carcinomas of 50 patients from the Sanitarium Education and Research Hospital, Ankara lung cancer collection. The relationships between expression of the glutathione-S-transferase isoenzymes, p53 in normal and tumor tissue by Student T test and the clinicopathological data were also examined by Spearman Rank tests. When the normal and tumor tissue of these cases were compared according to their staining intensity and percentage of positive staining, glutathione-S-transferase alpha, pi, mu, theta expressions in tumor cells was significantly higher than normal cells (p<0.05. There was no significant difference in the expression of p53 between normal and tumor cells (p>0.05. When the immunohistochemical results of glutathione-S-transferase isoenzymes and p53 were correlated with the clinical parameters, there were no significant associations between glutathione-S-transferases and p53 expressions and tumor stage, tumor grade and smoking status (p>0.05.

Reduction of nitric oxide level enhances the radiosensitivity of hypoxic non-small cell lung cancer

International Nuclear Information System (INIS)

Saleem, Wael; Suzuki, Yoshiyuki; Mobaraki, Abdulelah; Yoshida, Yukari; Noda, Shinei; Saitoh, Jun-ichi; Nakano, Takashi

2011-01-01

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (E-TKI) resistance has emerged as an important clinical issue. To overcome this resistance, researchers have examined different modalities, either for use as a monotherapy or in combination with E-TKI therapy. In the present study, we investigated whether a decrease in nitric oxide (NO) levels affects the radiosensitization of non-small cell lung cancer (NSCLC) cell lines. A549 and H3255 NSCLC cells were examined. They were subjected to hypoxic conditions and monotherapy, or combined therapy using radiation and N G -monomethyl- L -arginine, monoacetate (LNMMA). Reductions in nitric oxide levels enhanced the radiosensitivity of both cell lines and significantly reduced the expression of both hypoxia-inducible factor-1α (HIF-1α) and EGFR in H3255 cells compared to A549 cells. Since NO is significantly associated with cell metabolism, we measured the levels of pyruvate dehydrogenase kinase-1 (PDK-1), reactive oxygen species, and oxygen and observed that the expression of PDK-1 was significantly reduced. This reduction was seen simultaneously after the silencing of HIF-1α; however, not following LNMMA treatment. The oxygen concentration was significantly increased in the treated cells, and their viability decreased in parallel. Reactive oxygen species were decreased after LNMMA and radiation treatment. Adding EGFR-TKI to cells with reduced NO levels further suppressed cell viability when combined with radiation. This study suggests that a reduction in the NO level might substantially overcome the radioresistance of mutant NSCLC cells. (author)

Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer

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Senchenko, Vera N; Zabarovsky, Eugene R; Anedchenko, Ekaterina A; Kondratieva, Tatiana T; Krasnov, George S; Dmitriev, Alexei A; Zabarovska, Veronika I; Pavlova, Tatiana V; Kashuba, Vladimir I; Lerman, Michael I

2010-01-01

The short arm of human chromosome 3 is involved in the development of many cancers including lung cancer. Three bona fide lung cancer tumor suppressor genes namely RBSP3 (AP20 region),NPRL2 and RASSF1A (LUCA region) were identified in the 3p21.3 region. We have shown previously that homozygous deletions in AP20 and LUCA sub-regions often occurred in the same tumor (P < 10 -6 ). We estimated the quantity of RBSP3, NPRL2, RASSF1A, GAPDH, RPN1 mRNA and RBSP3 DNA copy number in 59 primary non-small cell lung cancers, including 41 squamous cell and 18 adenocarcinomas by real-time reverse transcription-polymerase chain reaction based on TaqMan technology and relative quantification. We evaluated the relationship between mRNA level and clinicopathologic characteristics in non-small cell lung cancer. A significant expression decrease (≥2) was found for all three genes early in tumor development: in 85% of cases for RBSP3; 73% for NPRL2 and 67% for RASSF1A (P < 0.001), more strongly pronounced in squamous cell than in adenocarcinomas. Strong suppression of both, NPRL2 and RBSP3 was seen in 100% of cases already at Stage I of squamous cell carcinomas. Deregulation of RASSF1A correlated with tumor progression of squamous cell (P = 0.196) and adenocarcinomas (P < 0.05). Most likely, genetic and epigenetic mechanisms might be responsible for transcriptional inactivation of RBSP3 in non-small cell lung cancers as promoter methylation of RBSP3 according to NotI microarrays data was detected in 80% of squamous cell and in 38% of adenocarcinomas. With NotI microarrays we tested how often LUCA (NPRL2, RASSF1A) and AP20 (RBSP3) regions were deleted or methylated in the same tumor sample and found that this occured in 39% of all studied samples (P < 0.05). Our data support the hypothesis that these TSG are involved in tumorigenesis of NSCLC. Both genetic and epigenetic mechanisms contribute to down-regulation of these three genes representing two tumor suppressor clusters in 3p21

Modelling non-homogeneous stochastic reaction-diffusion systems: the case study of gemcitabine-treated non-small cell lung cancer growth.

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Lecca, Paola; Morpurgo, Daniele

2012-01-01

Reaction-diffusion based models have been widely used in the literature for modeling the growth of solid tumors. Many of the current models treat both diffusion/consumption of nutrients and cell proliferation. The majority of these models use classical transport/mass conservation equations for describing the distribution of molecular species in tumor spheroids, and the Fick's law for describing the flux of uncharged molecules (i.e oxygen, glucose). Commonly, the equations for the cell movement and proliferation are first order differential equations describing the rate of change of the velocity of the cells with respect to the spatial coordinates as a function of the nutrient's gradient. Several modifications of these equations have been developed in the last decade to explicitly indicate that the tumor includes cells, interstitial fluids and extracellular matrix: these variants provided a model of tumor as a multiphase material with these as the different phases. Most of the current reaction-diffusion tumor models are deterministic and do not model the diffusion as a local state-dependent process in a non-homogeneous medium at the micro- and meso-scale of the intra- and inter-cellular processes, respectively. Furthermore, a stochastic reaction-diffusion model in which diffusive transport of the molecular species of nutrients and chemotherapy drugs as well as the interactions of the tumor cells with these species is a novel approach. The application of this approach to he scase of non-small cell lung cancer treated with gemcitabine is also novel. We present a stochastic reaction-diffusion model of non-small cell lung cancer growth in the specification formalism of the tool Redi, we recently developed for simulating reaction-diffusion systems. We also describe how a spatial gradient of nutrients and oncological drugs affects the tumor progression. Our model is based on a generalization of the Fick's first diffusion law that allows to model diffusive transport in non

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: A systematic review and cost-effectiveness analysis

NARCIS (Netherlands)

M. Westwood (Marie); M.A. Joore (Manuela); P. Whiting (Penny); T. van Asselt (Thea); B.L.T. Ramaekers (Bram); N. Armstrong (Nigel); K. Misso (Kate); J.L. Severens (Hans); J. Kleijnen (Jos)

2014-01-01

markdownabstract__Abstract__ Background: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment

Systematic Analysis of Icotinib Treatment for Patients with Non-Small Cell Lung Cancer.

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Shi, Bing; Zhang, Xiu-Bing; Xu, Jian; Huang, Xin-En

2015-01-01

This analysis was conducted to evaluate the efficacy and safety of icotinib based regimens in treating patients with non-small cell lung cancer (NSCLC). Clinical studies evaluating the efficacy and safety of icotinib-based regimens with regard to response and safety for patients with NSCLC were identified using a predefined search strategy. Pooled response rates of treatment were calculated. With icotinib-based regimens, 7 clinical studies which including 5,985 Chinese patients with NSCLC were considered eligible for inclusion. The pooled analysis suggested that, in all patients, the positive reponse rate was 30.1% (1,803/5,985) with icotinib-based regimens. Mild skin itching, rashes and diarrhea were the main side effects. No grade III or IV renal or liver toxicity was observed. No treatment-related death occurred in patients treated with icotinib-based regimens. This evidence based analysis suggests that icotinib based regimens are associated with mild response rate and acceptable toxicity for treating Chinese patients with NSCLC.

Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.

LENUS (Irish Health Repository)

Cathcart, Mary-Clare

2012-02-01

BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced\\/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC.

Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

International Nuclear Information System (INIS)

Berman, Abigail T.; James, Sara St.; Rengan, Ramesh

2015-01-01

Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

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Barr, Martin P.; Gray, Steven G.; Hoffmann, Andreas C.; Hilger, Ralf A.; Thomale, Juergen; O’Flaherty, John D.; Fennell, Dean A.; Richard, Derek; O’Leary, John J.; O’Byrne, Kenneth J.

2013-01-01

Introduction Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. Methods An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Results Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Conclusion Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing

Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature.

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Martin P Barr

Full Text Available Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC. Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin.An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460. Over a period of twelve months, cisplatin resistant (CisR cell lines were derived from original, age-matched parent cells (PT and subsequently characterized. Proliferation (MTT and clonogenic survival assays (crystal violet were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX and cellular platinum uptake (ICP-MS was also assessed.Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines.Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the

Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer.

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Kyle R Cron

Full Text Available Despite optimal radiation therapy (RT, chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80-90% decrease in homologous recombination (HR, a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.

Cypripedin, a phenanthrenequinone from Dendrobium densiflorum, sensitizes non-small cell lung cancer H460 cells to cisplatin-mediated apoptosis.

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Wattanathamsan, Onsurang; Treesuwan, Surassawadee; Sritularak, Boonchoo; Pongrakhananon, Varisa

2018-03-01

The life-threatening potential of lung cancer has increased over the years due to its acquisition of chemotherapeutic resistance, especially to cisplatin, a first-line therapy. In response to this development, researchers have turned their attention to several compounds derived from natural origins, including cypripedin (CYP), a phenanthrenequinone substance extracted from Dendrobium densiflorum. The aim of the present study was to investigate the ability of CYP to induce apoptosis and enhance cisplatin-mediated death of human lung cancer NCI-H460 cells using cell viability and apoptosis assays. The induction of apoptosis by CYP was observed at a concentration of > 50 μM with the appearance of morphological changes, including DNA condensation and chromatin fragmentation. Together with, CYP was able to activate caspase-3 and downregulate the anti-apoptotic proteins Bcl-2 and Bcl-xL. Also, a non-cytotoxic dose of CYP synergistically potentiated the effect of cisplatin in non-small cell lung cancer line H460 cells, which clearly exhibited the apoptotic phenotype. Western blot analysis revealed that the underlying mechanism involved the downregulation of anti-apoptotic Bcl-xL, whereas the levels of other apoptotic regulatory proteins were not altered. This study provides interesting information on the potent effect of CYP as a chemotherapeutic sensitizer that could be further developed to improve the clinical outcomes of lung cancer patients.

Application of detecting cerebrospinal fluid circulating tumor cells in the diagnosis of meningeal metastasis of non-small cell lung cancer

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Rong JIANG

2014-08-01

Full Text Available Objective To observe a new technology for the detection and enumeration of cerebrospinal fluid (CSF circulating tumor cells (CTCs in the diagnosis of non-small cell lung cancer (NSCLC with meningeal metastasis (MM.  Methods Five cases of NSCLC with MM that were diagnosed by CSF cytology were selected, and 20 ml CSF samples were obtained by lumbar puncture for every patient. The tumor marker immunostaining-fluorescence in situ hybridization (TM-iFISH technology was adapted to detect enrichment and enumeration of circulating tumor cells in 7.50 ml CSF samples; CSF cytology was checked in 10 ml CSF samples; CSF tumor markers were detected in 2.50 ml CSF samples. All of 5 cases were examined by MRI enhancement scan.  Results TM-iFISH detection found circulating tumor cells numbers ranging 18-1823/7.50 ml. Only 2 cases of patients with CSF cytology examination showed the tumor cells. The results of CSF tumor markers in all samples were higher than normal serum tumor markers detection results. The enhanced MRI scan of 5 cases revealed typical signs of MM.  Conclusions The TM-iFISH test showed certain advantages in the detection of malignant tumor cells in CSF. This technology may be a new method of detection and enumeration of tumor cells in CSF, but more studies are needed to prove its sensitivity and specificity. doi: 10.3969/j.issn.1672-6731.2014.08.011

The Mechanism of Gefitinib Resistance Induced by Hepatocyte Growth Factor 
in Sensitive Non-small Cell Lung Cancer Cells in Vitro

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Xianglan XUAN

2013-01-01

Full Text Available Background and objective Previous studies have reported that Met might be related to gefitinib resistance in non-small cell lung cancer (NSCLC. The present study aims to explore the mechanism of hepatocyte growth factor (HGF-induced gefitinib resistance in different gene types of sensitive NSCLC in vitro. Methods The PC-9 and H292 cell lines were chosen and induced by HGF. The cell survival was measured using MTT assay, the cell cycle distribution was measured using PI assay, and cell apoptosis with an Annexin V-PE assay, respectively. The c-Met and p-Met protein expression was determined via Western blot analysis. Results Gefitinib inhibited the growth of PC-9 and H292 cells in a dose-dependent manner. The concentration-survival curves of both cell lines shifted to the right when induced with HGF. HGF did not affect PC-9 and H292 cell proliferation. The cell also had a higher cell survival rate when treated with HGF and gefitinib compared with that under gefitinib alone (P<0.05. The apoptotic rate and cell cycle progression showed no significant difference between the HG and G group (P>0.05. HGF stimulated Met phosphorylation in the PC-9 and H292 cells. Gefitinib inhibited the HGF-induced Met phosphorylation in PC-9 cells, but not in H292 cells. Conclusion HGF induces gefitinib resistance in PC-9 and H292 cells. HGF-induced Met phosphorylation may be an important mechanism of gefitinib resistance in sensitive NSCLC.

Clinical value of detection of intrathoracic metastatic lymph nodes with radioguided technique in patients with non-small cell lung carcinoma

International Nuclear Information System (INIS)

Lu Ming; Hu Yongxiao

2008-01-01

Objective: To study the possible clinical feasibility of intraoperative detection of metastatic lymph node with radioguided technique after labeling with 99m Tc-MIBI in patients with non-small cell lung carcinoma. Methods: Gamma-detecting probe was used intra-operatively to examine the radioactivity of lungs, regional and mediastinal nodes in 30 patients with non-small cell lung carcinoma after intravenous injection of 99m Tc-MIBI (740MBq) 30 minutes before operation for radio-labeling of the nodes. Postoperatively, the radiologically positive but conventionally pathologically negative as well as all the other nodes judged to be negative with conventional standard (altogether 201 groups) were all meticulously examined with serial sections and immunohistologic staining for detection of the presence of micro-metastasis. Results: Altogether 41 groups of nodes specimens were radiologically positive (over twofolds of normal radio-activity measured with γ probe), of which conventional pathological examination revealed metastasis in 32 groups. The remaining 9 groups of specimens were examined further with serial sections and IHC studies and micro-metastasis was found in 3 of them. Thus, the sensitivity of the radioguided technique was 100%, specificity 96.9% and accuracy rate 97.42%. In the remaining 192 radiologically negative groups of lymph nodes studied, no false negative cases (i. e. micrometastasis positive) were demonstrated. Conclusion: The radio-guided technique is very sensitive (100%), highly specific and accurate (98.9%), and 97.4% respectively), without false negativity demonstrated. Its practical clinical application seems to be feasible. (authors)

Treatment decision-making for advanced non-small cell lung cancer and differences among European countries: 1st AIOT-ETOP meeting.

Science.gov (United States)

Gridelli, Cesare; Stahel, Rolf; Besse, Benjamin; Ciardiello, Fortunato; Felip, Enriqueta; Gasparini, Stefano; Graziano, Paolo; Rossi, Antonio; de Marinis, Filippo

2011-12-01

The Italian Association of Thoracic Oncology (AIOT) and the European Thoracic Oncology Platform (ETOP) realized the first conjunct educational meeting, open to European oncologists involved in the treatment of thoracic malignancies, entitled "Advanced non-small cell lung cancer: new perspectives in first-line setting". The educational meeting included 8 interactive talks, held by European key opinion leaders, and 5 related clinical cases in which the attendees, divided in working tables based on their country origin, were involved for interactive discussion. The aim of this course was to elucidate the differences or similarities among the European countries in the first-line treatment of patients affected by advanced non-small cell lung cancer (NSCLC). Twenty-two attendees of the following countries participated: Austria, France, Italy, Spain, Swiss, and UK. As expected, some discrepancies between the groups were identified concerning the approach to the diagnostic phase, the choice of first-line regimen, the duration of treatment and the use of maintenance therapy. These discrepancies were mainly due to familiarity with specific therapies and lack of access to certain therapies due to local regulatory issues. The European Medicine Agency grants marketing of drugs in all Europe, regulatory agency of each country can register the drug, but can also deny public reimbursement thus restricting the options of the oncologist. The European Oncology Associations should join to their effort to achieve a uniform access to the cancer therapy for all patients in Europe. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal F-18-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC)

NARCIS (Netherlands)

Kerner, Gerald S. M. A.; Fischer, Alexander; Koole, Michel J. B.; Pruim, Jan; Groen, Harry J. M.

2015-01-01

Background: Deformable image registration allows volume of interest (VOI)- and voxel-based analysis of longitudinal changes in fluorodeoxyglucose (FDG) tumor uptake in patients with non-small cell lung cancer (NSCLC). This study evaluates the performance of the elastix toolbox deformable image

[Prospect and Current Situation of Immune Checkpoint Inhibitors 
in First-line Treatment in Advanced Non-small Cell Lung Cancer Patients].

Science.gov (United States)

Wang, Haiyang; Yu, Xiaoqing; Fan, Yun

2017-06-20

With the breakthroughs achieved of programmed death-1 (PD-1)/PD-L1 inhibitors monotherapy as first-line and second-line treatment in advanced non-small cell lung cancer (NSCLC), the treatment strategy is gradually evolving and optimizing. Immune combination therapy expands the benefit population and improves the curative effect. A series of randomized phase III trials are ongoing. In this review, we discuss the prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced NSCLC patients.

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer : a systematic review and cost-effectiveness analysis

NARCIS (Netherlands)

Westwood, Marie; Joore, Manuela; Whiting, Penny; van Asselt, Thea; Ramaekers, Bram; Armstrong, Nigel; Misso, Kate; Severens, Johan; Kleijnen, Jos

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy.

The treatment of metastatic non-small cell lung cancer in the elderly: an evidence-based approach

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David E Dawe

2014-07-01

Full Text Available An increasing proportion of patients with advanced NSCLC are over 70 years old, raising unique challenges for treatment decision-making. While these patients are underrepresented in clinical trials, there is an emerging body of evidence associated with this group. The lesson of comprehensive geriatric assessment is that chronological age does not always correlate with physiological age and a variety of important comorbidities and geriatric syndromes can go undetected in a typical history and physical. These comorbidities and expected physiologic changes due to aging complicate decision-making around appropriate treatment. This review discusses geriatric assessment in elderly cancer patients and evaluates the current evidence for chemotherapy and targeted therapy for patients with advanced non-small cell lung cancer aged ≥70 years.

Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells.

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Saleha B Vuyyuri

Full Text Available Ascorbic acid (AA exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3-PO on the viability of three non-small cell lung cancer (NSCLC cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with

HOXA9 inhibits migration of lung cancer cells and its hypermethylation is associated with recurrence in non-small cell lung cancer.

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Hwang, Jung-Ah; Lee, Bo Bin; Kim, Yujin; Hong, Seung-Hyun; Kim, Young-Ho; Han, Joungho; Shim, Young Mog; Yoon, Chae-Yeong; Lee, Yeon-Su; Kim, Duk-Hwan

2015-06-01

This study was aimed at understanding the clinicopathological significance of HOXA9 hypermethylation in non-small cell lung cancer (NSCLC). HOXA9 hypermethylation was characterized in six lung cancer cell lines, and its clinicopathological significance was analyzed using methylation-specific PCR in 271 formalin-fixed paraffin-embedded tissues and 27 fresh-frozen tumor and matched normal tissues from 298 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA9 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC). Transient transfection of HOXA9 into H23 lung cancer cells resulted in the inhibition of cell migration but not proliferation. Conversely, sequence-specific siRNA-mediated knockdown of HOXA9 enhanced cell migration. The mRNA levels of HOXA9 in 27 fresh-frozen tumor tissues were significantly lower than in matched normal tissues (Precurrence-free survival (hazard ratio=3.98, 95% confidence interval = 1.07-17.09, P=0.01) in never-smokers, after adjusting for age, sex, tumor size, adjuvant therapy, pathologic stage, and histology. In conclusion, the present study suggests that HOXA9 inhibits migration of lung cancer cells and its hypermethylation is an independent prognostic factor for recurrence-free survival in never-smokers with NSCLC. © 2014 Wiley Periodicals, Inc.

The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive

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Yu S

2017-09-01

Full Text Available Su Yu,1,2 Yang Zhang,1 Yunjian Pan,1 Chao Cheng,1,3 Yihua Sun,1,3 Haiquan Chen1–4 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; 2Cancer Research Center, Fudan University Shanghai Cancer Center, Shanghai, China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 4Institutes of Biomedical Sciences, Fudan University, Shanghai, China Purpose: To identify novel oncogenic mutations in non-small cell lung cancer patient specimens that lack mutations in known targetable genes (“pan-negative” patients.Methods: Comprehensive mutational analyses were performed on 1,356 lung adenocarcinoma specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were detected in the epidermal growth factor receptor (EGFR kinase domain, the human epidermal growth factor receptor 2 kinase domain, as well as the KRAS, BRAF, ALK, ROS1 and RET genes. A sub-cohort of pan-negative patient specimens was assayed for mutations in the EGFR extracellular domain (ECD. Additionally, EGFR mutant NIH-3T3 stable cell lines were constructed and assessed for protein content, anchorage-independent growth, and tumor formation in xenograft models to identify oncogenic mutations. BaF3 lymphocytes were also used to test sensitivities of the mutations to tyrosine kinase inhibitors.Results: In pan-negative lung adenocarcinoma cases, a novel oncogenic EGFR ECD mutation was identified (M277E. EGFR M277E mutations encoded oncoproteins that transformed NIH-3T3 cells to grow in the absence of exogenous epidermal growth factor. Transformation was further evidenced by anchorage-independent growth and tumor formation in immunocompromised xenograft mouse models. Finally, as seen in the canonical EGFR L858R mutation, the M277E mutation conferred sensitivity to both erlotinib and cetuximab in BaF3 cell lines and to erlotinib in xenograft models.Conclusion: Here, a new EGFR driver mutation, M277E

Expression of TMPRSS4 in non-small cell lung cancer and its modulation by hypoxia

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NGUYEN, TRI-HUNG; WEBER, WILLIAM; HAVARI, EVIS; CONNORS, TIMOTHY; BAGLEY, REBECCA G.; McLAREN, RAJASHREE; NAMBIAR, PRASHANT R.; MADDEN, STEPHEN L.; TEICHER, BEVERLY A.; ROBERTS, BRUCE; KAPLAN, JOHANNE; SHANKARA, SRINIVAS

2012-01-01

Overexpression of TMPRSS4, a cell surface-associated transmembrane serine protease, has been reported in pancreatic, colorectal and thyroid cancers, and has been implicated in tumor cell migration and metastasis. Few reports have investigated both TMPRSS4 gene expression levels and the protein products. In this study, quantitative RT-PCR and protein staining were used to assess TMPRSS4 expression in primary non-small cell lung carcinoma (NSCLC) tissues and in lung tumor cell lines. At the transcriptional level, TMPRSS4 message was significantly elevated in the majority of human squamous cell and adenocarcinomas compared with normal lung tissues. Staining of over 100 NSCLC primary tumor and normal specimens with rabbit polyclonal anti-TMPRSS4 antibodies confirmed expression at the protein level in both squamous cell and adenocarcinomas with little or no staining in normal lung tissues. Human lung tumor cell lines expressed varying levels of TMPRSS4 mRNA in vitro. Interestingly, tumor cell lines with high levels of TMPRSS4 mRNA failed to show detectable TMPRSS4 protein by either immunoblotting or flow cytometry. However, protein levels were increased under hypoxic culture conditions suggesting that hypoxia within the tumor microenvironment may upregulate TMPRSS4 protein expression in vivo. This was supported by the observation of TMPRSS4 protein in xenograft tumors derived from the cell lines. In addition, staining of human squamous cell carcinoma samples for carbonic anhydrase IX (CAIX), a hypoxia marker, showed TMPRSS4 positive cells adjacent to CAIX positive cells. Overall, these results indicate that the cancer-associated TMPRSS4 protein is overexpressed in NSCLC and may represent a potential therapeutic target. PMID:22692880

P2X7 mRNA expression in non-small cell lung cancer: MicroRNA regulation and prognostic value

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BOLDRINI, LAURA; GIORDANO, MIRELLA; ALÌ, GRETA; MELFI, FRANCA; ROMANO, GAETANO; LUCCHI, MARCO; FONTANINI, GABRIELLA

2014-01-01

The human P2X7 receptor is significant and exhibits several functions in neoplasia. At present, little is known with regard to its regulation. P2X7 expression may be regulated post-transcriptionally and putative microRNA (miRNA) binding sites are considered to be involved. The aim of this study was to determine whether miRNAs (miR-21, let-7 g and miR-205) regulate P2X7 mRNA stability. In addition, the impact of P2X7 expression in patients with non-small cell lung cancer (NSCLC) was investigat...

Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress-mediated apoptosis in non-small cell lung cancer cells

International Nuclear Information System (INIS)

Liu, Zhiguo; Wang, Yi; Sun, Yusheng; Ren, Luqing; Huang, Yi; Cai, Yuepiao; Weng, Qiaoyou; Shen, Xueqian; Li, Xiaokun; Liang, Guang

2013-01-01

Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC

Successful Chemotherapy with Nab-Paclitaxel in a Heavily Treated Non-Small Cell Lung Cancer Patient: A Case Report

Directory of Open Access Journals (Sweden)

Mikiko Ishihara

2014-06-01

Full Text Available Non-small cell lung cancer (NSCLC accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient.

THE FIRST EXPERIENCE OF USING LOCAL HYPERTHERMIA IN COMBINED MODALITY TREATMENT OF OPERABLE NON-SMALL CELL LUNG CANCER

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A. Yu. Dobrodeev

2015-01-01

Full Text Available The paper presents the first experience in treating 5 patients with stage II–III non-small cell lung cancer using combined modality treatment including 40 Gy preoperative hyperfractionated radiotherapy with concurrent 2 cycles of paclitaxel/carboplatin chemotherapy and local hyperthermia (10 sessions followed by radical surgery. The overal response rate to preoperative treatment was 80 %. Chemotherapy was well tolerated and hyperthermia resulted no in adverse effects. All patients underwent surgery (4 lobectomies and 1 pneumonectomy. No complications were observed in the postoperative period. The follow-up period ranged from 6 to 20 months. No evidence of disease progression and radiation-induced damages were observed.

Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer.

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Yang, Guangdie; Yao, Yinan; Zhou, Jianya; Zhao, Qiong

2012-06-01

Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small cell lung cancer (NSCLC). Our study demonstrated the antitumor effects of icotinib hydrochloride, a highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in two EGFR-mutated lung cancer cell lines compared to A549, a cell line without EGFR mutations. We incubated PC-9 and HCC827 human lung cancer cell lines both with (E746-A750) mutations with various concentrations of icotinib and gefitinib for 48 h. Cell proliferation and migration were determined using a real-time cell invasion and migration assay and cytotoxicity assay. Apoptosis was assessed by measuring Annexin V staining using flow cytometry. The antitumor effects of icotinib compared to gefitinib were similar and were most effective in reducing the proliferation of EGFR-mutated cells compared to non-mutated controls. Our results suggest the possibility of icotinib as a new therapeutic agent of EGFR-mutated cancer cells, which has the potential to be used in the first-line treatment of EGFR-mutated NSCLC.

Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002).

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Miyauchi, Eisaku; Inoue, Akira; Kobayashi, Kunihiko; Maemondo, Makoto; Sugawara, Shunichi; Oizumi, Satoshi; Isobe, Hiroshi; Gemma, Akihiko; Saijo, Yasuo; Yoshizawa, Hirohisa; Hagiwara, Koichi; Nukiwa, Toshihiro

2015-07-01

Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptor mutations (the NEJ002 study). Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0). Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first- and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant. The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence

Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results.

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Zhao, Zhi-Hong; Wang, Sheng-Fa; Yu, Liang; Wang, Ju; Chang, Hao; Yan, Wei-Li; Zhang, Jian; Fu, Kai

2008-10-01

Transcription factor Pokemon, a central regulation gene of the important tumor suppressor alternative reading frame (ARF), exerted its activity by acting upstream of many tumor-suppressing genes and proto-oncogenes. Its expression in non-small cell lung cancer (NSCLC) and its clinical significance remains unclear. The aim of this study was to investigate the expression of Pokemon in non-small cell lung cancer and to explore its correlation with the clinical pathological characteristics and its influence on patients' prognosis. Observe the expression of Pokemon in NSCLC and investigate its mechanism and clinical significance. Determine the expression of Pokemon in human NSCLC cell lines as well as 55 cases of NSCLC tumor tissues, tumor adjacent tissues and surrounding tissues by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, and analyze the relationship between Pokemon expression in NSCLC tumor tissues and clinicopathological features. Determine 62 NSCLC tumor tissues (5 years ago) and p14(ARF) expression with immunohistochemical technique, discuss the correlation between them and assess the effect of Pokemon on prognosis of patients with lung cancer. Pokemon mRNA and protein took on high expression in lung cancer cell lines, and the expression difference between cancer tissues, tumor adjacent tissues and surrounding tissues had statistical significance (PPokemon expression and p14(ARF) expression were negatively correlated (r=-0.287). The expression of Pokemon was determined not to be associated with the patient's sex, age, smoking condition, tumor differentiation degree, histology and lymph node metastasis condition. However, its relationship with TNM staging was established (PPokemon expression was significantly higher than that of those with positive Pokemon expression (P=0.004), therefore, the expression of Pokemon is believed to be an independent factor affecting prognosis (P=0.034). There was high expression of Pokemon in NSCLC

Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

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Ma, Qin-Yun; Huang, Da-Yu; Zhang, Hui-Jun; Wang, Shaohua; Chen, Xiao-Feng

2017-11-15

LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4 + CD25 - T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4 + T cells directly ex vivo and primarily in the CD4 + CD25 - fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4 + CD25 - cells Compared to LAG3-nonexpressing CD4 + CD25 - cells, LAG3-expressing CD4 + CD25 - cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8 + T effector cells. LAG3-expressing CD4 + CD25 - cells also presented impaired proliferation compared with LAG3-nonexpressing CD4 + CD25 - cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8 + T cells co-incubated with LAG3-expressing CD4 + CD25 - cells at equal cell numbers demonstrated significantly lower proliferation than CD8 + T cells incubated alone. Co-culture with CD8 + T cell and LAG3-expressing CD4 + CD25 - T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4 + CD25 - T cells. In addition, we found that LAG3-expressing CD4 + CD25 - T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4 + CD25 - T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

LncRNA CCAT2 promotes tumorigenesis by over-expressed Pokemon in non-small cell lung cancer.

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Zhao, Zhihong; Wang, Ju; Wang, Shengfa; Chang, Hao; Zhang, Tiewa; Qu, Junfeng

2017-03-01

Non-small cell lung cancer (NSCLC) remains one of the most important death-related diseases, with poor effective diagnosis and less therapeutic biomarkers. LncRNA colon cancer-associated transcript 2 (CCAT2) was identified as an oncogenic lncRNA and over-expressed in many tumor cells. The aims of this study were to detect the correlation between CCAT2 and its regulatory genes and then explore the potential mechanism between them in NSCLC. In this study, qRT-PCR was used to detect CCAT2, Pokemon and p21 expression. Western-blot was used to detect protein levels of Pokemon and p21. CCK-8 assay and Transwell chambers were used to assess cell viability and invasion. CCAT2 and Pokemon were over-expressed in NSCLC tissue and cells. In NSCLC cells, CCAT2 knockdown significantly decreased cell viability and invasion as well as Pokemon expression, but increased the expression of p21; then CCAT2 overexpression revealed an opposite result. In addition, over-expressed Pokemon reversed the results that induced by si-CCAT2, while down-regulation of Pokemon significantly reversed the results that induced by CCAT2 overexpression. The results indicated that CCAT2 promotes tumorigenesis by over-expression of Pokemon, and the potential mechanism might relate to the Pokemon related gene p21. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Gallic acid induces apoptosis in EGFR-mutant non-small cell lung cancers by accelerating EGFR turnover.

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Nam, Boas; Rho, Jin Kyung; Shin, Dong-Myung; Son, Jaekyoung

2016-10-01

Gallic acid is a common botanic phenolic compound, which is present in plants and foods worldwide. Gallic acid is implicated in various biological processes such as cell growth and apoptosis. Indeed, gallic acid has been shown to induce apoptosis in many cancer types. However, the molecular mechanisms of gallic acid-induced apoptosis in cancer, particularly lung cancer, are still unclear. Here, we report that gallic acid induces apoptosis in EGFR-mutant non-small cell lung cancer (NSCLC) cells, but not in EGFR-WT NSCLC cells. Treatment with gallic acid resulted in a significant reduction in proliferation and induction of apoptosis, only in EGFR-mutant NSCLC cells. Interestingly, treatment with gallic acid led to a robust decrease in EGFR levels, which is critical for NSCLC survival. Treatment with gallic acid had no significant effect on transcription, but induced EGFR turnover. Indeed, treatment with a proteasome inhibitor dramatically reversed gallic acid-induced EGFR downregulation. Moreover, treatment with gallic acid induced EGFR turnover leading to apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, which are dependent on EGFR signaling for survival. Thus, these studies suggest that gallic acid can induce apoptosis in EGFR-dependent lung cancers that are dependent on EGFR for growth and survival via acceleration of EGFR turnover. Copyright © 2016 Elsevier Ltd. All rights reserved.

A competing risk model of first failure site after definitive (chemo) radiation therapy for locally advanced non-small cell lung cancer

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Nygård, Lotte; Vogelius, Ivan R; Fischer, Barbara M

2018-01-01

INTRODUCTION: The aim of the study was to build a model of first failure site and lesion specific failure probability after definitive chemo-radiotherapy for inoperable non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed 251 patients receiving definitive chemo......-regional failure, multivariable logistic regression was applied to assess risk of each lesion being first site of failure. The two models were used in combination to predict lesion failure probability accounting for competing events. RESULTS: Adenocarcinoma had a lower hazard ratio (HR) of loco-regional (LR...

Analysis of gene expression data from non-small cell lung carcinoma cell lines reveals distinct sub-classes from those identified at the phenotype level.

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Andrew R Dalby

Full Text Available Microarray data from cell lines of Non-Small Cell Lung Carcinoma (NSCLC can be used to look for differences in gene expression between the cell lines derived from different tumour samples, and to investigate if these differences can be used to cluster the cell lines into distinct groups. Dividing the cell lines into classes can help to improve diagnosis and the development of screens for new drug candidates. The micro-array data is first subjected to quality control analysis and then subsequently normalised using three alternate methods to reduce the chances of differences being artefacts resulting from the normalisation process. The final clustering into sub-classes was carried out in a conservative manner such that sub-classes were consistent across all three normalisation methods. If there is structure in the cell line population it was expected that this would agree with histological classifications, but this was not found to be the case. To check the biological consistency of the sub-classes the set of most strongly differentially expressed genes was be identified for each pair of clusters to check if the genes that most strongly define sub-classes have biological functions consistent with NSCLC.

Downregulation of Cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9

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Qian Zhe

2012-10-01

Full Text Available Abstract Background Cyclophilin A (CypA is a cytosolic protein possessing peptidyl-prolyl isomerase activity that was recently reported to be overexpressed in several cancers. Here, we explored the biology and molecular mechanism of CypA in non-small cell lung cancer (NSCLC. Methods The expression of CypA in human NSCLC cell lines was detected by real-time reverse transcription PCR. The RNA interference-mediated knockdown of CypA was established in two NSCLC cell lines (95C and A549. 239836 CypA inhibitor was also used to suppress CypA activity. Tumorigenesis was assessed based on cellular proliferation, colony formation assays, and anchorage-independent growth assays; metastasis was assessed based on wound healing and transwell assays. Results Suppression of CypA expression inhibited the cell growth and colony formation of A549 and 95C cells. CypA knockdown resulted in the inhibition of cell motility and invasion. Significantly, we show for the first time that CypA increased NSCLC cell invasion by regulating the activity of secreted matrix metallopeptidase 9 (MMP9. Likewise, suppression of CypA with 239836 CypA inhibitor decreased cell proliferation and MMP9 activity. Conclusions The suppression of CypA expression was correlated with decreased NSCLC cell tumorigenesis and metastasis.

DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines

International Nuclear Information System (INIS)

Salim, Hogir; Zong, Dali; Hååg, Petra; Novak, Metka; Mörk, Birgitta; Lewensohn, Rolf; Lundholm, Lovisa; Viktorsson, Kristina

2015-01-01

Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60 % of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA. The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness. We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells. The online version of this article (doi:10.1186/s12885-015-1635-9) contains supplementary material, which is available to authorized users

Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

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Abigail T. Berman

2015-07-01

Full Text Available Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT, through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC, as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning.

Subcarinal Lymph Nodes Should be Dissected in All Lobectomies for Non-Small Cell Lung Cancer

DEFF Research Database (Denmark)

Eckardt, Jens; Jakobsen, Erik; Licht, Peter B

2017-01-01

BACKGROUND: Mediastinal staging is of paramount importance for planning of treatment in non-small cell lung cancer (NSCLC). Single institution reports recently claimed that subcarinal lymph node dissection during resection of upper lobe NSCLC could be spared. We used a complete national lung cancer...... registry to investigate patterns of unsuspected mediastinal lymph node involvement after lobectomy. METHODS: During an 11-year period (2004 to 2014) 5,577 consecutive patients who underwent operations for NSCLC were investigated for unsuspected mediastinal lymph node involvement (N2 disease) discovered......: Mediastinal lymph node dissection was performed in 5,577 patients during the operation, and unsuspected N2 disease was discovered in 612 (11.0%), and 193 (3.5%) had subcarinal metastasis. Subcarinal N2 disease was significantly more common in patients with lower-lobe or middle-lobe cancers compared with upper...

The prognostic value of 18F-FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases

International Nuclear Information System (INIS)

Grut, Harald; Revheim, Mona Elisabeth; Dueland, Svein; Line, Paal Dag

2018-01-01

The main objective of this study was to evaluate the prognostic value of volumetric and metabolic information derivied from F-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) in combination with computed tomography (CT) prior to liver transplantation (LT) in patients with nonresectable colorectal liver metastases (CLM). Due to scarcity of liver grafts, prognostic information enabling selection of candidates who will gain the highest survival after LT is of vital importance. 18 F-FDG PET/CT was a part of the preoperative study protocol. Patients without evidence of extrahepatic malignant disease on 18 F-FDG PET/CT who also fulfilled all the other inclusion criteria underwent LT. The preoperative 18 F-FDG PET/CT examinations of all patients included in the SECA (secondary cancer) study were retrospectively assessed. Maximum, mean and peak standardized uptake values (SUV max , SUV mean and SUV peak ), tumor to background (T/B) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured and calculated for all liver metastases. Total MTV and TLG were calculated for each patient. Cut-off values were determined for each of these parameters by using receiver operating characteristic (ROC) analysis dividing the patients into two groups. One, three and five-year overall survival (OS) and disease free survival (DFS) for patients over and under the cut-off value were compared by using the Kaplan-Meier method and log rank test. Twenty-three patients underwent LT in the SECA study. Total MTV and TLG under the cut-off values were significantly correlated to improved OS at three and five years (p = 0.027 and 0.026) and DFS (p = 0.01). One, three and five-year OS and DFS were not significantly related to SUV max , SUV mean , SUV peak or T/B-ratio. Total MTV and TLG from 18 F FDG PET/CT prior to LT for nonresectable CLM were significantly correlated to improved three and five-year OS and DFS and can potentially improve the patient selection

Progesterone receptor (PR) polyproline domain (PPD) mediates inhibition of epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer cells.

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Kawprasertsri, Sornsawan; Pietras, Richard J; Marquez-Garban, Diana C; Boonyaratanakornkit, Viroj

2016-05-01

Recent evidence has suggested a possible role for progesterone receptor (PR) in the progression of non-small cell lung cancer (NSCLC). However, little is known concerning roles of PR in NSCLC. PR contains a polyproline domain (PPD), which directly binds to the SH3 domain of signaling molecules. Because PPD-SH3 interactions are essential for EGFR signaling, we hypothesized that the presence of PR-PPD interfered with EGFR-mediated signaling and cell proliferation. We examined the role of PR-PPD in cell proliferation and signaling by stably expressing PR-B, or PR-B with disrupting mutations in the PPD (PR-BΔSH3), from a tetracycline-regulated promoter in A549 NSCLC cells. PR-B dose-dependently inhibited cell growth in the absence of ligand, and progestin (R5020) treatment further suppressed the growth. Treatment with RU486 abolished PR-B- and R5020-mediated inhibition of cell proliferation. Expression of PR-BΔSH3 and treatment with R5020 or RU486 had no effect on cell proliferation. Furthermore, PR-B expression but not PR-BΔSH3 expression reduced EGF-induced A549 proliferation and activation of ERK1/2, in the absence of ligand. Taken together, our data demonstrated the significance of PR extranuclear signaling through PPD interactions in EGFR-mediated proliferation and signaling in NSCLC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Quality-of-care indicators for non-small cell lung cancer.

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Tanvetyanon, Tawee

2009-10-01

Quality-of-care indicators are measurable elements of practice performance that can be used to assess the quality or change in quality of the care provided. To date, the literature on quality-of-care indicators for non-small cell lung cancer (NSCLC) has not been reviewed. A search was performed to identify articles reporting on quality-of-care indicators specific for NSCLC published from January 2003 to May 2009 (using MEDLINE and American Society of Clinical Oncology abstract databases). Web sites of major quality care organizations were also searched. The identified indicators were then classified by their aspect of care provision (structure-of-care, process-of-care, or outcome-of-care indicator). For structure-of-care quality indicators, the most cited indicators were related to the quality of lung surgery. These included being National Cancer Institute-designated cancer centers or high-volume hospitals. For process-of-care quality indicators, the most common indicators were the receipt of surgery for early-stage NSCLC and the administration of chemotherapy for advanced-stage NSCLC. For outcome-of-care quality indicators, the most cited indicators were related to postoperative morbidity or mortality after lung surgery. Several quality-of-care indicators for NSCLC are available. Process-of-care indicators are the most studied. The use of these indicators to measure practice performance holds the promise of improving outcomes of patients with NSCLC.

Analysis of prognostic factors in patients with non-small cell lung cancer treated conventional radical teleradiotherapy

International Nuclear Information System (INIS)

Pluta, E.

2007-01-01

Radical surgery is the treatment of choice in non-small cell lung cancer, however, only about 20-30% of patients with early stage of disease (stage I, II and possibly IIIA) qualify for it. For the remaining patients, unable to tolerate surgery because of underlying medial disease, advanced age, respiratory insufficiency, or those who refused to undergo operation, radiation therapy is a clinically accepted alternative. Five - year survival for patients receiving radical radiation treatment alone ranges from 12-32%. We reviewed the records of 227 patients with inoperable non-small cell lung cancer, treated in our Institute between 1970-1990. In our group: 40% patients have unresectable tumor, 21% had bad pulmonary function tests results, 15% had cardiac risk, 6% were over 76 years of age, and 18% refused to agree to surgery. Treatment was delivered using megavoltage irradiation in doses ranging from 60 to 72 Gy. The survival probability was calculated by the Kaplan-Meier method. Overall survival (OS) probability at two years was 34% and at five years - 10%. Two - years local control was observed in 54% and five-year in 41%. The disease - specific survival (DSS) rates at 2 and 5 years were 30% and 8% respectively. The significant favorable prognostic factor for DSS and OS were tumor size (T1,T2, N0) and early stage (I), no weight loss, and complete radiological regression of the tumor 8 weeks after irradiation. The significant favorable prognostic factors for local control were good performance status (over 80 points acc. to Karnofsky scale), no weight loss, early stage (I), and complete radiological regression of the tumor 8 weeks after irradiation. 1. New therapeutic strategies involving chemotherapy should be considered for larger tumors (T2, T3, N1, N2). 2. Patients with a good performance status and small tumor (T1N0, T2N0) would benefit most from treatment with radiation alone. (author)

Expression of Bim, Noxa, and Puma in non-small cell lung cancer

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Sakakibara-Konishi, Jun; Oizumi, Satoshi; Kikuchi, Junko; Kikuchi, Eiki; Mizugaki, Hidenori; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Nishimura, Masaharu

2012-01-01

The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p < 0.001), smoking habit (p = 0.03), pathological histology (p = 0.001), pathological T stage (p = 0.03), pathological disease stage (p = 0.02), and differentiation of tumor (p < 0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p = 0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p = 0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p = 0.02) and the pathological histology (p = 0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation

Local recurrence after surgery for non-small cell lung cancer: a recursive partitioning analysis of multi-institutional data.

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Kelsey, Chris R; Higgins, Kristin A; Peterson, Bercedis L; Chino, Junzo P; Marks, Lawrence B; D'Amico, Thomas A; Varlotto, John M

2013-10-01

To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA). This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method. The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69). The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Anti-tumor effect of 131I labeled 17-allylamino-17-demethoxygeldanamycin on human non-small cell lung cancer in xenograft-bearing nude mice

International Nuclear Information System (INIS)

Sun Jin; Liu Lu; Zhu Xiaoli; Chen Daozhen; Gao Wen; Jiang Xinyu; Huang Ying

2008-01-01

Objective: 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been developed as a novel heat shock protein 90 (HSP90) inhibitor being used in clinical trials. HSP90 is known as a molecular target for tumor therapy. The goal of this study was to investigate the inhibitive effects of 131 I labeled 17-AAG on human non-small cell lung cancer in xenograft-bearing nude mice. Methods: 17-AAG was labeled with 131 I. Twenty-eight BALB/c nude mice bearing H460 human non-small cell lung carcinoma tumor xenograft were randomly divided into seven groups, one control group and six treatment groups according to the route of administration (via tail vein injection or intratumoral injection) and the doses of injected radio-activity (5.5 MBq x 2 with 8 d interval, 11.0 MBq and 5.5 MBq). Two additional mice were treated with intratumoral injection of Na 131 I solution that was served as seintigraphic imaging controls. In each group two mice underwent scintigraphy at 2 h, 6 h, 24 h, 2 d, 3 d, 7 d, 10 d and 16 d. After 16 d the tumor inhibition rate was calculated. Then all of the mice were sacrificed and the tumor tissues were obtained for histological examination and immunohistochemical assay. Results: Persistent accumulation of 131 I-17-AAG in the tumors was seen on seintigraphic images. Tumor inhibiting effect was demonstrated in all treatment groups with varying degrees. The highest tumor inhibition rate (86.77 ± 4.57)% was shown in the group with interval intratumoral injection (5.5 MBq x 2). There was no significant difference of tumor inhibition rates between 5.5 MBq x 2 group (via tail vein injection) and 11.0 MBq group( via tail vein injection, q=1.67, P>0.05). While among the other treatment groups, there was significant difference in tumor inhibition rates( q=3.16-24.34, all P 131 I-17-AAG may effectively inhibit the tumor growth and expression of HSP90α antigen expression in non-small cell lung cancer bearing nude mice. The more prominent anti-tumor effect may be

Promising survival with three-dimensional conformal radiation therapy for non-small cell lung cancer

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Armstrong, John; Raben, Adam; Zelefsky, Michael; Burt, Michael; Leibel, Steve; Burman, Chandra; Kutcher, Gerard; Harrison, Louis; Hahn, Cathy; Ginsberg, Robert; Rusch, Valerie; Kris, Mark; Fuks, Zvi

1997-01-01

Purpose: Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival. Methods: There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38-82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients. had combined favorable prognostic factors (i.e. KPS ≤ 80, and ≤5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2-72 Gy) delivered in fractions of 1.8 Gy, 5 days per week. Results: Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35-59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity ≥grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% ((3(8))) of patients with >30% of lung volume receiving ≥25 Gy, versus 4% ((1(23))) of patients with ≤30% lung receiving ≥25 Gy (P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% ((4(14))) of patients with a predicted pulmonary normal tissue

Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells

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Lin, Hui-Hsuan [School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Tsai, Chia-Wen [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Chou, Fen-Pi [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Wang, Chau-Jong [Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Hsuan, Shu-Wen [Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, No.89, Wen Hwa 1st St., Rende Shiang, Tainan County 717, Taiwan (China); Wang, Cheng-Kun [E-Chyun Dermatology Clinic, No.70, Sec. 3, Jhonghua E. Rd., East District, Tainan, Taiwan (China); Chen, Jing-Hsien [Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, No.89, Wen Hwa 1st St., Rende Shiang, Tainan County 717, Taiwan (China)

2011-02-01

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) in A549 cells. HIF-1{alpha} plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1{alpha} was correlated with a rapid ubiquitin-dependent degradation of HIF-1{alpha}, and was accompanied by increased expressions of hydroxyl-HIF-1{alpha} and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1{alpha} inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGF{beta}1/PHD2/HIF-1{alpha} pathway, as demonstrated by the transfection of TGF{beta}1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1{alpha} transduced VEGF expression in A549 cells and other NSCLC cell lines. In conclusion, these results highlighted the potential effects of Andro, which may be developed as a chemotherapeutic or an anti-angiogenesis agent for NSCLC in the future.

Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lung cancer A549 cells

International Nuclear Information System (INIS)

Lin, Hui-Hsuan; Tsai, Chia-Wen; Chou, Fen-Pi; Wang, Chau-Jong; Hsuan, Shu-Wen; Wang, Cheng-Kun; Chen, Jing-Hsien

2011-01-01

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1α (HIF-1α) in A549 cells. HIF-1α plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1α was correlated with a rapid ubiquitin-dependent degradation of HIF-1α, and was accompanied by increased expressions of hydroxyl-HIF-1α and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1α inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGFβ1/PHD2/HIF-1α pathway, as demonstrated by the transfection of TGFβ1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1α transduced VEGF expression in A549 cells and other NSCLC cell lines. In conclusion, these results highlighted the potential effects of Andro, which may be developed as a chemotherapeutic or an anti-angiogenesis agent for NSCLC in the future.

Radiochemotherapy in non-small cell lung cancer. A report of experiences

International Nuclear Information System (INIS)

Mueller, G.; Kiricuta, I.C.; Stiess, J.; Flentje, M.

1996-01-01

60 inoperable patients (42 M0- and 18 M1-stage) with non-small cell lung cancer who had received combined radiochemotherapy (RT+CT) were examined retrospectively. Different drugs or drug-combinations were used. The sequence of radiotherapy and chemotherapy also differed. The survival was compared to that of another group of patients who had received at least 50 Gy with definitive radiotherapy at the same period of time (RT: N=135). The Karnofsky-performance-index (KPI) was on an average of 80% in both groups. The primary of patients with systemic disease was treated by radiation when it became symptomatic or when it showed an evident progression. The two investigated treatment groups were comparable regarding KPI, histology, stage, tumor dose and age. The survival was significantly better when chemotherapy was added to radiotherapy. The median survival times in months were as follows: M0: RT 10.6/RT+CT 14.7; M1: RT 6.0/RT+CT 9.3. Lokal tumor control was the major problem with or without chemotherapy (local progression of about 70% in both groups). The toxicity of radiochemotherapy was acceptable (bonemarrow toxicity WHO-grade 4: 10.5%; nausea WHO-grade 4: 3%). (orig.) [de

Non-small cell lung cancer: RT out, pembrolizumab in, and vaccine hope or hype

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Robbins RA

2016-11-01

Full Text Available No abstract available. Article truncated at 150 words. Three articles on non-small cell lung cancer (NSCLC recently appeared which were of interest and might alter therapy. The first on whole brain radiation therapy (WBRT was presented at the at the European Respiratory Society (ERS International Congress 2016 and simultaneously published online in the Lancet (1. WBRT and dexamethasone have been the standard of care for patients with NSCLC brain metastases. However, the study of 538 randomized patients concludes that WBRT provides "little additional clinically significant benefit" with brain metastases. Notably, all the patients were unsuitable for surgical resection or stereotactic radiotherapy, owing to widespread metastases. However, patients younger than 60 years did seem to have a survival advantage and might represent an exception. The second study presented at the European Society for Medical Oncology (ESMO 2016 Congress reports that the addition of pembrolizumab to first-line treatment with pemetrexed and carboplatin significantly improved objective response rate and progression-free survival ...

Long noncoding RNA TUG1 is downregulated in non-small cell lung cancer and can regulate CELF1 on binding to PRC2

OpenAIRE

Lin, Pei-Chin; Huang, Hsien-Da; Chang, Chun-Chi; Chang, Ya-Sian; Yen, Ju-Chen; Lee, Chien-Chih; Chang, Wen-Hsin; Liu, Ta-Chih; Chang, Jan-Gowth

2016-01-01

Background Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, and lncRNA taurine-upregulated gene 1 (TUG1) has been proven to be associated with several human cancers. However, the mechanisms of TUG1-involved regulation remain largely unknown. Methods We examined the expressions of TUG1 in a cohort of 89 patients with non-small cell lung cancer (NSCLC) to determine the association between TUG1 expression and clinical parameters. We used circular chromosome conformation capture...

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

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Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

2015-08-21

Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

Effect of informing the diagnosis on depressive state in patients with non-small cell lung cancer of stage Ⅲ

Directory of Open Access Journals (Sweden)

Wei WANG

2008-10-01

Full Text Available Background and objective As other tumors, unresectabe lung cancer can cause many psychological problems to the patients, such as depression and anxiety. The present paper aims to evaluate the status of depression before and after knowing the state of illness in patients with non-small cell lung cancer of stage Ⅲ. Methods 43 casesof newly diagnosed non-small cell lung cancer (NSCLC with stage Ⅲ were enrolled in the study. All the patients were distributed into three groups and given different intervention, that was completely unknowing the state of illness (group A, partly knowing the state of illness (group B and completely knowing the state of illness (group C. Before and after knowing the state of illness, the depression status was assessed with the Hamilton depression rating scale for depression(HAMD. Results The mean total score of HAMD was unchanged both in group A and C, while significantly reduced in group B. The scores of anxiety somatization, cognitive disorder, retardation and feeling of despair were all significant lower in the group B after the patients partly knowing the state of illness, while the scores of sleep disorder was obviously higher in group C after the patients completely knowing the state of illness. The hypochondriasis was much severer in the group A, and in the group C, the score of suicidal idea became significantly higher after the patient knowing the diagnosis.Conclusion Depression is very common in the NSCLC patients with stage Ⅲ. Partly knowing the state of illness can obviously ameliorate the symptoms of depression, while completely knowing or completely unknowing the state of illness have no effect on relieving the patients' depression.

EGFR T790M mutation after chemotherapy for small cell lung cancer transformation of EGFR-positive non-small cell lung cancer

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Tomoaki Sonoda

Full Text Available In non-small cell lung cancer (NSCLC with an epidermal growth factor receptor (EGFR mutation, 50%–65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs because of an EGFR T790M point mutation and 3%–14% of these cases transformed to small cell lung cancer (SCLC. Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation. Keywords: NSCLC, EGFR mutation, SCLC transformation, T790M, Osimertinib

Resveratrol enhances radiosensitivity of human non-small cell lung cancer NCI-H838 cells accompanied by inhibition of nuclear factor-kappa B activation

International Nuclear Information System (INIS)

Liao, Hui-Fen; Kuo Cheng-Deng; Yang, Yuh-Cheng; Lin, Chin-Ping; Tai, Hung-Chi; Chen, Yu-Jen; Chen, Yu-Yawn

2005-01-01

Resveratrol, a polyphenol in red wine, possesses many pharmacological activities including cardio-protection, chemoprevention, anti-tumor effects, and nuclear factor-kappa B (NF-κB) inactivation. The present study was designed to evaluate the effects and possible mechanism of resveratrol in enhancing radiosensitivity of lung cancer cells. Human non-small cell lung cancer NCI-H838 cells were irradiated with or without resveratrol pretreatment. The surviving fraction and sensitizer enhancement ratio (SER) were estimated by using a colony formation assay and linear-quadratic model. The cell-cycle distribution was evaluated by using prospidium iodide staining and flow cytometry. An enzyme-linked immunosorbent assay (ELISA)-based assay with immobilized oligonucleotide was performed to assess the DNA binding activity of NF-κB. Resveratrol had no direct growth-inhibitory effect on NCI-H838 cells treated for 24 hours with doses up to 25 μM. Pretreatment with resveratrol significantly enhanced cell killing by radiation, with an SER up to 2.2. Radiation activated NF-κB, an effect reversed by resveratrol pretreatment. Resveratrol resulted in a decrease of cells in the G 0 /G 1 phase and an increase in the S phase. Our results demonstrate that resveratrol enhances the radiosensitivity of NCI-H838 cells accompanied by NF-κB inhibition and S-phase arrest. (author)

[Principles of radiotherapy of non-small cell lung cancer].

Science.gov (United States)

Esik, Olga; Horváth, Akos; Bajcsay, András; Hideghéty, Katalin; Agócs, László; Pikó, Béla; Lengyel, Zsolt; Petrányi, Agota; Pisch, Julianna

2002-01-01

The long-term survival probability for Hungarian lung cancer patients is 10% worse than the best results published in the most highly developed countries (the mean 5-year survival probability in Hungary is 5%, in contrast with the 15% survival probability in the USA). On the basis of the international recommendations and personal experience, an attempt was made to formulate the guidelines for radiotherapy as one of the fundamental non-small cell lung cancer (NSCLC) treatment modalities for national use. An expert panel was set up comprising physicians from 6 radiotherapeutic centers (the National Institute of Oncology / Semmelweis University, Budapest; the Beth Israel Medical Center, New York; the University of Kaposvár; the University of Essen; the University of Debrecen; and the County Hospital of Gyula). Experts in two important medical fields closely related to radiotherapy (surgery and diagnostic imaging) were also engaged in the elaboration of the manuscript. Discussion of the most important principles of the radiotherapy and an overview of the prognostic factors was followed by a critical analysis of the protocols applied in the radiotherapy of Hungarian NSCLC patients during recent decades. The new guidelines suggested for the radiotherapy of NSCLC are presented separately for the postoperative period, marginally resectable tumors, and the aggressive or non-aggressive radiotherapy of inoperable tumors. Detailed accounts are given of the techniques of external irradiation and brachytherapy, and of the acute and late radiation-induced damage of normal tissues. The authors believe that this document may be instrumental in improving the survival index of Hungarian NSCLC patients in the near future.

Hot spot mutations in Finnish non-small cell lung cancers.

Science.gov (United States)

Mäki-Nevala, Satu; Sarhadi, Virinder Kaur; Rönty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari

2016-09-01

Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bag3 promotes resistance to apoptosis through Bcl-2 family members in non-small cell lung cancer.

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Zhang, Yong; Wang, Jian-Hua; Lu, Qiang; Wang, Yun-Jie

2012-01-01

In non-small cell lung cancer (NSCLC) certain molecular characteristics, which are related to molecular alterations have been investigated. These are responsible for both the initiation and maintenance of the malignancy in lung cancer. The aim of this study was to evaluate the influence of Bag3 (Bcl-2 associated athanogene 3) in the regulation of apoptosis on NSCLC. Bag3 and Hsp70 expression were examined by immunohistochemistry to confirm their potential roles in the prevalence of NSCLC. We also established human normal bronchial epithelial cells and HOP-62 cell line as the model to analyze cell apoptosis and the expression of Hsp70, Bcl-XL and Bcl-2, which were affected by Bag3. In this study, we found that Bag3 and Hsp70 are highly expressed in few tissues and cell lines of NSCLC. Bag3 inhibits apoptosis in human normal bronchial epithelial cell lines and sustain the survival of NSCLC cells. Bag3, Hsp70, Bcl-XL and Bcl-2 are up-regulated in NSCLC cell lines. At the same time, the silencing of Bag3 results in diminishing protein levels of Bcl-XL and Bcl-2. The results of immunoprecipitation identified that Bag3 could interact with Hsp70, Bcl-XL and Bcl-2 NSCLC cells directly or indirectly. We conclude that NSCLC cells were protected from apoptosis through increasing Bag3 expression and consequently promoted the expression of Bcl-XL and Bcl-2.

Postoperative Radiation Therapy for Non-Small Cell Lung Cancer and Thymic Malignancies

International Nuclear Information System (INIS)

Gomez, Daniel R.; Komaki, Ritsuko

2012-01-01

For many thoracic malignancies, surgery, when feasible, is the preferred upfront modality for local control. However, adjuvant radiation plays an important role in minimizing the risk of locoregional recurrence. Tumors in the thoracic category include certain subgroups of non-small cell lung cancer (NSCLC) as well as thymic malignancies. The indications, radiation doses, and treatment fields vary amongst subtypes of thoracic tumors, as does the level of data supporting the use of radiation. For example, in the setting of NSCLC, postoperative radiation is typically reserved for close/positive margins or N2/N3 disease, although such diseases as superior sulcus tumors present unique cases in which the role of neoadjuvant vs. adjuvant treatment is still being elucidated. In contrast, for thymic malignancies, postoperative radiation therapy is often used for initially resected Masaoka stage III or higher disease, with its use for stage II disease remaining controversial. This review provides an overview of postoperative radiation therapy for thoracic tumors, with a separate focus on superior sulcus tumors and thymoma, including a discussion of acceptable radiation approaches and an assessment of the current controversies involved in its use

The End of Nihilism: Systemic Therapy of Advanced Non-Small Cell Lung Cancer.

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Ernani, Vinicius; Steuer, Conor E; Jahanzeb, Mohammad

2017-01-14

Lung cancer is the leading cause of cancer death in the United States and many other parts of the world. Non-small cell lung cancer (NSCLC) comprises 85-90% of lung cancers. Historically, the expected survival of patients with advanced disease has been estimated in months. In recent years, however, lung cancer has come to be seen as a treatable disease with multiple therapeutic options. Enormous advances in the understanding of its pathways and mechanisms have enabled personalized therapy in NSCLC. The evolving approach to therapy focuses on genomic profiling of the tumors to find molecular targets and develop specific agents for individualized therapy. In addition, maintenance therapy has emerged as a valid approach, and the choice of chemotherapy now varies by histology. Most recently, immunotherapy with checkpoint inhibitors has shown promising results, with impressive durations of response and a tolerable toxicity profile. Together, these discoveries have improved overall survival substantially in patient populations that have access to these advancements. We review the clinical data surrounding these impressive improvements.

Insulin-like Growth Factor Receptor 1 mRNA Expression as a Prognostic Marker in Advanced Non-small Cell Lung Cancer

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Vilmar, Adam; Santoni-Rugiu, Eric; Cillas, Jesus Garcia-Fon

2014-01-01

BACKGROUND: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain......-points. RESULTS: Surgical tissue samples were available from 33 patients deemed inoperable. IGF1R status varied according to histopathology. Patients with tumors positive for IGF1R mRNA expression had a shorter progression-free and overall survival when compared to the negative sub-group (6.1 vs. 7.4 months, p=0...

[Expression and clinical significance of BCL6 corepressor-like 1 in non-small cell lung cancer].

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Zhao, Xu; Tuo, Hang; Si, Meili; Wang, Lei; Liang, Ping

2015-12-01

To detect the expression of BCL6 corepressor-like 1 (BCORL1) in tumor tissues of human non-small cell lung cancer (NSCLC) and determine the effect of BCORL1 on cell migration and invasion in A549 cells by knockdown of BCORL1. Sixty-eight pairs of NSCLC and nontumor tissues were collected and the expressions of BCORL1 and E-cadherin in them were detected using immunohistochemical staining. The expression of BCORL1 was knocked down by siRNA in A549 cells. Transwell(TM) assays were performed to test NSCLC cell migration and invasion in vitro. The expression of BCORL1 in NSCLC was significantly higher than that in paired noncancerous tissues, while E-cadherin was down-regulated in NSCLC as compared with nontumor tissues. Pearson correlation coefficient analysis suggested that BCORL1 was negatively correlated with E-cadherin expression in NSCLC tissues. Clinical association analysis suggested that the elevated expression of BCORL1 was evidently associated with the higher incidence of lymph node metastasis and more advanced TNM stage. When the expression of BCORL1 was down-regulated by a specific siRNA, E-cadherin was up-regulated, and BCORL1 knockdown obviously inhibited cell migration and invasion in A549 cells. BCORL1 is overexpressed in NSCLC tissues and it is negatively correlated with E-cadherin expression. Its high expression is correlated with poor prognostic features. BCORL1 knockdown up-regulates E-cadherin expression and subsequently inhibits cell migration and invasion of lung cancer cells.

Role of chemotherapy in the treatment of lung cancer: evolving strategies for non-small cell histologies

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Muggia, F.M.; Blum, R.H.; Foreman, J.D.

1984-01-01

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages

Role of chemotherapy in the treatment of lung cancer: evolving strategies for non-small cell histologies

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Muggia, F.M. (NYU Medical Center, New York); Blum, R.H.; Foreman, J.D.

1984-01-01

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

Treatment and survival of patients with non-small cell lung cancer Stage IIIA diagnosed in 1989-1994: a study in the region of the Comprehensive Cancer Centre East, The Netherlands.

NARCIS (Netherlands)

Dijck, J.A.A.M. van; Festen, J.; Kleijn, E.M.H.A. de; Kramer, G.W.P.M.; Tjan-Heijnen, V.C.; Verbeek, A.L.M.

2001-01-01

The purpose of this study was to gain insight into the treatment policy and survival of patients with non-small cell lung cancer (NSCLC) clinical stage IIIA in daily practice. We selected 212 patients, who had been diagnosed between 1989 and 1994 and registered by the Cancer Registry, Comprehensive

Adenylyl cyclase-associated protein 1 in metastasis of squamous cell carcinoma of the head and neck and non-small cell lung cancer

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Kakurina, G. V.; Kolegova, E. S.; Cheremisina, O. V.; Zavyalov, A. A.; Shishkin, D. A.; Kondakova, I. V.; Choinzonov, E. L.

2016-08-01

Progression of tumors and metastasis in particular is one of the main reasons of the high mortality rate among cancer patients. The primary role in developing metastases plays cell locomotion which requires remodeling of the actin cytoskeleton. Form, dynamics, localization and mechanical properties of the actin cytoskeleton are regulated by a variety of actin-binding proteins, which include the adenylyl cyclase-associated protein 1 (CAP1). The study is devoted to the investigation of CAP1 level depending on the presence or absence of metastases in patients with squamous cell carcinoma of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). The results show the contribution of CAP1 to SCCHN and NSCLC progression. We detected the connection between the tissue protein CAP1 level and the stage of NSCLC and SCCHN disease. Also the levels of the CAP1 protein in tissues of primary tumors and metastases in lung cancer were different. Our data showed that CAP is important in the development of metastases, which suggests further perspectives in the study of this protein for projecting metastasis of NSCLC and SCCHN.

Long-term change in pulmonary function after definitive radiotherapy for non-small cell lung cancer

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Schytte, T.; Bentzen, S. M.; Brink, C.

2015-01-01

Purpose/Objective: Radiotherapy (RT) for non-small cell lung cancer (NSCLC) may cause late toxicities, such as heart toxicity, changes in pulmonary function (PF) and lung fibrosis, but late toxicity data are scarce in the literature for this category of patients. The objective of this study...... with 3063 pairs of pulmonary function test (PFTs) were screened for eligibility for inclusion in the analysis of late changes in PF. To be eligible, patients had at least 3 PFTs after baseline. In this study, baseline was defined as 12 months after RT commencement to overcome a possible effect of tumor...... finding was that high V60 was associated with less decline in FVC, but FVC may be a less reliable parameter for pulmonary damage. (Figure Presented) Conclusions: Patients experience a decline in FEV1 after the 12-month value following definitive RT for NSCLC. In a multivariable analysis, deterioration...

Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value

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Liao Rong-xia

2009-02-01

Full Text Available Abstract Background Our aim was to detect lymphatic endothelial marker podoplanin, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1 and vascular endothelial growth factor receptor-3 (VEGFR-3 and study the prognostic relevance of lymphangiogenesis in non-small cell lung cancer (NSCLC. Materials 82 paraffin-embedded tissues and 40 fresh frozen tissues from patients with NSCLC were studied. Tumor samples were immunostained for the lymphatic endothelial markers. Lymphangiogenesis was assessed by immunohistochemical double stains for Podoplanin and Ki-67. The prognostic relevance of lymphangiogenesis-related clinicopathological parameters in NSCLC was evaluated. Results We found that the number of podoplanin positive vessels was correlated positively with the number of LYVE-1 positive vessels. Most of VEGFR-3 positive, few of LYVE-1 positive and none of podoplanin positive vessels were blood vessels. Peritumoral lymphatic vessel density (ptLVD, pathologic stage, lymph node status, lymphatic vessel invasion (LVI, vascular endothelial growth factor-C (VEGF-C expression and Ki-67 index of the endothelium cells of the micro lymphatic vessels (Ki67% were associated significantly with a higher risk of tumor progress. ptLVD, pathologic stage, lymph-node metastasis and Ki67% were independent prognostic parameters for overall survival. Conclusion Podoplanin positive ptLVD might play important roles in the lymphangiogenesis and progression of NSCLC. Patients with high podoplanin+ ptLVD have a poor prognosis.

Targeted therapy of advanced non-small cell lung cancer: the role of bevacizumab.

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Stinchcombe, Thomas E

2007-09-01

Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced stage disease, and treatment with standard cytotoxic chemotherapy agents have been shown to provide a modest improvement in survival, reduce disease-related symptoms, and improve quality of life. However, with standard chemotherapy treatments the prognosis is poor with the majority of patients dying in less than a year from diagnosis. Treatment with standard chemotherapy agents has reached a therapeutic plateau, and recent investigations have focused on therapies that target a specific pathway within the malignant cell or related to angiogenesis. The most promising of the targeted therapies are agents that target the process of angiogenesis. Bevacizuamab is a monoclonal antibody that binds to circulating vascular endothelial growth factor (VEGF)-A, and prevents binding of VEGF to vascular endothelial growth factor receptors, thus inhibiting activation of the VEGF pathway and angiogenesis. A recent phase III trial of first-line treatment of advanced non-small cell lung cancer revealed a statistically significant improvement in response, progression-free survival, and overall survival with the combination of bevacizumab and standard chemotherapy in comparison to standard chemotherapy alone. Bevacizumab is the only targeted therapy that has been shown to improve survival when combined with standard chemotherapy in the first-line setting.

Terpinen-4-ol Induces Apoptosis in Human Nonsmall Cell Lung Cancer In Vitro and In Vivo

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Chieh-Shan Wu

2012-01-01

Full Text Available Terpinen-4-ol, a monoterpene component of the essential oils of several aromatic plants, exhibits antitumor effects. In this study, the antitumor effects of terpinen-4-ol and the cellular and molecular mechanisms responsible for it were evaluated and studied, respectively on human nonsmall cell lung cancer (NSCLC cells. Our results indicated that terpinen-4-ol elicited a dose-dependent cytotoxic effect, as determined by MTT assay. Increased sub-G1 population and annexin-V binding, activation of caspases 9 and 3, cleavage of poly(ADPribose polymerase (PARP, and a decrease of mitochondrial membrane potential (MMP indicated involvement of the mitochondrial apoptotic pathway in terpinen-4-ol-treated A549 and CL1-0 cells. Elevation of the Bax/Bcl-2 ratio and a decrease in IAP family proteins XIAP and survivin were also observed following terpinen-4-ol treatment. Notably, terpinen-4-ol was able to increase p53 levels in A549 and CL1-0 cells. Diminution of p53 by RNA interference induced necrosis instead of apoptosis in A549 cells following terpinen-4-ol treatment, indicating that terpinen-4-ol-elicited apoptosis is p53-dependent. Moreover, intratumoral administration of terpinen-4-ol significantly suppressed the growth of s.c. A549 xenografts by inducing apoptosis, as confirmed by TUNEL assay. Collectively, these data provide insight into the molecular mechanisms underlying terpinen-4-ol-induced apoptosis in NSCLC cells, rendering this compound a potential anticancer drug for NSCLC.

Short-Course Treatment With Gefitinib Enhances Curative Potential of Radiation Therapy in a Mouse Model of Human Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Bokobza, Sivan M.; Jiang, Yanyan; Weber, Anika M.; Devery, Aoife M.; Ryan, Anderson J.

2014-01-01

Purpose: To evaluate the combination of radiation and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models of human non-small cell lung cancer. Methods and Materials: Sensitivity to an EGFR TKI (gefitinib) or radiation was assessed using proliferation assays and clonogenic survival assays. Effects on receptor signal transduction pathways (pEGFR, pAKT, pMAPK) and apoptosis (percentage of cleaved PARP Poly (ADP-ribose) polymerase (PARP)) were assessed by Western blotting. Radiation-induced DNA damage was assessed by γH2AX immunofluorescence. Established (≥100 mm 3 ) EGFR-mutated (HCC287) or EGFR wild-type (A549) subcutaneous xenografts were treated with radiation (10 Gy, day 1) or gefitinib (50 mg/kg, orally, on days 1-3) or both. Results: In non-small cell lung cancer (NSCLC) cell lines with activating EGFR mutations (PC9 or HCC827), gefitinib treatment markedly reduced pEGFR, pAKT, and pMAPK levels and was associated with an increase in cleaved PARP but not in γH2AX foci. Radiation treatment increased the mean number of γH2AX foci per cell but did not significantly affect EGFR signaling. In contrast, NSCLC cell lines with EGFR T790M (H1975) or wild-type EGFR (A549) were insensitive to gefitinib treatment. The combination of gefitinib and radiation treatment in cell culture produced additive cell killing with no evidence of synergy. In xenograft models, a short course of gefitinib (3 days) did not significantly increase the activity of radiation treatment in wild-type EGFR (A549) tumors (P=.27), whereas this combination markedly increased the activity of radiation (P<.001) or gefitinib alone (P=.002) in EGFR-mutated HCC827 tumors, producing sustained tumor regressions. Conclusions: Gefitinib treatment increases clonogenic cell killing by radiation but only in cell lines sensitive to gefitinib alone. Our data suggest additive rather than synergistic interactions between gefitinib and radiation and that a

Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer.

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Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; Castro Junior, Gilberto de

2015-01-01

Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.

Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer *

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Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; de Castro, Gilberto

2015-01-01

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC. PMID:26398757

Development of an innovative 3D cell culture system to study tumour--stroma interactions in non-small cell lung cancer cells.

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Arno Amann

Full Text Available INTRODUCTION: We describe a novel 3D co-culture model using non-small cell lung cancer (NSCLC cell lines in combination with lung fibroblasts. This model allows the investigation of tumour-stroma interactions and addresses the importance of having a more in vivo like cell culture model. METHODS: Automation-compatible multi-well hanging drop microtiter plates were used for the production of 3D mono- and co-cultures. In these hanging drops the two NSCLC cell lines A549 and Colo699 were cultivated either alone or co-cultured with lung fibroblasts. The viability of tumour spheroids was confirmed after five and ten days by using Annexin V/Propidium Iodide staining for flow-cytometry. Tumour fibroblast spheroid formation was characterized by scanning electron microscope (SEM, semi-thin sections, fluorescence microscope and immunohistochemistry (IHC. In addition to conventional histology, protein expression of E-Cadherin, vimentin, Ki67, fibronectin, cytokeratin 7 and α-smooth muscle actin (α-SMA was investigated by IHC. RESULTS: Lower viability was observed in A549 monocultures compared to co-cultures, whereas Colo699 monocultures showed better viability compared to co-cultures. Ki67 expression varied significantly between mono- and co-cultures in both tumour cell lines. An increase of vimentin and decreased E-Cadherin expression could be detected during the course of the cultivation suggesting a transition to a more mesenchymal phenotype. Furthermore, the fibroblast cell line showed an expression of α-SMA only in co-culture with the cancer cell line A549, thereby indicating a mesenchymal to mesenchymal shift to an even more myofibroblast phenotype. CONCLUSION: We demonstrate that our method is a promising tool for the generation of tumour spheroid co-cultures. Furthermore, these spheroids allow the investigation of tumour-stroma interactions and a better reflection of in vivo conditions of cancer cells in their microenvironment. Our method holds

Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer.

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Yang, Xuebin; Liu, Yongjun; Mani, Haresh; Olson, Jeffrey; Clawson, Gary; Caruso, Carla; Bruggeman, Richard; Varlotto, John M; Zander, Dani S; Rassaei, Negar

2017-01-01

A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-β), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-β, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.

Prognostic significance of CD44s expression in resected non-small cell lung cancer

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Ko Yoon

2011-08-01

Full Text Available Abstract Background CD44s is a cell adhesion molecule known to mediate cellular adhesion to the extracellular matrix, a prerequisite for tumor cell migration. CD44s plays an important role in invasion and metastasis of various cancers. In the present study, we sought to determine whether CD44s is involved in clinical outcomes of patients with resected non-small cell lung cancer (NSCLC. Methods Using immunohistochemical staining, we investigated CD44s protein expression using tissue array specimens from 159 patients with resected NSCLC (adenocarcinoma (AC; n = 82 and squamous cell carcinoma (SCC; n = 77. Additionally, the immunoreactivity of cyclooxygenase (COX-2 was also studied. The clinicopathological implications of these molecules were analyzed statistically. Results High CD44s expression was detected more frequently in NSCLC patients with SCC (66/72; 91.7% than in those with AC histology (P 0.001. Additionally, high CD44s expression was significant correlated with more advanced regional lymph node metastasis (P = 0.021. In multivariate analysis of survival in NSCLC patients with AC histology, significant predictors were lymph node metastasis status (P P = 0.046, and high CD44s expression (P = 0.014. For NSCLC patients with SCC histology, the significant predictor was a more advanced tumor stage (P = 0.015. No significant association was found between CD44s and clinical outcome (P = 0.311. Conclusions High CD44s expression was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with AC histology, and was independent of tumor stage.

Prognostic significance of CD44s expression in resected non-small cell lung cancer

International Nuclear Information System (INIS)

Ko, Yoon Ho; Won, Hye Sung; Jeon, Eun Kyoung; Hong, Sook Hee; Roh, Sang Young; Hong, Young Seon; Byun, Jae Ho; Jung, Chan-Kwon; Kang, Jin Hyoung

2011-01-01

CD44s is a cell adhesion molecule known to mediate cellular adhesion to the extracellular matrix, a prerequisite for tumor cell migration. CD44s plays an important role in invasion and metastasis of various cancers. In the present study, we sought to determine whether CD44s is involved in clinical outcomes of patients with resected non-small cell lung cancer (NSCLC). Using immunohistochemical staining, we investigated CD44s protein expression using tissue array specimens from 159 patients with resected NSCLC (adenocarcinoma (AC; n = 82) and squamous cell carcinoma (SCC; n = 77). Additionally, the immunoreactivity of cyclooxygenase (COX)-2 was also studied. The clinicopathological implications of these molecules were analyzed statistically. High CD44s expression was detected more frequently in NSCLC patients with SCC (66/72; 91.7%) than in those with AC histology (P <0.001). Additionally, high CD44s expression was significant correlated with more advanced regional lymph node metastasis (P = 0.021). In multivariate analysis of survival in NSCLC patients with AC histology, significant predictors were lymph node metastasis status (P < 0.001), high-grade tumor differentiation (P = 0.046), and high CD44s expression (P = 0.014). For NSCLC patients with SCC histology, the significant predictor was a more advanced tumor stage (P = 0.015). No significant association was found between CD44s and clinical outcome (P = 0.311). High CD44s expression was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with AC histology, and was independent of tumor stage

Cyberknife Stereotactic Body Radiation Therapy for Nonresectable Tumors of the Liver: Preliminary Results

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K. Goyal

2010-01-01

Full Text Available Purpose. Stereotactic body radiation therapy (SBRT has emerged as a treatment option for local tumor control of primary and secondary malignancies of the liver. We report on our updated experience with SBRT in patients with non-resectable tumors of the liver. Methods. Our first 17 consecutive patients (mean age 58.1 years receiving SBRT for HCC (=6, IHC (=3, and LM (=8 are presented. Mean radiation dose was 34Gy delivered over 1–3 fractions. Results. Treated patients had a mean decrease in maximum pretreatment tumor diameter from 6.9±4.6 cm to 5.0±2.1 cm at three months after treatment (<.05. The mean total tumor volume reduction was 44% at six months (<.05. 82% of all patients (14/17 achieved local control with a median follow-up of 8 months. 100% of patients with HCC (=6 achieved local control. Patients with surgically placed fiducial markers had no complications related to marker placement. Conclusion. Our preliminary results showed that SBRT is a safe and effective local treatment modality in selected patients with liver malignancies with minimal adverse events. Further studies are needed to define its role in the management of these malignancies.

Targetting in atelectatic lung by positron emission tomography in non-small cell lung cancer patients treated with three-dimensional conformal radiation therapy

International Nuclear Information System (INIS)

Wang Kai; Wang Luhua; Liang Jun; Ou Guangfei; Lu Jima

2006-01-01

Objective: To investigate the potential benefit of incorporating fluorodeoxyglucose positron e- mission tomography (FDG PET) to delineate tire gross tumor volume(GTV) in patients with non-small cell lung cancer (NSCLC) complicated with atelectasis who are to be treated with three-dimensional conformal radiation therapy (3DCRT). Methods: Fourteen patients histopathologically proven as having NSCLC with image diagnosed as complicated with various degrees were studied in this study. All patients were scanned with both thoracic CT and thoracic or whole body PET. The GTV was delineated basing on both CT image and PET image (CT-GTV, PET- GTV) and the volume of each GTV(designated CT-GTV and PET-GTV) was compared by 3DCRT plan. Results: Each paired CT-GTV and PET-GTV was different from each other. All patients' GTV was reduced to an average of 27 cm 3 (20.4%) with median CT-PET of 133 cm 3 (90-180 cm 3 ) and median PET-GTV of 106 cm 3 , with a in- crease of 16.9%, 22 cm 3 ). The reduction of PET-GTV was due to PET could so differ cancer-induced atelectasis from gross tumor that it reduced the tarbet volume and spared more surrounding normal tissues. Conclusions: The incorporation of FDG PET data with gross tumor delineation is able to improve the accuracy of 3DCRT for non-small cell lung cancer patients complicated with atelectasis. (authors)

Phase I study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first line therapy in patients with non-resectable gastric cancer

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Dupont, Jeanette; Jensen, Helle A; Jensen, Benny V

2007-01-01

A phase I trial of short-time oxaliplatin (E), capecitabine (X) and epirubicin (E) for patients with metastatic gastric cancer was initiated to establish the recommended dose for further therapy with short-time EXE. Patients received out-patient therapy with a fixed dose of epirubicin 50 mg/m2 day......-8), median survival was 9.2 months and median TTP was 7.5 months. A combination of epirubicin 50 mg/m2 day 1, capecitabine 1,000 mg/m2 continuously and oxaliplatin 130 mg/m2 day 1 each 3 weeks is an easily administered and well tolerated out-patient regimen for patients with non-resectable gastric cancer....

Green tea extract induces protective autophagy in A549 non-small lung cancer cell line.

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Izdebska, Magdalena; Klimaszewska-Wiśniewska, Anna; Hałas, Marta; Gagat, Maciej; Grzanka, Alina

2015-12-31

For many decades, polyphenols, including green tea extract catechins, have been reported to exert multiple anti-tumor activities. However, to date the mechanisms of their action have not been completely elucidated. Thus, the aim of this study was to assess the effect of green tea extract on non-small lung cancer A549 cells. A549 cells following treatment with GTE were analyzed using the inverted light and fluorescence microscope. In order to evaluate cell sensitivity and cell death, the MTT assay and Tali image-based cytometer were used, respectively. Ultrastructural alterations were assessed using a transmission electron microscope. The obtained data suggested that GTE, even at the highest dose employed (150 μM), was not toxic to A549 cells. Likewise, the treatment with GTE resulted in only a very small dose-dependent increase in the population of apoptotic cells. However, enhanced accumulation of vacuole-like structures in response to GTE was seen at the light and electron microscopic level. Furthermore, an increase in the acidic vesicular organelles and LC3-II puncta formation was observed under the fluorescence microscope, following GTE treatment. The analysis of the functional status of autophagy revealed that GTE-induced autophagy may provide self-protection against its own cytotoxicity, since we observed that the blockage of autophagy by bafilomycin A1 decreased the viability of A549 cells and potentiated necrotic cell death induction in response to GTE treatment. Collectively, our results revealed that A549 cells are insensitive to both low and high concentrations of the green tea extract, probably due to the induction of cytoprotective autophagy. These data suggest that a potential utility of GTE in lung cancer therapy may lie in its synergistic combinations with drugs or small molecules that target autophagy, rather than in monotherapy.

Green tea extract induces protective autophagy in A549 non-small lung cancer cell line

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Magdalena Izdebska

2015-12-01

Full Text Available Background and objectives: For many decades, polyphenols, including green tea extract catechins, have been reported to exert multiple anti-tumor activities. However, to date the mechanisms of their action have not been completely elucidated. Thus, the aim of this study was to assess the effect of green tea extract on non-small lung cancer A549 cells. Material and methods: A549 cells following treatment with GTE were analyzed using the inverted light and fluorescence microscope. In order to evaluate cell sensitivity and cell death, the MTT assay and Tali image-based cytometer were used, respectively. Ultrastructural alterations were assessed using a transmission electron microscope.Results: The obtained data suggested that GTE, even at the highest dose employed (150 μM, was not toxic to A549 cells. Likewise, the treatment with GTE resulted in only a very small dose-dependent increase in the population of apoptotic cells. However, enhanced accumulation of vacuole-like structures in response to GTE was seen at the light and electron microscopic level. Furthermore, an increase in the acidic vesicular organelles and LC3-II puncta formation was observed under the fluorescence microscope, following GTE treatment. The analysis of the functional status of autophagy revealed that GTE-induced autophagy may provide self-protection against its own cytotoxicity, since we observed that the blockage of autophagy by bafilomycin A1 decreased the viability of A549 cells and potentiated necrotic cell death induction in response to GTE treatment.Conclusion: Collectively, our results revealed that A549 cells are insensitive to both low and high concentrations of the green tea extract, probably due to the induction of cytoprotective autophagy. These data suggest that a potential utility of GTE in lung cancer therapy may lie in its synergistic combinations with drugs or small molecules that target autophagy, rather than in monotherapy.

Multigene expression profile for predicting efficacy of cisplatin and vinorelbine in non-small cell lung cancer

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Buhl, I. K.; Christensen, I. J.; Santoni-Rugiu, E.

2016-01-01

Background: There is a need for biomarkers to predict efficacy of adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a combined cisplatin and vinorelbine marker from a previously validated model system [1] tested in two cohorts. Methods: The profiles consist...... and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS) [2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival. Results: The combined cisplatin and vinorelbine profiles scored as a continuous...... of correlated in vitro cytotoxicity of cisplatin and vinorelbine and mRNA expressions. Then each profile is correlated to mRNA expression of 3500 tumors. The cohorts are 1) a publically available dataset with 133 completely resected stage Ib-II NSCLC patients, 71 of whom received adjuvant cisplatin...

Video-assisted Thoracoscope versus Video-assisted Mini-thoracotomy for Non-small Cell Lung Cancer: A Meta-analysis

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Bing WANG

2017-05-01

Full Text Available Background and objective The aim of this study is to assess the effect of video-assisted thoracoscopic surgery (VATS and video-assisted mini-thoracotomy (VAMT in the treatment of non-small cell lung cancer (NSCLC. Methods We searched PubMed, EMbase, CNKI, VIP and ISI Web of Science to collect randomized controlled trials (RCTs of VATS versus VAMT for NSCLC. Each database was searched from May 2006 to May 2016. Two reviewers independently assessed the quality of the included studies and extracted relevant data, using RevMan 5.3 meta-analysis software. Results We finally identified 13 RCTs involving 1,605 patients. There were 815 patients in the VATS group and 790 patients in the VAMT group. The results of meta-analysis were as follows: statistically significant difference was found in the harvested lymph nodes (SMD=-0.48, 95%CI: -0.80--0.17, operating time (SMD=13.56, 95%CI: 4.96-22.16, operation bleeding volume (SMD=-33.68, 95%CI: -45.70--21.66, chest tube placement time (SMD=-1.05, 95%CI: -1.48--0.62, chest tube drainage flow (SMD=-83.69, 95%CI: -143.33--24.05, postoperative pain scores (SMD=-1.68, 95%CI: -1.98--1.38 and postoperative hospital stay (SMD=-2.27, 95%CI: -3.23--1.31. No statistically significant difference was found in postoperative complications (SMD=0.83, 95%CI: 0.54-1.29 and postoperative mortality (SMD=0.95, 95%CI: 0.55-1.63 between videoassisted thoracoscopic surgery lobectomy and video-assisted mini-thoracotomy lobectomy in the treatment of NSCLC. Conclusion Compared with video-assisted mini-thoracotomy lobectomy in the treatment of non-small cell lung cancer, the amount of postoperative complications and postoperative mortality were almost the same in video-assisted thoracoscopic lobectomy, but the amount of harvested lymph nodes, operating time, blood loss, chest tube drainage flow, and postoperative hospital stay were different. VATS is safe and effective in the treatment of NSCLC.

Successful Management of Crizotinib-Induced Neutropenia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Case Report

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Jun Osugi

2016-01-01

Full Text Available Crizotinib, the first clinically available inhibitor of anaplastic lymphoma kinase (ALK gene rearrangement, is generally well tolerated. In contrast, neutropenia induced by crizotinib is a commonly reported grade 3 or 4 adverse event. In such cases, interruption and dose reduction of crizotinib might be necessary for some patients with severe neutropenia. However, information concerning clinical experience and management of severe neutropenia is currently limited. In this report, the successful management of crizotinib-induced neutropenia by dose reduction of crizotinib in a patient with ALK-positive non-small cell lung cancer is described.

Radiotherapy in stage 3, unresectable, asymptomatic non-small cell lung cancer. Final results of a prospective randomized study of 240 patients

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Reinfuss, M.; Glinski, B.; Kowalska, T.; Kulpa, J.; Zawila, K.; Reinfuss, K.; Dymek, P.; Herman, K.; Skolyszewski, J.

1999-01-01

Purpose: to report the results of a prospective randomized study concerning the role of radiotherapy in the treatment of stage III, unresectable, asymptomatic non-small cell lung cancer. Material and methods: between 1992 and 1996, 240 patients with stage III, unresectable, asymptomatic non-small cell lung cancer were enrolled in this study, and sequentially randomized to one of the three treatment arms: conventional irradiation, hypo-fractionated irradiation and control group. In the conventional irradiation arm (79 patients), a dose of 50 Gy in 25 fractions in five weeks was delivered to the primary tumor and the mediastinum. In the hypo-fractionated irradiation arm (81 patients), there were two courses of irradiation separated by an interval of four weeks. In each series, patients received 20 Gy in five fractions in five days, in the same treatment volume as the conventional irradiation group. in the control group arm, 80 patients initially did not receive radiotherapy and were only observed. Delayed palliative hypo-fractionated irradiation (20-25 Gy in four to five fractions in four to five days) was given to the primary tumor when major symptoms developed. Results: the two-year actuarial survival rates for patients in the conventional irradiation, hypo-fractionated irradiation and control group arms were 18%, 6% and 0%, with a median survival time of 12 months, nine months and six months respectively. The differences between survival rates were statistically significant at the 0.05 level. Conclusion: although irradiation provides good palliation the results are disappointing. The comparison of conventional and hypo-fractionated irradiation shows an advantage for conventional schedules. (author)

Cardenolide-Induced Lysosomal Membrane Permeabilization Demonstrates Therapeutic Benefits in Experimental Human Non-Small Cell Lung Cancers

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Tatjana Mijatovic

2006-05-01

Full Text Available Non-small cell lung cancers (NSCLCs are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70 expression and function, together with the induction of lysosomal membrane permeabilization (LMP, could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450 on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxeland oxaliplatin-resistant subcutaneous human NCIH727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/ TonEBP (a factor responsible for the transcriptional control of Hsp70. These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.

Degradation of Mcl-1 through GSK-3β Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells

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Xiao-hong Kang

2017-04-01

Full Text Available Background/Aims: Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC. Bufalin has been reported to induce apoptosis in various tumor cells. However, there is no report showing that bufalin could downregulate Mcl-1 expression in NSCLC. Methods: Cell proliferation was analyzed by cell counting kit-8 (CCK-8 assay in H1975 cells. Cell apoptosis was detected by flow cytometry. Mcl-1 mRNA was detected by RT-PCR. The expression of apoptosis-associated proteins in H1975 cells was detected by western blotting. The levels of Mcl-1 ubiquitination and NOXA were analyzed by Immunoprecipitation assay. Results: Cell growth was inhibited by bufalin in a time and dose-dependent manner. Bufalin induced apoptosis in NSCLC cells by activating caspase cascades and downregulating Mcl-1 expression. However, overexpression of Mcl-1 diminished bufalin-induced apoptosis. Furthermore, bufalin did not reduce Mcl-1 mRNA expression in H1975 cells, but strongly promoted Mcl-1 protein degradation. Proteasome inhibitor MG132 markedly prevented the degradation of Mcl-1 and blocked bufalin-induced Mcl-1 reduction. Bufalin did not significantly affect NOXA protein levels, but downregulated the expression of p-GSK-3β. GSK-3 inhibitor and GSK-3β siRNA resulted in increased levels of Mcl-1 and reversed the bufalin-induced Mcl-1 degradation. Conclusion: Bufalin induced cell apoptosis in H1975 cells may be through downregulation of Mcl-1. Proteasomal degradation of Mcl-1 via GSK-3β activation was involved in bufalin-induced apoptosis.

Phase I study of cisplatin analogue nedaplatin, paclitaxel, and thoracic radiotherapy for unresectable stage III non-small cell lung cancer

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Sekine, Ikuo; Sumi, Minako; Ito, Yoshinori

2007-01-01

The standard treatment of unresectable stage III non-small cell lung cancer is concurrent chemoradiotherapy in patients in good general condition, but where the optimal chemotherapeutic regimen has not been determined. Patients with unresectable stage III non-small cell lung cancer received nedaplatin (80 mg/m 2 ) and paclitaxel on day 1 every 4 weeks for 3-4 cycles and concurrent thoracic radiotherapy (60 Gy/30 fractions for 6 weeks) starting on day 1. The dose of paclitaxel was escalated from 120 mg/m 2 in level 1, 135 mg/m 2 in level 2 to 150 mg/m 2 in level 3. A total of 18 patients (14 males and 4 females, with a median age of 62.5 years) were evaluated in this study. Full cycles of chemotherapy were administered in 83% of patients in level 1, and in 50% of patients in levels 2 and 3. No more than 50% of patients developed grade 4 neutropenia. Transient grade 3 esophagitis and infection were noted in one patient, and unacceptable pneumonitis was noted in three (17%) patients, two of whom died of the toxicity. Dose-limiting toxicity (DLT), evaluated in 15 patients, noted in one of the six patients in level 1, three of the six patients in level 2 and one of the three patients in level 3. One DLT at level 2 developed later as radiation pneumonitis. Thus, the maximum tolerated dose was determined to be level 1. The overall response rate (95% confidence interval) was 67% (41-87%) with 12 partial responses. The doses of paclitaxel and nedaplatin could not be escalated as a result of severe pulmonary toxicity. (author)

Loss of expression of BAP1 is very rare in non-small cell lung carcinoma.

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Andrici, Juliana; Parkhill, Thomas R; Jung, Jason; Wardell, Kathryn L; Verdonk, Brandon; Singh, Arjun; Sioson, Loretta; Clarkson, Adele; Watson, Nicole; Sheen, Amy; Farzin, Mahtab; Toon, Christopher W; Gill, Anthony J

2016-06-01

Germline mutations of the BAP1 gene have been implicated in a cancer predisposition syndrome which includes mesothelioma, uveal melanoma, cutaneous melanocytic lesions, renal cell carcinoma, and possibly other malignancies. Double hit inactivation of BAP1 with subsequent loss of expression of the BAP1 protein also occurs in approximately 50% of mesotheliomas. The link between BAP1 mutation and lung cancer is yet to be fully explored. We sought to assess BAP1 expression in a large cohort of lung cancers undergoing surgery with curative intent. We searched the Anatomical Pathology database of our institution for lung cancer patients undergoing surgery with curative intent between 2000 and 2010. Immunohistochemistry for BAP1 was then performed in tissue microarray format. Our cohort included 257 lung cancer patients, of which 155 (60%) were adenocarcinomas and 72 (28%) were squamous cell carcinomas, with no other subtype comprising more than 3%. BAP1 loss of expression was found in only one lung cancer. We conclude that BAP1 mutation occurs very infrequently (0.4%) in non-small cell lung cancer. Given that the pathological differential diagnosis between lung carcinoma and mesothelioma may sometimes be difficult, this finding increases the specificity of loss of expression for BAP1 for the diagnosis of mesothelioma. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

The option value of innovative treatments for non-small cell lung cancer and renal cell carcinoma.

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Thornton Snider, Julia; Batt, Katharine; Wu, Yanyu; Tebeka, Mahlet Gizaw; Seabury, Seth

2017-10-01

To develop a model of the option value a therapy provides by enabling patients to live to see subsequent innovations and to apply the model to the case of nivolumab in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). A model of the option value of nivolumab in RCC and NSCLC was developed and estimated. Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and published clinical trial results were used to estimate survival curves for metastatic cancer patients with RCC, squamous NSCLC, or nonsquamous NSCLC. To estimate the conventional value of nivolumab, survival with the pre-nivolumab standard of care was compared with survival with nivolumab assuming no future innovation. To estimate the option value of nivolumab, long-term survival trends in RCC and squamous and nonsquamous NSCLC were measured in SEER to forecast mortality improvements that nivolumab patients may live to see. Compared with the previous standard of care, nivolumab extended life expectancy by 6.3 months in RCC, 7.5 months in squamous NSCLC, and 4.5 months in nonsquamous NSCLC, according to conventional methods. Accounting for expected future mortality trends, nivolumab patients are likely to gain an additional 1.2 months in RCC, 0.4 months in squamous NSCLC, and 0.5 months in nonsquamous NSCLC. These option values correspond to 18%, 5%, and 10% of the conventional value of nivolumab, respectively. Option value is important when valuing therapies like nivolumab that extend life in a rapidly evolving area of care.

Surgical management of oligometastatic non-small cell lung cancer.

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Novoa, Nuria M; Varela, Gonzalo; Jiménez, Marcelo F

2016-11-01

The oligometastatic stage IV non-small cell lung cancer (NSCLC) offers a new surgical opportunity. New reported data is showing that surgery can offer a reasonable benefit, in terms of long-term survival, to some patients. The advantages of surgical treatment rely on a more adequate patient selection and a better understanding of the biology of these tumors. Currently, mediastinal involvement of the primary tumor can be identified as the most important prognostic variable after curative-intent of synchronous or metachronous metastasis. It seems clear that the routine use of combined FDG-PET and CT will help to detect the more favorable cohort of oligometastatic patients. As expected, pathological T staging of the primary tumor and the completeness of its resection are also crucial factors influencing final results. The real benefit of the local treatment over synchronous or metachronous metastasis is controversial with series showing better outcomes for metachronous lesions than for synchronous and others offering equal results. Also non conclusive results appear when analyzing different sites of metastasis. Retrospective series tend to show different outcomes depending on the affected organ while usually no differences are found in prospective ones. Most of the current evidence is based on retrospective studies on patients collected along extended periods of time. That represents a great limitation to the knowledge on this topic. Some prospective analyses have added some insight, but still the quality of the evidence is too low to allow drawing robust conclusions. As frequently concluded, prospective well designed investigation is requested to ascertain the value of surgery in this specific population of patients with extended NSCLC.

Hyperfractionated radiotherapy alone for clinical stage I nonsmall cell lung cancer

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Jeremic, Branislav; Shibamoto, Yuta; Acimovic, Ljubisa; Milisavljevic, Slobodan

1997-01-01

Purpose: Among patients with Stage I nonsmall cell lung cancer (NSCLC), those treated with conventional radiotherapy show poorer prognosis than those treated by surgery. To improve the prognosis of such patients, we have used hyperfractionated radiation therapy. Methods and Materials: Between 1988 and 1993, 49 patients were treated with hyperfractionated radiotherapy with 1.2 Gy twice daily to a total dose of 69.6 Gy. All patients were technically operable, but 29 had medical problems and 20 refused surgery. The median age and Karnofsky Performance Status was 63 years and 90, respectively. No patient received chemotherapy or immunotherapy. Prophylactic mediastinal irradiation was not given. Results: The median survival time was 33 months, and the 5-year survival rate was 30%. The rate at 5 years for freedom from each of relapse, local recurrence, mediastinal lymphnode metastasis, and distant metastasis was 41%, 55%, 89%, and 75%, respectively. Univariate analysis revealed that higher Karnofsky Performance Status score, absence of weight loss before treatment, and T1 stage were associated with better survival, although the T stage became insignificant on multivariate analysis. There were two Grade 3 acute toxicities and three Grade 3 late toxicities, but there was no Grade 4-5 toxicity. Conclusion: The results of this study compare favorably with those of most previous studies employing conventional fractionation. Further studies on hyperfractionation seem to be warranted for Stage I NSCLC

Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives.

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Tomasello, Chiara; Baldessari, Cinzia; Napolitano, Martina; Orsi, Giulia; Grizzi, Giulia; Bertolini, Federica; Barbieri, Fausto; Cascinu, Stefano

2018-03-01

In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months. Many genetic aberrations have been described as possible mechanisms of EGFR TKIs acquired resistance and can be clustered in four main sub-groups: 1. Development of secondary EGFR mutations; 2. Activation of parallel signaling pathways; 3. Histological transformation; 4. Activation of downstream signaling pathways. In this review we will describe the molecular alterations underlying each of these EGFR TKIs resistance mechanisms, focusing on the currently available and future therapeutic strategies to overcome these phenomena. Copyright © 2018 Elsevier B.V. All rights reserved.

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Non-Small Cell Lung Cancer.

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Raju, G K; Gurumurthi, K; Domike, R; Kazandjian, D; Blumenthal, G; Pazdur, R; Woodcock, J

2016-12-01

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic. © 2016 American Society for Clinical Pharmacology and Therapeutics.

[Current Status and Development of Traditional Chemotherapy in Non-small Cell Lung Cancer under the Background of Targeted Therapy].

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Zhang, Guowei; Wang, Huijuan; Zhang, Mina; Li, Peng; Ma, Zhiyong

2015-09-20

In recent years, along with rapid development of targeted therapy in non-small cell lung cancer, traditional chemotherapy get less and less attention. Yet it still can not be ignored in the current that how to locate and use traditional chemotherapy so patients could derive maximum benefit. For this purpose, through the literature review and analysis, we point out there are still many traditional chemotherapy irreplaceable places whatever patients' driver gene status. And there are some new treatment modalities of traditional chemotherapy which have been developed to further improve patients' survival. At the same time, through exposition of predictive bio-markers development in chemotherapy, we pointed out that the future of traditional chemotherapy must be part of "targeted therapy".

The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer

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Deben, Christophe; Wouters, An; de Beeck, Ken Op; van Den Bossche, Jolien; Jacobs, Julie; Zwaenepoel, Karen; Peeters, Marc; Van Meerbeeck, Jan; Lardon, Filip; Rolfo, Christian; Deschoolmeester, Vanessa; Pauwels, Patrick

2015-01-01

The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3. PMID:26125230

Current treatments for advanced stage non-small cell lung cancer.

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Stinchcombe, Thomas E; Socinski, Mark A

2009-04-15

Lung cancer remains the leading cause of cancer mortality in the United States, and the majority of patients will have non-small cell lung cancer (NSCLC) and will present with locally advanced or metastatic disease. In the United States, the most common histology is adenocarcinoma, followed by squamous cell, large cell, and not otherwise specified. For patients with a preserved performance status (PS), double agent platinum-based therapy extends survival, improves quality of life (Qol), and reduces disease-related symptoms. The addition of a third cytotoxic agent increases toxicity without any clinical benefit. However, the addition of a targeted agent (bevacizumab, an antiangioegenesis agent, or cetuximab, an antibody against the epidermal growth factor receptor [EGFR]) to platinum-based therapy has yielded an improvement in survival compared with platinum-based therapy alone. To receive bevacizumab, patients are required to have nonsquamous histology, a PS of 0 or 1, and no evidence of brain metastases, hemoptysis, uncontrolled hypertension, and no need for therapeutic anticoagulation. The benefits of chemotherapy for patients with a poor performance status are less well defined, and the current recommendations are for treatment with single-agent chemotherapy. Elderly patients (defined as age > or = 70 yr) derive a survival and Qol benefit from chemotherapy treatment, and for the majority of elderly patients single-agent chemotherapy is the standard. However, elderly patients with a good performance status and without co-morbidities can tolerate platinum-based therapy without excessive toxicity and appear to derive a survival benefit similar to that in younger patients. Recently, a separate population of patients defined by a light or never-smoking history has been identified. This patient population appears to have unique clinical and molecular characteristics, and may benefit from initial therapy with an EGFR tyrosine kinase inhibitor. Once patients have

A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

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Nan Hua

Full Text Available Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs. In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.

[Analysis of tissue-specific differentially methylated genes with differential gene expression in non-small cell lung cancer].

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Yin, L G; Zou, Z Q; Zhao, H Y; Zhang, C L; Shen, J G; Qi, L; Qi, M; Xue, Z Q

2014-01-01

Adenocarcinoma (ADC) and squamous cell carcinomas (SCC) are two subtypes of non-small cell lung carcinomas which are regarded as the leading cause of cancer-related malignancy worldwide. The aim of this study is to detect the differentially methylated loci (DMLs) and differentially methylated genes (DMGs) of these two tumor sets, and then to illustrate the different expression level of specific methylated genes. Using TCGA database and Illumina HumanMethylation 27 arrays, we first screened the DMGs and DMLs in tumor samples. Then, we explored the BiologicalProcess terms of hypermethylated and hypomethylated genes using Functional Gene Ontology (GO) catalogues. Hypermethylation intensively occurred in CpG-island, whereas hypomethylation was located in non-CpG-island. Most SCC and ADC hypermethylated genes involved GO function of DNA dependenit regulation of transcription, and hypomethylated genes mainly 'enriched in the term of immune responses. Additionally, the expression level of specific differentially methylated genesis distinctbetween ADC and SCC. It is concluded that ADC and SCC have different methylated status that might play an important role in carcinogenesis.

Accelerated Fractionation In The Treatment of Brain Metastasis From Non-Small Cell Carcinoma of The Lung

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Hong, Seong Eon

1994-01-01

Purpose: Metastatic cancer to the brain is a major problem for the patients with bronchogenic carcinoma, and most of these patients have a limited survival expectancy. To increase tumor control and/or to decrease late morbidity with possible shortening in over-all treatment period, multiple daily fraction technique for brain metastasis was performed. The author represented the results of accelerated fractionation radiotherapy in patients with brain metastases from non-small cell lung cancer. Materials and Methods: Twenty-six patients with brain metastases from non-small cell lung cancer between 1991 and 1993 received brain radiotherapy with a total dose of 48 Gy, at 2 Gy per fraction, twice a day with a interfractional period of 6 hours, and delivered 5 days a week. The whole brain was treated to 40 Gy and boost dose escalated to 8 Gy for single metastatic lesion by reduced field. Twenty-four of the 26 patients completed the radiotherapy. Radiotherapy was interrupted in two patients suggesting progressive intracerebral disease. Results: This radiotherapy regimen appears to be comparable to the conventional schema in relief from symptoms. Three of the 24 patients experienced nausea and or vomiting during the course of treatment because of acute irradiation toxicity. The author observed no excessive toxicity with escalating dose of irradiation. An increment in median survival, although not statistically significant (p>0.05), was noted with escalating doses(48 Gy) of accelerated fractionation (7 months) compared to conventional treatment(4.5 months). Median survival also increased in patients with brain solitary metastasis(9 months) compared to multiple extrathoracic sites(4 months), and in patients with good performance status(9 months versus 3.5 months), they were statistically significant(p<0.01). Conclusion: The increment in survival in patients with good prognostic factors such as controlled primary lesion, metastasis in brain only, and good performance status

Palliative radiotherapy in asymptomatic patients with locally advanced, unresectable, non-small cell lung cancer

International Nuclear Information System (INIS)

Reinfuss, M.; Skolyszewski, J.; Kowalska, T.; Rzepecki, W.; Kociolek, D.

1993-01-01

Between 1983 and 1990, 332 patients with non-small cell lung cancer (NSCLC) were referred to short-time, split-course palliative thoracic radiotherapy. The group consisted of patients with locally advanced (III o ), unresectable cancer, not suitable for curative radiotherapy, asymptomatic or having only minimal symptoms related to intrathoracic tumor. The therapeutic plan involved two series of irradiation. Tumor dose delivered in each series was 20 Gy given in five daily fractions over five treatment days. There were four weeks interval between series. Of 332 patients initially qualified to thoracic radiotherapy only 170 patients received the treatment; the other 162 patients were not irradiated because of treatment refusal or logistic problems concerning therapy. They made the control group of the study, receiving the best possible symptomatic care. Twelve-month survivals in the radiotherapy and control groups were 32.4% and 9.3%, respectively; 24-month survivals 11.2% and 0%, respectively. Improvement of survival after palliative thoracic radiotherapy was observed only in patients with clinical stage IIIA and Karnofsky's performance status (KPS) ≥ 70. (orig.) [de

Expression and Bioinformatic Analysis of Ornithine Aminotransferase 
in Non-small Cell Lung Cancer

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Danfei ZHOU

2012-09-01

Full Text Available Background and objective It has been proven that ornithine aminotransferase (OAT might play an important role in the oncogenesis and progression of numerous malignant tumors. The aim of this study is to detect the mRNA and protein expression of OAT in non-small cell lung cancer (NSCLC, as well as to analyze the bioinformatic features and binary interactions. Methods OAT mRNA expression was detected in A549 and 16HBE cell lines by reverse transcription-polymerase chain reaction. OAT protein expression was determined in 55 cases of NSCLC and 17 cases of adjacent non-tumor lung tissues by immunohistochemical staining. The bioinformatic features and binary interactions of OAT were analyzed. Gene ontology annotation and signal pathway analysis were performed. Results OAT mRNA expression in A549 cells was 2.85-fold lower than that in 16HBE cells. OAT protein expression was significantly higher in NSCLC tissues than that in adjacent non-tumor lung tissues. A significant difference of OAT protein expression was existed between squamous cell lung cancer and adenocarcinoma (P<0.05, but was not correlated with the gender, age, lymph node metastasis, tumor size, and TNM stages. Bioinformatic analysis suggested that OAT was a highly homologous and stable protein located in the mitochondria. An aminotran-3 domain and several sites of phosphorylation, which may function in signal transduction, gene transcription, and molecular transit, were found. In the 54 selected binary interactions of OAT, TNF and TRAF6 play roles in the NF-κB pathway. Conclusion OAT may play an important role in the oncogenesis and progression of NSCLC. Thus, OAT may be a novel biomarker for the diagnosis of NSCLC or a new target for its treatment.

Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer.

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Cho, Arthur; Hur, Jin; Hong, Yoo Jin; Lee, Hye-Jeong; Kim, Young Jin; Hong, Sae Rom; Suh, Young Joo; Im, Dong Jin; Kim, Yun Jung; Lee, Jae Seok; Shim, Hyo Sup; Choi, Byoung Wook

2016-03-01

The serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21-1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS.

Second-line combination therapies in nonsmall cell lung cancer without known driver mutations

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Maria-Virginia Bluthgen

2015-12-01

Full Text Available In advanced nonsmall cell lung cancer (NSCLC patients, platinum-based combination chemotherapy is standard treatment in the first-line setting; however, the large majority of patients ultimately progress. For more than a decade, single-agent therapy with docetaxel, pemetrexed or erlotinib has been the standard of care after failure with platinum salts, showing some benefit over best supportive care. Nonetheless, prognosis remains poor and new second-line strategies are urgently needed. Combinations of cytotoxic agents, including rechallenge with platinum salts, do not offer clear benefit over single-agent therapy for the majority of patients. In patients without a known tumoural oncogenic driver mutation, regimens based on combinations of targeted agents have shown promising results; however, a clear role in therapeutic management is yet to be established. Some success has been reported in recent research combining a cytotoxic agent with targeted therapies. In this review, we summarise published data for the various strategies evaluated over the past decade in second-line treatment of NSCLC patients without a known driver mutation. We focus on combination treatments and consider future perspectives, including the need to identify predictive markers to support personalised therapeutic strategies.

Sleeve lobectomy versus pneumonectomy for non-small cell lung cancer: a meta-analysis

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Shi Woda

2012-12-01

Full Text Available Abstract Aim It is controversial that whether sleeve lobectomy (SL should be promoted more worthy than pneumonectomy (PN in suitable patients. Methods We searched all studies that had been published in English from PUBMED and Embase which compared the short-term and long-term outcomes of SL and pneumonectomy (PN in patients with non-small cell lung cancer (NSCLC. Results Nineteen studies met our criteria with a combined total of 3878 subjects, of which 1316 (33.9% underwent SL and 2562 (66.1% underwent PN. The odds ratio was 0.50 (95% CI: 0.34-0.72 for postoperative mortality, 1.17 (95% CI: 0.82-1.67 for postoperative complications, 0.78 (95% CI: 0.47-1.29 for locoregional recurrences. The risk difference for 1-, 3-, 5- year was 0.11 (95% CI: 0.07-0.14, 0.15 (95% CI: 0.06-0.24, 0.15 (95% CI: 0.09-0.20,respectively. The pooled hazard ratio was 0.63 (95% CI: 0.56-0.71 in favor of SL group. Conclusion SL is more worthy to be done than PN in suitable patients with less mortality and better long-term survival.

Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer

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Gabriel Lima Lopes

2015-08-01

Full Text Available AbstractLung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21, first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs. Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.